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BY 4.0 license Open Access Published by De Gruyter September 16, 2021

Neurological susceptibility to environmental exposures: pathophysiological mechanisms in neurodegeneration and multiple chemical sensitivity

  • John Molot EMAIL logo , Margaret Sears , Lynn Margaret Marshall and Riina I. Bray

Abstract

The World Health Organization lists air pollution as one of the top five risks for developing chronic non-communicable disease, joining tobacco use, harmful use of alcohol, unhealthy diets and physical inactivity. This review focuses on how host defense mechanisms against adverse airborne exposures relate to the probable interacting and overlapping pathophysiological features of neurodegeneration and multiple chemical sensitivity. Significant long-term airborne exposures can contribute to oxidative stress, systemic inflammation, transient receptor subfamily vanilloid 1 (TRPV1) and subfamily ankyrin 1 (TRPA1) upregulation and sensitization, with impacts on olfactory and trigeminal nerve function, and eventual loss of brain mass. The potential for neurologic dysfunction, including decreased cognition, chronic pain and central sensitization related to airborne contaminants, can be magnified by genetic polymorphisms that result in less effective detoxification. Onset of neurodegenerative disorders is subtle, with early loss of brain mass and loss of sense of smell. Onset of MCS may be gradual following long-term low dose airborne exposures, or acute following a recognizable exposure. Upregulation of chemosensitive TRPV1 and TRPA1 polymodal receptors has been observed in patients with neurodegeneration, and chemically sensitive individuals with asthma, migraine and MCS. In people with chemical sensitivity, these receptors are also sensitized, which is defined as a reduction in the threshold and an increase in the magnitude of a response to noxious stimulation. There is likely damage to the olfactory system in neurodegeneration and trigeminal nerve hypersensitivity in MCS, with different effects on olfactory processing. The associations of low vitamin D levels and protein kinase activity seen in neurodegeneration have not been studied in MCS. Table 2 presents a summary of neurodegeneration and MCS, comparing 16 distinctive genetic, pathophysiological and clinical features associated with air pollution exposures. There is significant overlap, suggesting potential comorbidity. Canadian Health Measures Survey data indicates an overlap between neurodegeneration and MCS (p < 0.05) that suggests comorbidity, but the extent of increased susceptibility to the other condition is not established. Nevertheless, the pathways to the development of these conditions likely involve TRPV1 and TRPA1 receptors, and so it is hypothesized that manifestation of neurodegeneration and/or MCS and possibly why there is divergence may be influenced by polymorphisms of these receptors, among other factors.

Introduction

All humans are regularly exposed to thousands of chemicals in the air we breathe, the water we drink, the food we eat, and the products we buy and use [1, 2]. Our exposures are ubiquitous, complex and dynamic mixtures [3, 4]. To understand the many potential exposures that affect health over the life span, the concept of the exposome has been developed [5]. With knowledge of beneficial and adverse effects of exposures, the exposome captures the cumulative hazards, from preconception to death, associated with multiple environmental exposures, including the microbiome, according to one’s genome and epigenetic features and the intracellular, metabolic, inflammatory and stress pathway responses [6]. Our most common route of exposure to toxicants is inhalation [7].

There is potential for any organ system to be impacted by the systemic absorption and response to pollutants. The purpose of this review is to focus on the potential biological impacts of air pollution exposure on the central nervous system (CNS), and in particular to compare and contrast the pathophysiology of neurodegeneration and multiple chemical sensitivity (MCS).

Literature review search criteria

Pubmed/Medline was searched using the terms “oxidative stress”, “systemic inflammation”, “blood-brain barrier”, TRPV1, TRPA1, upregulation, sensitization, “air pollution”, translocation, olfactory, trigeminal, “neurodevelopmental disorder”, neurodegeneration, detoxification, “central sensitization”, “multiple chemical sensitivity”, “capsaicin challenge”, and related terms (see Supplementary Material – Glossary), alone and combined. Articles from 1991 to January 2021 were selected based on the purpose of this review. We also reviewed pertinent publications found on the website of the World Health Organization.

Airborne pollutant exposures

Diverse air pollutants are ubiquitous in both outdoor and indoor environments.

Sources – outdoors

The urban outdoor air is contaminated with a complex mixture of numerous pollutants, such as airborne particulate matter (PM) and gases, including carbon monoxide, polyaromatic hydrocarbons, sulfur dioxide, nitrogen oxides, ozone and volatile organic compounds (VOCs) [8, 9].

Most studies showing increased risks of developing chronic disease with outdoor air pollution consider the effects of long-term exposure. Many studies demonstrate adverse health effects associated with residing in proximity to major roadways [10]. It is noteworthy, however, that we spend more than 90% of our time indoors [11], with 70% at home [12]. The building envelope of our homes and workplaces may reduce our exposures somewhat but we still remain exposed to outdoor air pollution while indoors [13]. Indeed, about 65% of PM from outdoor sources is inhaled while indoors [14].

PM originates from both natural and anthropogenic sources, and is a heterogeneous mixture of solid and liquid particles suspended in the air, varying in concentration, size, chemical composition and surface area [15], [16], [17]. PM is categorized according to size: particles between 2.5 and 10 μm diameter (PM10) is defined as ‘coarse’; 2.5 μm or smaller (PM2.5) is ‘fine’; and PM <0.1 µm or 100 nm is defined as ‘ultrafine’ (UFP) or nanoparticles [18]. In contrast to PM10 and PM2.5, UFPs have negligible mass but they are the dominant contributor to the total number of particles in ambient air, typically 80–90% of all particles [4, 19]. The highest UFP concentrations in urban areas are observed in proximity to traffic, particularly when vehicles are idling and accelerating [20]. There is no recognized threshold for health effects of outdoor PM2.5 regardless of whether the exposure occurs indoors or outdoors, and there is evidence that adverse health effects occur at current levels of exposure [21].

Airborne PM tends to adsorb harmful substances on its surface, such as heavy metals, polyaromatic hydrocarbons, and volatile and semi-volatile organic compounds (VOCs and SVOCs) [22], [23], [24], [25], [26]. VOCs and SVOCs equilibrate between vapour and adsorbed states, with SVOCs in greater preponderance on particles. The partitioning of VOCs onto nanoparticles is less studied [27], but they readily partition and adsorb to surfaces too, including on and within irregular and porous PM [28].

Exposure can also occur to exogenous free radicals and reactive oxygen species (ROS) that are formed outdoors through photochemical reactions (between NOx, carbon monoxide, formaldehyde and VOCs) [29]. ROS are particle-bound [30, 31], and can be transported into buildings. ROS are also generated in the indoor environment, where they are produced via the interaction of ozone and airborne chemicals, such as terpenes [32]. The levels of ROS on particles in the indoor environment generally mirrors the ROS on particles outdoors [29].

Sources – indoors

Total VOC concentrations are approximately four times higher indoors than in outdoor air, with higher VOC concentrations observed from building materials in new or renovated locations [13, 33]. Other common indoor sources of VOCs include household cleaning and laundry products, air fresheners, fragrances, and cooking odors [34], [35], [36]. There is also considerable, ubiquitous indoor exposure to SVOCs, many of which are high production volume chemicals used in plastics, detergents, synthetic musks, pest control products, building components and furnishings (e.g. flame retardants and stain repellents) [37, 38].

Being semi-volatile, SVOCs continuously vaporize and re-condense, redistributing from their original source to the indoor air and interior surfaces, including surfaces of airborne particles [39]. Inhaled SVOCs on smaller particles (e.g. nanoparticles) are likely to penetrate deeper into the respiratory tract and to linger and interact longer with contacted tissues [40, 41].

As a gas, the bulk of inhaled VOCs are exhaled immediately; however, desorption of VOCs from PM maintains elevated VOC concentrations on the surface of the bronchial tubes and alveoli for an extended period of time [42]. VOCs emanating from particles may diffuse from the extracellular space into the cellular membrane and into the cells themselves [42]. Thus the toxicities of PM are magnified by transport and release of both VOCs and SVOCs [42].

The burden of disease from air pollution appears to be due to the combined effects of indoor and outdoor ambient exposures [8]. See Table 1.

Table 1:

Common sources of ambient air pollutants.

Air pollutants Outdoor air Indoor air
Particulates, PM Fossil fuel combustion, forming liquid droplets or solids in the atmosphere. Cooking at high heat, especially meat, combustion activities (including gas stoves, burning of candles, use of fireplaces, use of unvented space heaters or kerosene heaters, cigarette and cannabis smoking, and domestic burning of solid fuels). 
Ground level ozone (O3) Chemical reactions between oxides of nitrogen (NOx) and volatile organic compounds (VOCs) in the presence of sunlight. Some indoor air cleaners, photocopiers and printers.
Sulfur dioxide (SO2) Burning of sulphur-containing fossil fuels in power plants and other industrial facilities, and by heavy machinery. Largely from outdoor sources.
Nitrogen dioxide (NO2) Burning fossil fuels at high temperatures. Domestic burning of solid fuels 
Carbon monoxide (CO) Incomplete combustion of fossil fuels. Tobacco smoke, gas stove ranges, domestic burning of solid fuels .
Volatile organic compounds (VOCs) Scented exhaust from clothes dryers and indoor air in cities. Fossil fuels, industrial emissions, asphalt paving [43]. Fragrances, scented products (personal care, “deodorizers,” cleaning and laundry products, disinfectants), dry-cleaned clothes, building materials, fumes from attached garage.
Semi-volatile organic compounds (SVOCs) Pesticides, fumes from paving, diesel fuel. Carpets, textiles, electronics, furniture, building materials, cleaning products, personal care products, cosmetics, pesticides.
Polyaromatic hydrocarbons, PAHs Naturally occurring in heavy petrochemicals and asphalt. Thermal and industrial processes such as incomplete burning of coal (coking), oil, waste. Burning tobacco or cannabis and charbroiling meat. Burning tobacco or cannabis and charbroiling meat.
Aldehydes e.g. formaldehyde Not significant. Ozone reactions with terpenes, cigarette and cannabis smoke and vape, fresh paints, varnish and floor finishes.
Microbes Not significant. Water damaged buildings: mould, bacteria and very small arthropods such as mites.
Antimicrobial agents Disinfectants (including pool chemicals) and pesticides. Cleaning and disinfection products, and pesticides.
  1. Adapted from US Centers for Disease Control and Prevention [44]; Mannan M et al. Indoor Air Quality in Buildings: A Comprehensive Review of the Factors Influencing Air Pollution in Residential and Commercial Structures [45]; Lucattini L. et al. A review of semi-volatile organic compounds (SVOCs) in the indoor environment: occurrence in consumer products, indoor air and dust [46].

Toxicodynamics

Air pollution is now recognized as a fifth major risk factor for developing non-communicable diseases by the World Health Organization, joining tobacco use, harmful use of alcohol, unhealthy diets and physical inactivity [47, 48]. Scientific consensus continues to build that inhaled pollutants induce oxidative stress [49], which occurs when the cellular or organism detoxification systems are overwhelmed or deficient [50]. Oxidative stress is a phenomenon caused by an imbalance between the production of oxidants and antioxidants leading to an accumulation of reactive oxygen species (ROS) and other free radicals in cells and tissues [10]. It causes molecular damage to cells due to adverse modifications of cell components, such as lipids, proteins and DNA [51], which can eventually lead to many chronic diseases [52].

Studies examining the effects of air pollution exposure in cell culture, animal models, and human patients repeatedly demonstrate changes in oxidative stress and inflammatory markers [53], [54], [55]. Elevated circulating levels of inflammatory biomarkers define systemic inflammation [56]. Oxidative stress and systemic inflammation are intricately linked [57], and both play key roles mediating the hazardous effects of environmental stressors [58]. It has been repeatedly demonstrated that oxidative stress occurs with exposures to a wide range of ubiquitous indoor and outdoor pollutants [59], [60], [61], [62], [63], including PM; especially UFPs from major traffic [64], photocopiers or laser printers used in the workplace [65], and even the by-products formed by the effects of ozone on house dust [66]. VOCs can induce oxidative stress at levels typically found in the indoor air [67], [68], [69], [70]. Oxidative stress has been demonstrated in individuals complaining of poor indoor air quality associated with “sick building syndrome.” [71], [72], [73].

The brain is particularly vulnerable to oxidative stress because it has naturally high oxygen requirements and is high in polyunsaturated fatty acids, which are readily oxidized [74]. Long-term oxidative stress is a key component of neurotoxicity mechanisms and plays a causal role in a range of brain pathologies [75]. Systematic reviews and meta-analyses have established strong associations between air pollution exposures and neurodegeneration [76, 77].

Host defense mechanisms

The body uses many mechanisms and responses to defend itself against foreign substances, microorganisms, viruses, toxins, and non-compatible living cells [78]. Defense against air pollutants is such a prominent factor in preventing chronic, complex, environmentally-linked conditions, that for the purposes of this paper, we review the mechanisms for this defense. These include respiratory tract defenses, the blood-brain barrier, transient potential receptor family and detoxification systems.

Respiratory tract defenses

A large fraction of inhaled PM will be removed via mucociliary clearance in the upper airways or through engulfment by macrophages, predominantly residing in the alveolar regions [79]. Epithelial cells also form a barrier with tight junctions, which regulate the paracellular movement of ions and macromolecules [80]. Components of air pollution, such as ozone and PM can disrupt the integrity of tight junctions [81]. Particles or their components can reach underlying cells and exert effects, including oxidative stress and inflammation [82], [83], [84].

Of most relevance are the UFPs that, because of their small size, are better able to enter cells and exert toxic effects [85], [86], [87], [88]. Geometry dictates that smaller particles have proportionately greater surface area, and this greater contact area for transfer of toxicants magnifies their potential toxicity [89, 90]. Some UFPs can still be absorbed from the lungs to the blood stream [91], and potentially penetrate the blood-brain barrier (BBB). Moreover, some reach the brain directly by neuronal trans-synaptic transport (translocation) [92], [93], [94]. These neurons originate within the olfactory epithelium, and pass through the skull, ultimately terminating in the olfactory bulb. Translocation enables UFPs to bypass the BBB and to gain access to the brain directly through the nasal olfactory mucosa, migrating via the olfactory nerve, to reach the olfactory bulb and beyond [94], [95], [96], [97], [98], [99]. Once UFPs reach the brain they can migrate and be deposited in more distal regions, causing damage and disruption of function and morphology, including in the hippocampus, corpus callosum and olfactory cortex [100], [101], [102]. Multiple adverse effects can be observed, including inflammation, oxidative stress and neurodegeneration [100, 103, 104].

Blood-brain barrier

The BBB is a complex structure that regulates and controls the diffusion and transport of substances into the brain [105]. The barrier refers to the unique properties of the capillary blood vessels that vascularize the CNS, which include tight junctions, a much lower rate of pinocytosis, and a lack of intracellular fenestrations [106]. It is critical for protecting the brain from metabolic waste products, toxins and xenobiotics [107]. Xenobiotics are defined as molecules not naturally produced by or expected to be present in an organism, including environmental pollutants, drugs, food additives, pesticides, and microbial-derived metabolites [108].

When considering the effects of inhaled particles and pollutants on the CNS, a fundamental question is whether they reach the brain. Despite the tightness of the BBB, it has been demonstrated that some blood-borne particles may translocate through an intact BBB [109]. More importantly, exposure to particulate matter can also damage the BBB [92, 110], [111], [112], [113], [114], which enhances the potential for exposure of the CNS to circulating xenobiotics. Alterations of BBB properties are recognized as a significant component of the pathophysiology mechanisms and progression of different degenerative diseases, including Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis and others [107, 115].

Transient receptor potential (TRP) family

Transient receptor potential (TRP) receptors are a group of unique, polymodal ion channels widely expressed in the nervous system [116]. They function as cellular sensors and can detect a wide spectrum of potentially harmful physical stimuli, such as temperature and mechanical or osmotic stress. More relevantly, they respond to biochemical stimuli, including mediators of inflammation and oxidative stress [117], [118], [119], [120]. In particular, they are fundamentally involved in the molecular physiology of chemical perception [121]. This article is focussed on two particular TRP receptors: subfamily vanilloid 1 (TRPV1) and subfamily ankyrin 1 (TRPA1).

Under normal physiological conditions, regulated TRPV1 activity contributes to many basic neuronal functions including resting membrane potential, neurotransmitter release, synaptic plasticity and mitochondrial function, and promotes various processes, such as resistance to oxidative stress [122]. The TRPA1 receptor plays a crucial role as a sensory receptor in several physiological and pathophysiological processes, such as pain sensation and inflammation [123].

Both channels function as chemosensory receptors. The TRPV1 channel senses environmental pollutants and is activated by various common volatile compounds, such as m-xylene, toluene, styrene, benzene, ethylbenzene, acetone, diethyl ether, hexane, heptane and cyclohexane and formaldehyde [124], [125], [126], plus particulate matter pollution [127, 128].

The TRPA1 channel is robustly activated by a multitude of environmental chemical substances, including isocyanates, heavy metals, oxidizing agents, styrene, naphthalene, formaldehyde, tobacco smoke and multiple other VOCs [127, 129, 130]. This receptor is the most broadly-tuned chemosensory channel known. To date, more than 130 different chemicals have been identified as activators of TRPA1 receptors [131].

These receptors are highly expressed in the olfactory and trigeminal nerve endings, which extend within a few microns of the surface of the nasal epithelium, just below the tight junctions, thereby giving lipid soluble chemical stimuli almost direct access [132, 133]. They are also expressed in the brain, including such areas as the dopaminergic neurons of the substantia nigra, hippocampal pyramidal neurons, hypothalamus, locus coeruleus and cortex [123, 134].

Multiple in vitro and in vivo studies have demonstrated that both types of receptors can be activated by air pollution [135], [136], [137], oxidative stress [138], [139], [140], [141], and systemic inflammation [142], [143], [144], [145], [146]. When inflammation is induced, a systemic response of the body is required to redirect energy-rich fuels to the activated immune system [147]. Primary afferent sensory nerve fibers are activated to inform the CNS of the peripheral inflammation. TRPV1 and TRPA1 receptors play important roles in both initiating and maintaining activation of the systemic immune response [117].

TRPA1 and TRPV1 receptors are extensively co-localized. While 30% of TRPV1-positive neurons co-express TRPA1, TRPA1-positive neurons co-express TRPV1 97% of the time [148]. The functional properties, and therefore the pathophysiological roles, of TRPA1 receptors are regulated by their almost universal co-expression with TRPV1 [131]. TRPV1 and TRPA1 function together [134, 149], and their co-expression result in unique activation profiles that can be distinct from those of cells expressing only TRPA1 or TRPV1 [150]. Jointly, they modulate sensitivity, and they can sensitize each other [151, 152]. For example, sensitization of TRPA1 receptors via repeated low dose exposures to acrolein can enhance sensitization of TRPV1 receptors to its well known agonist, capsaicin [203]. In fact, the sensitization of each of these receptors is dependent on co-expression with each other [153, 154]. When activated simultaneously, the effect can be synergistic [155].

Of major interest is the fact that repeated, chronic activation of TRPA1 and TRPV1 receptors can lead to upregulation and sensitization [140, 141, 156], [157], [158], [159], [160]. In the current work, “upregulation” refers to a greater number or density of cell surface receptors and their activity, which may result in a stronger cellular response to an activating substance [161]. Sensitization involves receptor hyperexcitability and the perception of an input as noxious, even if it is from a normal, or even subthreshold, generally innocuous stimulus [162].

Sensitization encompasses a lowered threshold for activation plus increased firing of action potential (sending of a signal along a neuron) with stimulation. TRP receptors can become sensitized following repetitive noxious stimuli or inflammation [162]. This may be related to the fact that TRPV1 and TRPA1 can form complex units (TRPA1V1) in sensory neurons, called heterotetramers, which have distinct properties that are different from the individual channels [149]. When cells co-expressing these channels are challenged with chemicals, the TRPA1V1 heterotetramer is more commonly activated than either TRPA1 or TRPV1 alone [150]. In other words, the more oxidative stress and systemic inflammation, the more there is upregulation of these receptors. When they are both upregulated by shared triggers, they are co-expressed in close proximity [163], and thus they are more likely to form heterotetramers. This results in a lower threshold for a cellular response to chemical stimuli and enhances the strength and duration of the reactions [149].

Detoxification

The impact of chemical exposures is related to both the level of exposure and the ability to detoxify and eliminate the substances [164]. Detoxification is a fundamental and essential component of the defense mechanism inherent in every cell. Being deficient in nutritional support [165], or being overwhelmed by xenobiotic exposures can contribute to inadequate detoxification. Furthermore, genetic polymorphisms and epigenetic changes can reduce the capacity to metabolize xenobiotics and may thereby enhance their toxic effects [166]. Some people have more effective detoxification systems than others [167], [168], [169], which can help to explain the inter-individual variations in disease susceptibility.

Potential consequences: neurodegeneration

When the protective mechanisms are insufficient or overloaded, air pollution can affect the CNS through a variety of cellular, molecular, and inflammatory pathways that can potentially lead to a predisposition to neurological diseases or damaged brain structures [95]. In fact, associations between air pollution exposures and neurodegeneration are well established [76, 77]. There is a significant body of evidence demonstrating a strong correlation between air pollution exposure and cognitive decline [170, 171], such as that found in Parkinson’s disease [76, 172, 173], as well as Alzheimer’s and other dementias [174], [175], [176], [177], [178].

Even at levels below the recommended upper limit, chronic exposure to PM can be associated with physical reductions in grey and white matter mass [179, 180]. According to studies conducted in the United Kingdom, both PM exposure and living in proximity to major roadways are associated with reductions in the volume of the left hippocampus, thalamus and prefrontal cortex [181], [182], [183]. Brain atrophy is associated with neurodegenerative disorders [184, 185].

Environmental exposures of the CNS can be increased due to alterations of the BBB properties, which are recognized as a significant component of the pathophysiology mechanisms and progression of different degenerative diseases [107, 115]. Furthermore, systematic reviews provide strong evidence of the association of genetic detoxification polymorphisms with susceptibility to neurodegeneration [186, 187], likely related to increased oxidative stress. Long-term oxidative stress is a key component of neurotoxicity mechanisms and plays a causal role in neurodegenerative disorders [75, 188, 189].

Reduced olfactory function, such as deficits in odor identification and recognition and increased olfactory threshold, are commonly associated with neurodegeneration [190], [191], [192], [193], [194]. Olfactory loss can appear years before the development of any motor symptoms and cognitive decline [195, 196], and is considered an early sign for the diagnosis of neurodegenerative disorders [197, 198]. This could be the result of direct exposure to polluted air on the olfactory nerve via the olfactory epithelium [132], and/or the translocation of pollutants [94].

Another sensory dysfunction commonly seen in patients with neurodegenerative conditions is chronic pain. The prevalence of pain ranges from 38 to 75% in Alzheimer’s and from 40 to 86% in Parkinson’s disease [199]. It can be an early symptom in Parkinson’s and precede the motor symptoms by two to 10 years [200, 201]. The pathogenesis of chronic pain in these conditions is complex, multifactorial and poorly understood [202]. It can appear as nociceptive, neuropathic, or miscellaneous pain [203], but there is evidence for hyperalgesia and allodynia, which is convincing evidence for TRPV1 and TRPA1 sensitization [206], even before the onset of any movement dysfunction in Parkinson’s [207, 208]. These channels are involved in the development and perpetuation of chronic pain [157209]. Therefore, given that these channels are involved in the progression of neurodegenerative diseases and have a role in pain, it is feasible to propose that these channels could act as central players common to both processes [199].

Sensitivity to noxious stimulation is increased in patients with Parkinson’s with or without pain symptoms. Although not consistent in all cases, numerous clinical studies have reported reduced thermal, electrical, cold or mechanical pain thresholds in Parkinson’s disease patients, reflective of hypersensitivity [188]. This suggests that hypersensitive TRPV1 and TRPA1 receptors may be playing a role. There is support for this concept from animal studies [210]. Increased pain responses and/or greater pain sensitivity is found in cognitively impaired patients with widespread brain atrophy or neural degeneration [211]. Sensitization of TRPV1 receptors is also suggested by the finding of thermal hyperalgesia and mechanical allodynia in a mouse model of Alzheimer’s disease [212].

Calcium in neurons

TRPV1 and TRPA1 are calcium channels and when stimulated, they facilitate the transmembrane entry of calcium ions (Ca2+) into cells [213, 214]. These ions contribute to the electrochemical gradient in cells and are critical to cellular excitability. The regulation of TRPV1 and TRPA1 activity is complex [215], and over-activation of these channels under pathological conditions can lead to elevated levels of intracellular Ca2+ causing subsequent mitochondrial damage and apoptosis [216].

Deregulated TRPV1 activation promotes the loss of hippocampal neurons and an impairment of cognitive functions and has been directly implicated in cell death [217]. To reduce this excitability and maintain cell homeostasis, tight control of intracellular Ca2+ levels in neurons is crucial to prevent neurodegeneration [218]. Most important in this regard are the Ca2+ pumps, which export Ca2+ ions out of the cell within milliseconds to restore physiological homeostasis promptly [219, 220]. Disruption of this precise regulation of intracellular Ca2+ is considered to be a final common pathway leading to neuron dysfunction and cell death [221], and may also possibly play a role in nociception [222].

Vitamin D and protein kinase

Vitamin D also plays a significant role in maintaining the plasma membrane expression of the Ca2+ pumps and buffers that reduce intracellular Ca2+ levels [223]. The vitamin D status is defined by the total 25-hydroxy vitamin D (25OHD), which is the sum of the concentrations of 25(OH)D3 and 25(OH)D2 [224]. Low vitamin D status is a global problem and is associated with dementia, Alzheimer’s and Parkinson’s diseases [225, 226], and disorders of nociception [227]. Vitamin D modulates the function of TRPV1; for example, it antagonizes the stimulatory effects of TRPV1 agonists like capsaicin because it binds to TRPV1 within the same vanilloid binding pocket and reduces trigeminal signalling mediated by TRPV1 [228]. This suggests that when vitamin D levels are low this protection could be reduced. Another example of modulation is the effect of 25OHD on protein kinase C (PKC), which sensitizes but does not activate TRPV1 [229]. Enhanced activity of PKC is associated with neurodegeneration [230], but 25OHD reduces the PKC effect on TRPV1 sensitization [231].

Protein kinases regulate diverse cellular functions. They are also activated by oxidative stress and pollutants [214, 232, 233], and their overexpression has been implicated in various diseases, including neurological disorders [234, 235]. There are several hundred kinases encoded in the human genome, comprising 1.7% of human genes [236]. There are genetic links between kinases and neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease, due to mutations, epigenetic changes, enhanced activation or altered expression [237]. Protein kinases can sensitize TRPV1 and TRPA1 receptors [238], [239], [240], [241].

Central sensitization

TRPV1 and TRPA1 also contribute to central sensitization (CS) [242], [243], [244], [245], which is defined by the International Association for the Study of Pain as an “increased responsiveness of nociceptive neurons in the CNS to their normal or subthreshold afferent input” [246]. CS is also characterized by hyperalgesia and allodynia [247].

CS has also been defined as a state in which the CNS amplifies sensory input from many organ systems [248]. It is a common pathophysiological mechanism in several overlapping syndromes, such as chronic fatigue syndrome, fibromyalgia and irritable bowel syndrome [249]. A systematic literature review of the definitions of CS found that the one main theme is the hyperexcitability of the CNS to sensory input [247]. Individuals with a central sensitivity syndrome may find other normally innocuous stimuli, such as touch, heat, cold, sight, sound, smell, to be noxious as well [250]. Chronic nociceptive pain and the cardinal features of CS are also commonly found in neurodegenerative disorders [207, 251, 252].

Potential consequences: multiple chemical sensitivity (MCS)

There is a significant body of evidence that many individuals are observing sensitivity to common chemicals. A 2015 national survey in the U.S.A. measured the prevalence of self-reported sensitivity to chemicals and medically diagnosed multiple chemical sensitivity (MCS) at 25.9 and 12.8% respectively [253].

MCS is an acquired condition in which the person experiences a range of recurrent symptoms attributed to exposures to low levels of chemicals that most people regard as unproblematic, and which the person used to tolerate previously as well [254]. Almost half of MCS patients have comorbid migraines, up to 70% are asthmatic, and almost 90% report adverse effects from exposure to fragranced consumer products [253].

Up to 60% of asthmatics report that odors of perfumes and cleaning sprays provoke asthma symptoms [255], and 70% of migraine patients report that headaches are triggered by the odors of perfume, paints and gasoline [256]. Having migraine headaches increases the likelihood of being an asthmatic, and vice versa [234, 257], and one common denominator for this bidirectional association is the sensitivity to chemical odors. Both conditions are also impacted by air pollutants, including PM, nitrogen dioxide, ozone, and carbon monoxide [258, 259]. Furthermore, TRPV1 and TRPA1 channels are implicated in their triggering mechanisms [260, 261].

Several case definitions for MCS were proposed in the 1980s and 90s, with differing characteristics other than one feature in common: that symptoms were linked to low levels of chemical exposures [262]. The most widely Accessed case definitions are those proposed by Cullen in 1987 [263], and the MCS consensus proposed in 1999 [264]. Cullen defined MCS as an acquired disorder characterized by recurrent symptoms referable to multiple organ systems and occurring in response to exposure to chemically unrelated compounds at doses far below those established in the general population to cause harmful effects. The MCS consensus definition was validated in 2000 [265], and includes the following [264]:

  1. The symptoms are reproducible with [repeated] chemical exposure.

  2. The condition is chronic.

  3. Low levels of exposure [lower than previously or commonly tolerated] result in manifestation of the symptoms.

  4. The symptoms improve or resolve when the incitants are removed.

  5. Responses occur to multiple chemically unrelated substances.

  6. Symptoms involve multiple organ systems.

Interestingly, in a study by McKeown-Eyssen et al. it was found that symptoms which most commonly distinguished patients with MCS from controls involved the CNS, and included having a stronger sense of smell than others, feeling “spacey”, feeling dull or groggy, and having difficulty concentrating [262]. In 2005, Lacour suggested an extension of the criteria, opining that multiple symptoms in other body systems be mentioned, but this would decrease specificity of the definition [266].

Similar to neurodegenerative disorders, genetic polymorphisms predisposing to less efficient metabolism and excretion of commonly encountered environmental chemicals are more common in people who meet the criteria for MCS [267], [268], [269], [270], [271], [272]. These findings have not been completely consistent [273, 274] however, a regression analysis published in 2019 reinforces the concept that a genetic risk related to phase I and II liver enzymes involved in xenobiotic detoxification can play a role in the pathophysiological route towards sensitization to olfactory compounds in MCS [275]. Nevertheless, even in the absence of an abnormality among detoxification polymorphisms, oxidative stress and systemic inflammation are universally observed in MCS patients [276, 277]. There is also evidence suggesting that the BBB may be dysfunctional in MCS [278], which would enable greater chemical exposures in the CNS.

A strong association between pollutant exposure and MCS is evidenced by the onset. Many published papers report the onset of MCS following recognized or well-defined chemical exposures [279], such as in new or renovated homes or nonindustrial offices because of the gassing off of construction materials such as paints, solvents and new carpets, or immediate or lingering effects of pesticides [280, 281]. The most commonly reported factors associated with the onset of MCS (estimates in brackets) include [282, 283]:

  • – exposure to indoor air contaminants caused by new construction or renovation of a home or office (63.2%)

  • – exposure to various solvents and cleaners (54%)

  • – indoor air contaminants (45%)

  • – pesticides or agricultural chemicals (27.4%) and

  • – chemicals encountered at work or used in hobbies (26.3%).

Other clinical studies similarly describe exposures at the onset of symptoms. Initiating agents include organic solvents, hydrocarbon compounds and pesticides, and chemicals described as irritating or having an odor. Clusters of cases may emerge in what have been described as “sick buildings” with chemical mixtures and/or molds and other agents generated within or infiltrating poorly ventilated structures [284], [285], [286], [287], [288], [289], [290].

The initiation of MCS is more likely to be associated with identified exposures and differs from neuro-degenerative disorders, which begin more insidiously with non-specific symptoms, such as chronic pain and loss of olfaction, perhaps years before the hallmark symptoms and signs of the specific disease.

TRPV1 and TRPA1 sensitization in MCS

TRPV1 receptors are heat sensitive and respond to capsaicin [291], the pungent ingredient in hot chili peppers that produces the sensation of heat [292]. Capsaicin is also a well-known cough-inducing agent when inhaled because it provokes cough in a safe, reliable and dose-dependent manner [273, 293], by stimulating the TRPV1 receptors [294]. The more sensitive the receptors on the sensory neurons lining the bronchial tubes, the more easily coughing can be provoked with capsaicin inhalation [295]. Capsaicin has been used in clinical research for more than three decades [296].

Capsaicin inhalation challenge and chemical sensitivity

In 1996, a small study was performed in Sweden on nine patients with at least a two-year history of airway symptoms as well as headache, fatigue, dizziness and chest pain [297]. Demonstrable bronchial obstruction and IgE‐mediated allergy had been ruled out and there was no benefit from prescribed beta-agonist or steroid inhalers. Symptoms were purported to be induced by chemical odors, such as house paint and perfume. The patients were challenged with inhalations of perfume or a saline placebo and a nasal clamp was used to prevent the detection of the scent of perfume. The patients’ observations of symptom provocation by perfume were verified by blinded perfume inhalation and were reproduced in a second round of testing at least one week later. Since the patients could not detect the odor of perfume, the authors concluded that the symptoms were not transmitted via the olfactory nerve but may have been induced by a trigeminal response via the respiratory tract or the eyes.

This same research group then tested a similar group of patients claiming to have asthma-like symptoms provoked by multiple chemical exposures [298]. The respiratory symptoms included heavy breathing, difficulties in getting air, pressure over the chest, coughing, phlegm, hoarseness, stuffy nose and eye irritation. Many were on long term disability. As in their first study, the authors demonstrated that asthma and allergies were ruled out by normal methacholine challenge testing and negative skin prick tests. These patients also alleged to have other symptoms in multiple systems, including eye irritation, fatigue and headache. Since the authors had postulated symptom induction by a trigeminal reflex, the patients were challenged with capsaicin inhalation. Compared to controls, the patients with purported sensitivity to chemical odors with asthma-like symptoms coughed more after capsaicin inhalation in a dose-dependent manner and were provoked at lower doses. Furthermore, the same respiratory and non-respiratory symptoms were also provoked yet the pulmonary function tests remained normal.

Since 1998, this research group has produced multiple other papers supporting the finding of respiratory hyperreactivity in those who also meet the criteria for MCS, even when asthma has been ruled out by methacholine challenge [284, 299], [300], [301], [302], [303]. The non-respiratory symptoms included headaches, lightheadedness, nausea and/or fatigue. These patients have respiratory sensory hyperreactivity probably due to the sensitization of TRPV1 receptors and follow-up after five and 10 years later showed no reduction in sensitivity to inhaled capsaicin [304, 305]. Similar findings of capsaicin inhalation hypersensitivity in patients meeting the criteria for MCS have been published by other centres in Denmark [306], and Japan [307]. MCS patients consistently demonstrate TRPV1 sensitivity with capsaicin inhalation challenge, which is a reliable clinical research tool with good short- and long-term reproducibility [293].

We identified one single-blind inhalant challenge study in MCS patients using acrolein [308], that also demonstrated greater cough sensitivity than in controls, suggesting that TRPA1 receptor sensitization may be contributing to chemical hypersensitivity as well.

The evidenced sensitization of TRPV1 and TRPA1 receptors in MCS provides the explanation for the multitude of structurally unrelated chemicals to which these patients observe and attribute sensitivity reactions [309].

Olfactory sensitivity and MCS

Having a stronger sense of smell than others since the onset of MCS is a very frequent subjective complaint that distinguishes MCS patients [262, 310], [311], [312], [313]; however, a number of studies have not found any difference in odor detection thresholds [310, 314], [315], [316], or odor identification [317]. In other words, there was no direct evidence of olfactory nerve dysfunction. Nevertheless, some objective support for the patients’ observed increased sense of smell experience comes from a brain imaging study showing that the responses at the recognition threshold level are stronger in those with MCS, and perceived intensity and unpleasantness of odors are significantly higher [318]. This may be because the capacity to detect and react to volatile chemicals is mediated by both the olfactory and trigeminal systems, which interact [319], [320], [321]. Most odorants also stimulate the trigeminal nerve; even anosmics are able to distinguish between odorants based on their trigeminally-mediated sensitivity [319]. Central processing of olfactory and trigeminal stimuli activate synonymous somatosensory and primary olfactory regions [322]. The perceived increase in olfaction sensitivity reported by those with MCS may be related to the lower stimulation threshold of the trigeminal nerve in MCS, as demonstrated in numerous studies using capsaicin inhalation challenge. This differs from neurodegeneration, in which there frequently is loss of olfaction.

CNS dysfunction in MCS

Unfortunately, studies in which MCS patients are challenged directly with chemicals [323], such as perfume, have not been consistent because of multiple problems with design [324]. As a result, the focus of MCS research more recently has shifted from experimental models of chemical stimulation and symptom provocation to searching for and measuring neurological dysfunction to understand the clinical aspects of MCS. MCS patients frequently attribute neurocognitive symptoms to chemical exposures [262, 266, 325]. This observation is supported by a 2010 chemical challenge study using simultaneous single photon-emission computed tomography brain scan imaging, which found an association of simultaneous dysfunction processing odors with cognitive impairment [326]. Abnormalities in brain imaging in patients with MCS at rest have been described since 1994 [327], [328], [329], although differences are not consistently found at baseline [330]. There is no loss of brain mass observed, in contrast to neurodegeneration, but multiple studies employing functional brain scan imaging provide measurable evidence that patients with MCS process odors differently compared with normal, healthy controls, including the finding of prolonged recovery time after exposure [314, 318, 331], [332], [333], [334]. It is noteworthy that when challenged with chemical exposures, compared to controls, MCS patients demonstrate a stronger signal-intensity reaction in magnetic resonance imaging (MRI) of the limbic system [335], and particularly in odor-processing areas such as the hippocampus, amygdala, and thalamus [326]. Functional MRI has also demonstrated that MCS patients do not habituate to repeated sensory stimulation when compared to healthy controls, but instead show evidence of sensitization, as evidenced by increased reactivity to repeated, consistent stimulation [336, 337].

The evidence is compelling that there is CNS dysfunction in MCS patients. A 2018 systematic review found consistent evidence that MCS patients have altered processing of ascending sensory pathways with overactivation in the limbic system, and olfactory and cognitive manifestations [338]. A 2019 systematic review identified nine studies that used functional imaging to assess cerebral responses to several different odorous stimuli and all demonstrated that odors are processed differently by MCS patients compared with controls [339]. In addition, EEG measurements of olfactory event-related potentials provides evidence for TRPV1 sensitivity to carbon dioxide [340], which may help to explain why MCS patients may experience panic attacks when provoked by carbon dioxide challenge [341].

Central sensitization has also been evidenced in MCS [342], which is not surprising given that central sensitization involves the action of TRPV1 receptors. This may help to explain why fibromyalgia and MCS are frequently comorbid [343, 344]. Interestingly, increased hyperalgesia and temporal summation of pain can be observed in MCS patients, even without other comorbid disorders [342, 345].

There are as yet no published studies on MCS examining a potential relationship with low vitamin D levels or increased protein kinase activity, despite the evidence for TRPV1 modulation and sensitization respectively [228, 229].

Comparison of neurodegeneration and MCS

The major risks to the CNS from chronic air pollution exposure are the development of neurodegenerative disease and/or MCS (Table 2). There are both similar and distinctive associated exposures, and genetic, pathophysiological and clinical features of neurodegenerative disorders and MCS (Table 2). Shared features include associated risks for adverse effects from airborne chemical pollutants according to one’s genotype for detoxification and dysfunctional BBB; adverse effects on a cellular level, including oxidative stress, systemic inflammation and changes in polymodal TRPA1 and TRPV1 receptor function; and chronic pain and central sensitization. Neurodegenerative conditions involve olfactory nerve dysfunction, and MCS most likely involves the trigeminal nerve. The conditions diverge in how the TRPV1 and TRPA1 channels respond. Intriguingly, while people with neurodegeneration or MCS are more likely to experience hyperalgesia and allodynia [206, 342, 345], due to receptor upregulation and sensitization, symptomatic responses to low-dose chemical exposures are reported only by those with MCS. Reasons for this difference are unknown but may possibly be a reflection of receptor phenotypes.

Table 2:

Associations of exposures and markers of neurodegeneration vs. MCS.

Neurodegeneration Multiple chemical sensitivity
Air pollution exposure
Genotype for detoxification
Oxidative stress
Systemic inflammation
Disruption of BBB
Chronic pain
Central sensitization
Decreased cognition
Loss of brain mass None
Olfactory dysfunction Loss of function Dysfunctional processing
Trigeminal dysfunction None
TRPV1 upregulation
TRPA1 upregulation
TRPV1 chemical sensitivity None
TRPA1 chemical sensitivity None
Onset with chemical exposure Insidious
Low vitamin D Unknown
Protein kinase activity Unknown

Sensitization to multiple unrelated chemicals is diagnostic for MCS; a condition that has been evidenced by multiple studies of capsaicin challenge tests and functional MRIs. Unlike neurodegenerative disorders, MCS patients do not demonstrate loss of olfactory nerve function or CNS mass, but do show olfactory processing dysfunction. The reason for this divergence of the pathophysiologic pathways to dysfunction and damage is not clear. Despite the overlapping exposures and mechanisms, there is no robust published evidence for comorbidity of neurodegeneration with MCS.

A clue to possible comorbidity is offered by the 2015-16 Canadian Community Health Survey (CCHS) [346]; a cross-sectional survey that collects information about the health behaviors and health care use of the non-institutionalized household population aged 12 or older. Statistics Canada provided a tabulation from the CCHS 2015–2016, of Canadians aged 40 y or older (representing 745,700 people) who reported having MCS, or “Alzheimer’s or other dementia” (Table 3). No information was gathered regarding other neurodegenerative disorders. People experiencing MCS are statistically significantly more likely to develop Alzheimer’s or other dementia (p=0.046). Further research is required to corroborate these findings that there is an associated risk of neurodegeneration for patients with MCS, and if not, how the commonalities illustrated in Table 2 diverge such that those with MCS would be spared dementia.

Table 3:

Overlap between MCS and dementia in 2015–2016 CCHS MCS respondents over 40 years old.

CCHS cohort > 40y With MCS
No dementia 17,955,000 745,700
Alzheimer’s or other dementia 157,900 (0.9%) 12,200 (1.6%)
  1. p-value for difference in dementia prevalence in respondents with and without MCS=0.046

Finally, a number of nonsynonymous single-nucleotide polymorphisms (SNPs) have been described in the human TRPV1 gene, associated with increases in both the response to capsaicin and the expression of TRPV1 on the cell surface [347, 348]. Genetic mutations in TRPV1 and TRPA1 have been found which are associated with increased sensitivity to chemicals [320, 349], [350], [351], as well as an enhanced perception of odorous stimulants that is likely trigeminal [351]. MCS patients may have TRPV1 and/or TRPA1 polymorphisms that predispose them to develop sensitization to pollutant exposures and odors.

Conclusion

There are interacting and overlapping pathophysiological features of responses to environmental exposures that are associated with neurodegeneration and MCS. These include genotypes for detoxification, oxidative stress, systemic inflammation, disruption of the BBB, chronic pain, central sensitization, decreased cognition and upregulation of TRPV1 and TRPA1 receptors.

TRPA1 is the most promiscuous sensor of chemicals known. While much less literature examines sensitization of TRPA1 than TRPV1 receptors in MCS, it is clear that these receptors are frequently co-expressed and can sensitize and provoke responses in each other when stimulated. They can combine to form a complex unit (which is the structure most commonly activated when challenged with chemicals in vitro) and they can interact synergistically. TRPA1 and TRPV1 sensitization explains the myriad of chemicals to which MCS patients attribute reactions and observe sensitivities. Co-expression of TRPA1 and TRPV1 and formation of complex units may contribute to the severity of MCS. Further research on MCS should investigate TRPA1 sensitization, singularly and in conjunction with TRPV1. This may assist in finding a clinical marker for the diagnosis of MCS. Identifying TRPV1 and TRPA1 polymorphisms in neurodegenerative disorders and MCS may help to understand how air pollution influences the divergent development of these conditions and provide targets for management and treatment beyond placing a high priority on air pollution prevention and abatement.


Corresponding author: John Molot, Family Medicine, University of Ottawa Faculty of Medicine, PO Box 35555, RPO York Mills Plaza, North York, ON, M2L 2Y4, Canada, Email:

Funding source: Association pour la santé environnemental du Québec – Environmental Health Association of Québec (ASEQ-EHAQ)

  1. Research funding: The Association pour la santé environnemental du Québec – Environmental Health Association of Québec (ASEQ-EHAQ) has generously provided the funding for online publication.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: John Molot: medical legal opinion; no other competing interests. Margaret Sears: None. Lynn Marshall: None. Riina Bray: Medical legal opinion; no other competing interests.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

References

1. Thornton, JW, McCally, M, Houlihan, J. Biomonitoring of industrial pollutants: health and policy implications of the chemical body burden. Publ Health Rep 2002;117:9. https://doi.org/10.1093/phr/117.4.315.Search in Google Scholar PubMed PubMed Central

2. Marshall, L, Weir, E, Abelsohn, A, Sanborn, MD. Identifying and managing adverse environmental health effects: 1. Taking an exposure history. CMAJ Can Med Assoc J J Assoc Medicale Can 2002;166:1049–55.Search in Google Scholar

3. Li, M, Gao, S, Lu, F, Tong, H, Zhang, H. Dynamic estimation of individual exposure levels to air pollution using trajectories reconstructed from mobile phone data. Int J Environ Res Publ Health 2019;16:4522. https://doi.org/10.3390/ijerph16224522.Search in Google Scholar PubMed PubMed Central

4. Hofman, J, Staelens, J, Cordell, R, Stroobants, C, Zikova, N, Hama, SML, et al.. Ultrafine particles in four European urban environments: results from a new continuous long-term monitoring network. Atmos Environ 2016;136:68–81. https://doi.org/10.1016/j.atmosenv.2016.04.010.Search in Google Scholar

5. Wild, CP. The exposome: from concept to utility. Int J Epidemiol 2012;41:24–32. https://doi.org/10.1093/ije/dyr236.Search in Google Scholar PubMed

6. Buck Louis, GM, Smarr, MM, Patel, CJ. The exposome research paradigm: an opportunity to understand the environmental basis for human health and disease. Curr Environ Health Rep 2017;4:89–98. https://doi.org/10.1007/s40572-017-0126-3.Search in Google Scholar PubMed PubMed Central

7. Steinritz, D, Stenger, B, Dietrich, A, Gudermann, T, Popp, T. TRPs in tox: involvement of transient receptor potential-channels in chemical-induced organ toxicity-A structured review. Cells 2018;7. https://doi.org/10.3390/cells7080098.Search in Google Scholar PubMed PubMed Central

8. WHO World Health Organization. Burden of disease from the joint effects of household and ambient air pollution for 2016. 2018. Available from: https://www.who.int/airpollution/data/AP_joint_effect_BoD_results_May2018.pdf?ua=1 [Accessed 23 Oct 2020].Search in Google Scholar

9. Nováková, Z, Novák, J, Kitanovski, Z, Kukučka, P, Smutná, M, Wietzoreck, M, et al.. Toxic potentials of particulate and gaseous air pollutant mixtures and the role of PAHs and their derivatives. Environ Int 2020;139:105634. https://doi.org/10.1016/j.envint.2020.105634.Search in Google Scholar PubMed

10. Huang, S, Lawrence, J, Kang, C-M, Li, J, Martins, M, Vokonas, P, et al.. Road proximity influences indoor exposures to ambient fine particle mass and components. Environ Pollut Barking Essex 2018;243:978–87. https://doi.org/10.1016/j.envpol.2018.09.046.Search in Google Scholar PubMed

11. Leech, JA, Nelson, WC, Burnett, RT, Aaron, S, Raizenne, ME. It’s about time: a comparison of Canadian and American time-activity patterns. J Expo Anal Environ Epidemiol 2002;12:427–32. https://doi.org/10.1038/sj.jea.7500244.Search in Google Scholar PubMed

12. Klepeis, NE, Nelson, WC, Ott, WR, Robinson, JP, Tsang, AM, Switzer, P, et al.. The national human activity pattern survey (NHAPS): a resource for assessing exposure to environmental pollutants. J Expo Anal Environ Epidemiol 2001;11:231–52. https://doi.org/10.1038/sj.jea.7500165.Search in Google Scholar PubMed

13. Leung, DYC. Outdoor-indoor air pollution in urban environment: challenges and opportunity. Front Environ Sci. 2015;2. https://doi.org/10.3389/fenvs.2014.00069.Search in Google Scholar

14. Fisk, W. Review of some effects of climate change on indoor environmental quality and health and associated No-regrets mitigation measures. Build Environ 2015;86:70–80. https://doi.org/10.1016/j.buildenv.2014.12.024.Search in Google Scholar

15. Brook, RD. Cardiovascular effects of air pollution. Clin Sci Lond Engl 2008;115:175–87. https://doi.org/10.1042/cs20070444.Search in Google Scholar

16. Brook, RD, Rajagopalan, S, Pope, CA, Brook, JR, Bhatnagar, A, Diez-Roux, AV, et al.. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010;121:2331–78. https://doi.org/10.1161/cir.0b013e3181dbece1.Search in Google Scholar

17. Marchini, T, Wolf, D, Michel, NA, Mauler, M, Dufner, B, Hoppe, N, et al.. Acute exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages. Basic Res Cardiol 2016;111:44. https://doi.org/10.1007/s00395-016-0562-5.Search in Google Scholar PubMed PubMed Central

18. US EPA National Center for Environmental Assessment RTPN. Air Quality Criteria for Particulate Matter. (Final Report, 2004). Available from: https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=87903 [Accessed 22 Oct 2020].Search in Google Scholar

19. Baldauf, RW, Devlin, RB, Gehr, P, Giannelli, R, Hassett-Sipple, B, Jung, H, et al.. Ultrafine particle metrics and research considerations: review of the 2015 UFP workshop. Int J Environ Res Publ Health 2016;13. https://doi.org/10.3390/ijerph13111054.Search in Google Scholar PubMed PubMed Central

20. Wang, Y, Zhu, Y, Salinas, R, Ramirez, D, Karnae, S, John, K. Roadside measurements of ultrafine particles at a busy urban intersection. J Air Waste Manag Assoc 2008;58:1449–57. https://doi.org/10.3155/1047-3289.58.11.1449.Search in Google Scholar PubMed

21. World Health Organization. Health effects of particulate matter. Policy implications for countries in eastern Europe, Caucasus and central Asia. 2013. Available from: https://www.euro.who.int/en/health-topics/environment-and-health/air-quality/publications/2013/health-effects-of-particulate-matter.-policy-implications-for-countries-in-eastern-europe,-caucasus-and-central-asia-2013 [Accessed 24 Oct 2020].Search in Google Scholar

22. Marris, CR, Kompella, SN, Miller, MR, Incardona, JP, Brette, F, Hancox, JC, et al.. Polyaromatic hydrocarbons in pollution: a heart‐breaking matter. J Physiol 2020;598:227–47. https://doi.org/10.1113/jp278885.Search in Google Scholar

23. O’Driscoll, CA, Gallo, ME, Hoffmann, EJ, Fechner, JH, Schauer, JJ, Bradfield, CA, et al.. Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro. PloS One 2018;13:e0209690. https://doi.org/10.1371/journal.pone.0209690.Search in Google Scholar PubMed PubMed Central

24. Liu, X, Ouyang, W, Shu, Y, Tian, Y, Feng, Y, Zhang, T, et al.. Incorporating bioaccessibility into health risk assessment of heavy metals in particulate matter originated from different sources of atmospheric pollution. Environ Pollut Barking Essex 2019;254:113113. https://doi.org/10.1016/j.envpol.2019.113113.Search in Google Scholar PubMed

25. Calderón-Garcidueñas, L, González-Maciel, A, Mukherjee, PS, Reynoso-Robles, R, Pérez-Guillé, B, Gayosso-Chávez, C, et al.. Combustion- and friction-derived magnetic air pollution nanoparticles in human hearts. Environ Res 2019;176:108567. https://doi.org/10.1016/j.envres.2019.108567.Search in Google Scholar PubMed

26. Nel, A. Atmosphere. air pollution-related illness: effects of particles. Science 2005;308:804–6. https://doi.org/10.1126/science.1108752.Search in Google Scholar PubMed

27. Rao, G, Ahn, J, Evans, A, Casey, M, Vejerano, E. A method to measure the partitioning coefficient of volatile organic compounds in nanoparticles. MethodsX 2020;7:101041. https://doi.org/10.1016/j.mex.2020.101041.Search in Google Scholar PubMed PubMed Central

28. Algrim, LB, Pagonis, D, de Gouw, JA, Jimenez, JL, Ziemann, PJ. Measurements and modeling of absorptive partitioning of volatile organic compounds to painted surfaces. Indoor Air 2020;30:745–56. https://doi.org/10.1111/ina.12654.Search in Google Scholar PubMed

29. Khurshid, SS, Siegel, JA, Kinney, KA. Indoor particulate reactive oxygen species concentrations. Environ Res 2014;132:46–53. https://doi.org/10.1016/j.envres.2014.03.026.Search in Google Scholar PubMed

30. Brown, RA, Stevanovic, S, Bottle, S, Wang, H, Hu, Z, Wu, C, et al.. Relationship between atmospheric PM-bound reactive oxygen species, their half-lives, and regulated pollutants: investigation and preliminary model. Environ Sci Technol 2020;54:4995–5002. https://doi.org/10.1021/acs.est.9b06643.Search in Google Scholar PubMed

31. European Commission. Reactive Oxygen Species (ROS) in atmospheric aerosols: exploring formation, sources and dynamics of a new air pollution toxicity metric | Particle-bound ROS Project | H2020 | CORDIS | European Commission. 2018. Available from: https://cordis.europa.eu/project/id/792746 [Accessed 22 Jul 2021].Search in Google Scholar

32. Khurshid, SS, Siegel, JA, Kinney, KA. Particulate reactive oxygen species on total suspended particles – measurements in residences in Austin, Texas. Indoor Air 2016;26:953–63. https://doi.org/10.1111/ina.12269.Search in Google Scholar PubMed

33. US EPA, O. Indoor air quality. US EPA; 2017. Available from: https://www.epa.gov/report-environment/indoor-air-quality [Accessed 22 Oct 2020].Search in Google Scholar

34. Nazaroff, WW, Weschler, CJ. Cleaning products and air fresheners: exposure to primary and secondary air pollutants. Atmos Environ 2004;38:2841–65. https://doi.org/10.1016/j.atmosenv.2004.02.040.Search in Google Scholar

35. Klein, F, Baltensperger, U, Prévôt, ASH, El Haddad, I. Quantification of the impact of cooking processes on indoor concentrations of volatile organic species and primary and secondary organic aerosols. Indoor Air 2019;29:926–42. https://doi.org/10.1111/ina.12597.Search in Google Scholar PubMed PubMed Central

36. Chin, J-Y, Godwin, C, Parker, E, Robins, T, Lewis, T, Harbin, P, et al.. Levels and sources of volatile organic compounds in homes of children with asthma. Indoor Air 2014;24:403–15. https://doi.org/10.1111/ina.12086.Search in Google Scholar PubMed PubMed Central

37. Rudel, RA, Perovich, LJ. Endocrine disrupting chemicals in indoor and outdoor air. Atmospheric Environ 2009;43:170–81. https://doi.org/10.1016/j.atmosenv.2008.09.025.Search in Google Scholar PubMed PubMed Central

38. Weschler, CJ, Nazaroff, WW. Semivolatile organic compounds in indoor environments. Atmos Environ 2008;42:9018–40. https://doi.org/10.1016/j.atmosenv.2008.09.052.Search in Google Scholar

39. Heudorf, U, Mersch-Sundermann, V, Angerer, J. Phthalates: toxicology and exposure. Int J Hyg Environ Health 2007;210:623–34. https://doi.org/10.1016/j.ijheh.2007.07.011.Search in Google Scholar PubMed

40. Lippmann, M, Albert, RE. The effect of particle size on the regional deposition of inhaled aerosols in the human respiratory tract. Am Ind Hyg Assoc J 1969;30:257–75. https://doi.org/10.1080/00028896909343120.Search in Google Scholar PubMed

41. Liu, C, Zhang, Y, Weschler, CJ. Exposure to SVOCs from inhaled particles: impact of desorption. Environ Sci Technol 2017;51:6220–8. https://doi.org/10.1021/acs.est.6b05864.Search in Google Scholar PubMed

42. Ebersviller, S, Lichtveld, K, Sexton, KG, Zavala, J, Lin, Y-H, Jaspers, I, et al.. Gaseous VOCs rapidly modify particulate matter and its biological effects – Part 1: simple VOCs and model PM. Atmospheric Chem Phys Discuss ACPD 2012;12:5065–105. https://doi.org/10.5194/acpd-12-5065-2012.Search in Google Scholar PubMed PubMed Central

43. Kim, K-H, Ho, DX, Park, CG, Ma, C-J, Pandey, SK, Lee, SC, et al.. Volatile organic compounds in ambient air at four residential locations in Seoul, Korea. Environ Eng Sci. 2012;29:875–89.10.1089/ees.2011.0280Search in Google Scholar PubMed PubMed Central

44. CDC. Centers for Disease Control and Prevention. Air quality – air pollutants | CDC. 2021. Available from: http://www.cdc.gov/air/pollutants.htm [Accessed 1 Jun 2021].Search in Google Scholar

45. Mannan, M, Al-Ghamdi, SG. Indoor air quality in buildings: a comprehensive review on the factors influencing air pollution in residential and commercial structure. Int J Environ Res Publ Health 2021;18:3276. https://doi.org/10.3390/ijerph18063276.Search in Google Scholar PubMed PubMed Central

46. Lucattini, L, Poma, G, Covaci, A, de Boer, J, Lamoree, MH, Leonards, PEG. A review of semi-volatile organic compounds (SVOCs) in the indoor environment: occurrence in consumer products, indoor air and dust. Chemosphere 2018;201:466–82. https://doi.org/10.1016/j.chemosphere.2018.02.161.Search in Google Scholar PubMed

47. WHO. Noncommunicable diseases country profiles. WHO. World Health Organization; 2018. [Accessed 2020 Oct 23]. Available from: http://www.who.int/nmh/publications/ncd-profiles-2018/en/.Search in Google Scholar

48. Linou, N, Beagley, J, Huikuri, S, Renshaw, N. Air pollution moves up the global health agenda. BMJ 2018;363:k4933. https://doi.org/10.1136/bmj.k4933.Search in Google Scholar PubMed

49. Mudway, IS, Kelly, FJ, Holgate, ST. Oxidative stress in air pollution research. Free Radic Biol Med 2020;151:2–6. https://doi.org/10.1016/j.freeradbiomed.2020.04.031.Search in Google Scholar PubMed PubMed Central

50. Ayres, JG, Borm, P, Cassee, FR, Castranova, V, Donaldson, K, Ghio, A, et al.. Evaluating the toxicity of airborne particulate matter and nanoparticles by measuring oxidative stress potential – a workshop report and consensus statement. Inhal Toxicol 2008;20:75–99. https://doi.org/10.1080/08958370701665517.Search in Google Scholar PubMed

51. Tönnies, E, Trushina, E. Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimers Dis;57:1105–21.10.3233/JAD-161088Search in Google Scholar PubMed PubMed Central

52. Burton, GJ, Jauniaux, E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol 2011;25:287–99. https://doi.org/10.1016/j.bpobgyn.2010.10.016.Search in Google Scholar PubMed PubMed Central

53. Cheng, H, Saffari, A, Sioutas, C, Forman, HJ, Morgan, TE, Finch, CE. Nanoscale particulate matter from urban traffic rapidly induces oxidative stress and inflammation in olfactory epithelium with concomitant effects on brain. Environ Health Perspect 2016;124:1537–46. https://doi.org/10.1289/ehp134.Search in Google Scholar

54. Guerra, R, Vera-Aguilar, E, Uribe-Ramirez, M, Gookin, G, Camacho, J, Osornio-Vargas, AR, et al.. Exposure to inhaled particulate matter activates early markers of oxidative stress, inflammation and unfolded protein response in rat striatum. Toxicol Lett 2013;222:146–54. https://doi.org/10.1016/j.toxlet.2013.07.012.Search in Google Scholar PubMed PubMed Central

55. Morgan, TE, Davis, DA, Iwata, N, Tanner, JA, Snyder, D, Ning, Z, et al.. Glutamatergic neurons in rodent models respond to nanoscale particulate urban air pollutants in vivo and in vitro. Environ Health Perspect 2011;119:1003–9. https://doi.org/10.1289/ehp.1002973.Search in Google Scholar PubMed PubMed Central

56. Brenner, DR, Scherer, D, Muir, K, Schildkraut, J, Boffetta, P, Spitz, MR, et al.. A review of the application of inflammatory biomarkers in epidemiologic cancer research. Cancer Epidemiol Prev Biomark 2014;23:1729–51. https://doi.org/10.1158/1055-9965.epi-14-0064.Search in Google Scholar

57. Mittal, M, Siddiqui, MR, Tran, K, Reddy, SP, Malik, AB. Reactive oxygen species in inflammation and tissue injury. Antioxidants Redox Signal 2014;20:1126–67. https://doi.org/10.1089/ars.2012.5149.Search in Google Scholar PubMed PubMed Central

58. Münzel, T, Daiber, A. Environmental stressors and their impact on health and disease with focus on oxidative stress. Antioxidants Redox Signal 2018;28:735–40. https://doi.org/10.1089/ars.2017.7488.Search in Google Scholar PubMed

59. Hong, Y-C, Park, E-Y, Park, M-S, Ko, JA, Oh, S-Y, Kim, H, et al.. Community level exposure to chemicals and oxidative stress in adult population. Toxicol Lett 2009;184:139–44. https://doi.org/10.1016/j.toxlet.2008.11.001.Search in Google Scholar PubMed

60. de Oliveira, BFA, Chacra, APM, Frauches, TS, Vallochi, A, Hacon, S. A curated review of recent literature of biomarkers used for assessing air pollution exposures and effects in humans. J Toxicol Environ Health B Crit Rev 2014;17:369–410. https://doi.org/10.1080/10937404.2014.976893.Search in Google Scholar PubMed

61. Genuis, SJ, Kyrillos, E. The chemical disruption of human metabolism. Toxicol Mech Methods 2017;27:477–500. https://doi.org/10.1080/15376516.2017.1323986.Search in Google Scholar PubMed

62. Gao, Q. Oxidative stress and autophagy. Adv Exp Med Biol 2019;1206:179–98. https://doi.org/10.1007/978-981-15-0602-4_9.Search in Google Scholar PubMed

63. Byun, H-M, Baccarelli, AA. Environmental exposure and mitochondrial epigenetics: study design and analytical challenges. Hum Genet 2014;133:247–57. https://doi.org/10.1007/s00439-013-1417-x.Search in Google Scholar PubMed PubMed Central

64. Walker, DI, Lane, KJ, Liu, K, Uppal, K, Patton, AP, Durant, JL, et al.. Metabolomic assessment of exposure to near-highway ultrafine particles. J Expo Sci Environ Epidemiol 2019;29:469–83. https://doi.org/10.1038/s41370-018-0102-5.Search in Google Scholar PubMed PubMed Central

65. Khatri, M, Bello, D, Gaines, P, Martin, J, Pal, AK, Gore, R, et al.. Nanoparticles from photocopiers induce oxidative stress and upper respiratory tract inflammation in healthy volunteers. Nanotoxicology 2013;7:1014–27. https://doi.org/10.3109/17435390.2012.691998.Search in Google Scholar PubMed

66. Jantzen, K, Jensen, A, Kermanizadeh, A, Elholm, G, Sigsgaard, T, Møller, P, et al.. Inhalation of house dust and ozone alters systemic levels of endothelial progenitor cells, oxidative stress, and inflammation in elderly subjects. Toxicol Sci Off J Soc Toxicol 2018;163:353–63. https://doi.org/10.1093/toxsci/kfy027.Search in Google Scholar PubMed

67. Wang, F, Li, C, Liu, W, Jin, Y. Oxidative damage and genotoxic effect in mice caused by sub-chronic exposure to low-dose volatile organic compounds. Inhal Toxicol 2013;25:235–42. https://doi.org/10.3109/08958378.2013.779767.Search in Google Scholar PubMed

68. Bönisch, U, Böhme, A, Kohajda, T, Mögel, I, Schütze, N, von Bergen, M, et al.. Volatile organic compounds enhance allergic airway inflammation in an experimental mouse model. PloS One 2012;7:e39817. https://doi.org/10.1371/journal.pone.0039817.Search in Google Scholar PubMed PubMed Central

69. Mörbt, N, Tomm, J, Feltens, R, Mögel, I, Kalkhof, S, Murugesan, K, et al.. Chlorinated benzenes cause concomitantly oxidative stress and induction of apoptotic markers in lung epithelial cells (A549) at nonacute toxic concentrations. J Proteome Res 2011;10:363–78. https://doi.org/10.1021/pr1005718.Search in Google Scholar PubMed

70. Mögel, I, Baumann, S, Böhme, A, Kohajda, T, von Bergen, M, Simon, J-C, et al.. The aromatic volatile organic compounds toluene, benzene and styrene induce COX-2 and prostaglandins in human lung epithelial cells via oxidative stress and p38 MAPK activation. Toxicology 2011;289:28–37. https://doi.org/10.1016/j.tox.2011.07.006.Search in Google Scholar PubMed

71. Ruotsalainen, M, Hyvärinen, A, Nevalainen, A, Savolainen, KM. Production of reactive oxygen metabolites by opsonized fungi and bacteria isolated from indoor air, and their interactions with soluble stimuli, fMLP or PMA. Environ Res 1995;69:122–31. https://doi.org/10.1006/enrs.1995.1033.Search in Google Scholar PubMed

72. Lu, C-Y, Ma, Y-C, Lin, J-M, Li, C-Y, Lin, RS, Sung, F-C. Oxidative stress associated with indoor air pollution and sick building syndrome-related symptoms among office workers in Taiwan. Inhal Toxicol 2007;19:57–65. https://doi.org/10.1080/08958370600985859.Search in Google Scholar PubMed

73. Lu, C-Y, Ma, Y-C, Chen, P-C, Wu, C-C, Chen, Y-C. Oxidative stress of office workers relevant to tobacco smoking and inner air quality. Int J Environ Res Publ Health 2014;11:5586–97. https://doi.org/10.3390/ijerph110605586.Search in Google Scholar PubMed PubMed Central

74. Rock, KD, Patisaul, HB. Environmental mechanisms of neurodevelopmental toxicity. Curr Environ Health Rep 2018;5:145–57. https://doi.org/10.1007/s40572-018-0185-0.Search in Google Scholar PubMed PubMed Central

75. Cahill-Smith, S, Li, J-M. Oxidative stress, redox signalling and endothelial dysfunction in ageing-related neurodegenerative diseases: a role of NADPH oxidase 2. Br J Clin Pharmacol 2014;78:441–53. https://doi.org/10.1111/bcp.12357.Search in Google Scholar PubMed PubMed Central

76. Hu, C-Y, Fang, Y, Li, F-L, Dong, B, Hua, X-G, Jiang, W, et al.. Association between ambient air pollution and Parkinson’s disease: systematic review and meta-analysis. Environ Res 2019;168:448–59. https://doi.org/10.1016/j.envres.2018.10.008.Search in Google Scholar PubMed

77. Dimakakou, E, Johnston, HJ, Streftaris, G, Cherrie, JW. Exposure to environmental and occupational particulate air pollution as a potential contributor to neurodegeneration and diabetes: a systematic review of epidemiological research. Int J Environ Res Publ Health 2018;15. https://doi.org/10.3390/ijerph15081704.Search in Google Scholar PubMed PubMed Central

78. Beisel William R I of M (US) C on MN. Overview of the Immune System and Other Host Defense Mechanisms [Internet]. Military Strategies for Sustainment of Nutrition and Immune Function in the Field. National Academies Press (US); 1999. Available from: http://www.ncbi.nlm.nih.gov/books/NBK230976/ [Accessed 7 Jun 2021].Search in Google Scholar

79. Heusinkveld, HJ, Wahle, T, Campbell, A, Westerink, RHS, Tran, L, Johnston, H, et al.. Neurodegenerative and neurological disorders by small inhaled particles. Neurotoxicology 2016;56:94–106. https://doi.org/10.1016/j.neuro.2016.07.007.Search in Google Scholar PubMed

80. Huff, RD, Carlsten, C, Hirota, JA. An update on immunologic mechanisms in the respiratory mucosa in response to air pollutants. J Allergy Clin Immunol 2019;143:1989–2001. https://doi.org/10.1016/j.jaci.2019.04.012.Search in Google Scholar PubMed

81. Goossens, J, Jonckheere, A-C, Dupont, LJ, Bullens, DMA. Air pollution and the airways: lessons from a century of human Urbanization. Atmosphere 2021;12:898. https://doi.org/10.3390/atmos12070898.Search in Google Scholar

82. Cooper, DM, Loxham, M. Particulate matter and the airway epithelium: the special case of the underground? Eur Respir Rev Off J Eur Respir Soc 2019;28:190066. https://doi.org/10.1183/16000617.0066-2019.Search in Google Scholar PubMed PubMed Central

83. Xia, T, Zhu, Y, Mu, L, Zhang, Z-F, Liu, S. Pulmonary diseases induced by ambient ultrafine and engineered nanoparticles in twenty-first century. Natl Sci Rev 2016;3:416–29. https://doi.org/10.1093/nsr/nww064.Search in Google Scholar PubMed PubMed Central

84. Tetrault, GA. Air pollution and lung function. N Engl J Med 2004;351:2652–3. https://doi.org/10.1056/nejm200412163512517.Search in Google Scholar PubMed

85. Block, ML, Wu, X, Pei, Z, Li, G, Wang, T, Qin, L, et al.. Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase. FASEB J Off Publ Fed Am Soc Exp Biol 2004;18:1618–20. https://doi.org/10.1096/fj.04-1945fje.Search in Google Scholar PubMed

86. Schmid, O, Möller, W, Semmler-Behnke, M, Ferron, GA, Karg, E, Lipka, J, et al.. Dosimetry and toxicology of inhaled ultrafine particles. Biomark Biochem Indic Expo Response Susceptibility Chem 2009;14:67–73. https://doi.org/10.1080/13547500902965617.Search in Google Scholar PubMed

87. Win-Shwe, T-T, Fujimaki, H. Nanoparticles and neurotoxicity. Int J Mol Sci 2011;12:6267–80. https://doi.org/10.3390/ijms12096267.Search in Google Scholar PubMed PubMed Central

88. Gillespie, P, Tajuba, J, Lippmann, M, Chen, L-C, Veronesi, B. Particulate matter neurotoxicity in culture is size-dependent. Neurotoxicology 2013;36:112–7. https://doi.org/10.1016/j.neuro.2011.10.006.Search in Google Scholar PubMed PubMed Central

89. Hong, G, Jee, Y-K. Special issue on ultrafine particles: where are they from and how do they affect us? Exp Mol Med 2020;52:309–10. https://doi.org/10.1038/s12276-020-0395-z.Search in Google Scholar PubMed PubMed Central

90. Oberdörster, G, Oberdörster, E, Oberdörster, J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 2005;113:823–39. https://doi.org/10.1289/ehp.7339.Search in Google Scholar PubMed PubMed Central

91. Traboulsi, H, Guerrina, N, Iu, M, Maysinger, D, Ariya, P, Baglole, CJ. Inhaled pollutants: the molecular scene behind respiratory and systemic diseases associated with ultrafine particulate matter. Int J Mol Sci 2017;18. https://doi.org/10.3390/ijms18020243.Search in Google Scholar PubMed PubMed Central

92. Migliore, L, Coppedè, F. Environmental-induced oxidative stress in neurodegenerative disorders and aging. Mutat Res 2009;674:73–84. https://doi.org/10.1016/j.mrgentox.2008.09.013.Search in Google Scholar PubMed

93. Block, ML, Calderón-Garcidueñas, L. Air pollution: mechanisms of neuroinflammation & CNS disease. Trends Neurosci 2009;32:506–16. https://doi.org/10.1016/j.tins.2009.05.009.Search in Google Scholar PubMed PubMed Central

94. Peters, A, Veronesi, B, Calderón-Garcidueñas, L, Gehr, P, Chen, LC, Geiser, M, et al.. Translocation and potential neurological effects of fine and ultrafine particles a critical update. Part Fibre Toxicol 2006;3:13. https://doi.org/10.1186/1743-8977-3-13.Search in Google Scholar PubMed PubMed Central

95. Genc, S, Zadeoglulari, Z, Fuss, SH, Genc, K. The adverse effects of air pollution on the nervous system. Porte C, editor. J Toxicol 2012;2012:782462.https://doi.org/10.1155/2012/782462.Search in Google Scholar PubMed PubMed Central

96. Oberdörster, G, Utell, MJ. Ultrafine particles in the urban air: to the respiratory tract – and beyond? Environ Health Perspect 2002;110:A440–1. https://doi.org/10.1289/ehp.110-1240959.Search in Google Scholar PubMed PubMed Central

97. Oberdörster, G, Sharp, Z, Atudorei, V, Elder, A, Gelein, R, Kreyling, W, et al.. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 2004;16:437–45. https://doi.org/10.1080/08958370490439597.Search in Google Scholar PubMed

98. Garcia, GJM, Schroeter, JD, Kimbell, JS. Olfactory deposition of inhaled nanoparticles in humans. Inhal Toxicol 2015;27:394–403. https://doi.org/10.3109/08958378.2015.1066904.Search in Google Scholar PubMed PubMed Central

99. Lucchini, RG, Dorman, DC, Elder, A, Veronesi, B. Neurological impacts from inhalation of pollutants and the nose-brain connection. Neurotoxicology 2012;33:838–41. https://doi.org/10.1016/j.neuro.2011.12.001.Search in Google Scholar PubMed PubMed Central

100. Liu, Y, Gao, Y, Liu, Y, Li, B, Chen, C, Wu, G. Oxidative stress and acute changes in murine brain tissues after nasal instillation of copper particles with different sizes. J Nanosci Nanotechnol 2014;14:4534–40. https://doi.org/10.1166/jnn.2014.8290.Search in Google Scholar PubMed

101. Babadjouni, R, Patel, A, Liu, Q, Shkirkova, K, Lamorie-Foote, K, Connor, M, et al.. Nanoparticulate matter exposure results in neuroinflammatory changes in the corpus callosum. PLoS One 2018;13:e0206934. https://doi.org/10.1371/journal.pone.0206934.Search in Google Scholar PubMed PubMed Central

102. Ajmani, GS, Suh, HH, Pinto, JM. Effects of ambient air pollution exposure on olfaction: a review. Environ Health Perspect 2016;124:1683–93. https://doi.org/10.1289/ehp136.Search in Google Scholar

103. Calderón-Garcidueñas, L, Torres-Jardón, R, Kulesza, RJ, Park, S-B, D’Angiulli, A. Air pollution and detrimental effects on children’s brain. The need for a multidisciplinary approach to the issue complexity and challenges. Front Hum Neurosci 2014;8:613. https://doi.org/10.3389/fnhum.2014.00613.Search in Google Scholar PubMed PubMed Central

104. Mir, RH, Sawhney, G, Pottoo, FH, Mohi-Ud-Din, R, Madishetti, S, Jachak, SM, et al.. Role of environmental pollutants in Alzheimer’s disease: a review. Environ Sci Pollut Res Int 2020;27:44724–42. https://doi.org/10.1007/s11356-020-09964-x.Search in Google Scholar PubMed

105. Abbott, NJ, Patabendige, AAK, Dolman, DEM, Yusof, SR, Begley, DJ. Structure and function of the blood-brain barrier. Neurobiol Dis 2010;37:13–25. https://doi.org/10.1016/j.nbd.2009.07.030.Search in Google Scholar PubMed

106. Reese, TS, Karnovsky, MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 1967;34:207–17. https://doi.org/10.1083/jcb.34.1.207.Search in Google Scholar PubMed PubMed Central

107. Daneman, R. The blood-brain barrier in health and disease. Ann Neurol 2012;72:648–72. https://doi.org/10.1002/ana.23648.Search in Google Scholar PubMed

108. Minzaghi, D, Pavel, P, Dubrac, S. Xenobiotic receptors and their mates in atopic dermatitis. Int J Mol Sci 2019;20. https://doi.org/10.3390/ijms20174234.Search in Google Scholar PubMed PubMed Central

109. Oberdörster, G, Elder, A, Rinderknecht, A. Nanoparticles and the brain: cause for concern? J Nanosci Nanotechnol 2009;9:4996–5007. https://doi.org/10.1166/jnn.2009.gr02.Search in Google Scholar PubMed PubMed Central

110. Calderón-Garcidueñas, L, Solt, AC, Henríquez-Roldán, C, Torres-Jardón, R, Nuse, B, Herritt, L, et al.. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol 2008;36:289–310. https://doi.org/10.1177/0192623307313011.Search in Google Scholar PubMed

111. Kim, H, Kim, W-H, Kim, Y-Y, Park, H-Y. Air pollution and central nervous system disease: a review of the impact of fine particulate matter on neurological disorders. Front Public Health 2020;8:575330. https://doi.org/10.3389/fpubh.2020.575330.Search in Google Scholar PubMed PubMed Central

112. Hartz, AMS, Bauer, B, Block, ML, Hong, J-S, Miller, DS. Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier. FASEB J 2008;22:2723–33. https://doi.org/10.1096/fj.08-106997.Search in Google Scholar PubMed PubMed Central

113. Varatharaj, A, Galea, I. The blood-brain barrier in systemic inflammation. Brain Behav Immun 2017;60:1–12. https://doi.org/10.1016/j.bbi.2016.03.010.Search in Google Scholar PubMed

114. Coisne, C, Engelhardt, B. Tight junctions in brain barriers during central nervous system inflammation. Antioxidants Redox Signal 2011;15:1285–303. https://doi.org/10.1089/ars.2011.3929.Search in Google Scholar PubMed

115. Zlokovic, BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008;57:178–201. https://doi.org/10.1016/j.neuron.2008.01.003.Search in Google Scholar PubMed

116. Vennekens, R, Menigoz, A, Nilius, B. TRPs in the brain. Rev Physiol Biochem Pharmacol 2012;163:27–64. https://doi.org/10.1007/112_2012_8.Search in Google Scholar PubMed

117. Straub, RH. TRPV1, TRPA1, and TRPM8 channels in inflammation, energy redirection, and water retention: role in chronic inflammatory diseases with an evolutionary perspective. J Mol Med Berl Ger 2014;92:925–37. https://doi.org/10.1007/s00109-014-1175-9.Search in Google Scholar PubMed

118. Clapham, DE. TRP channels as cellular sensors. Nature 2003;426:517–24. https://doi.org/10.1038/nature02196.Search in Google Scholar PubMed

119. Ramsey, IS, Delling, M, Clapham, DE. An introduction to TRP channels. Annu Rev Physiol 2006;68:619–47. https://doi.org/10.1146/annurev.physiol.68.040204.100431.Search in Google Scholar PubMed

120. Zheng, J. Molecular mechanism of TRP channels. Comp Physiol 2013;3:221–42. https://doi.org/10.1002/cphy.c120001.Search in Google Scholar PubMed PubMed Central

121. Bessac, BF, Jordt, S-E. Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology 2008;23:360–70. https://doi.org/10.1152/physiol.00026.2008.Search in Google Scholar PubMed PubMed Central

122. Ramírez-Barrantes, R, Cordova, C, Poblete, H, Muñoz, P, Marchant, I, Wianny, F, et al.. Perspectives of TRPV1 function on the neurogenesis and neural plasticity. Neural Plast 2016;2016:1568145. https://doi.org/10.1155/2016/1568145.Search in Google Scholar PubMed PubMed Central

123. Borbély, É, Payrits, M, Hunyady, Á, Mező, G, Pintér, E. Important regulatory function of transient receptor potential ankyrin 1 receptors in age-related learning and memory alterations of mice. GeroScience 2019;41:643–54. https://doi.org/10.1007/s11357-019-00083-1.Search in Google Scholar PubMed PubMed Central

124. Futamura, M, Goto, S, Kimura, R, Kimoto, I, Miyake, M, Ito, K, et al.. Differential effects of topically applied formalin and aromatic compounds on neurogenic-mediated microvascular leakage in rat skin. Toxicology 2009;255:100–6. https://doi.org/10.1016/j.tox.2008.10.012.Search in Google Scholar PubMed

125. Saito, A, Tanaka, H, Usuda, H, Shibata, T, Higashi, S, Yamashita, H, et al.. Characterization of skin inflammation induced by repeated exposure of toluene, xylene, and formaldehyde in mice. Environ Toxicol 2011;26:224–32. https://doi.org/10.1002/tox.20547.Search in Google Scholar PubMed

126. Usuda, H, Endo, T, Shimouchi, A, Saito, A, Tominaga, M, Yamashita, H, et al.. Transient receptor potential vanilloid 1 – a polymodal nociceptive receptor – plays a crucial role in formaldehyde-induced skin inflammation in mice. J Pharmacol Sci 2012;118:266–74. https://doi.org/10.1254/jphs.11193fp.Search in Google Scholar PubMed

127. Lübbert, M, Kyereme, J, Schöbel, N, Beltrán, L, Wetzel, CH, Hatt, H. Transient receptor potential channels encode volatile chemicals sensed by rat trigeminal ganglion neurons. PloS One 2013;8:e77998. https://doi.org/10.1371/journal.pone.0077998.Search in Google Scholar PubMed PubMed Central

128. Verones, B, Oortgiesen, M. Neurogenic inflammation and particulate matter (PM) air pollutants. Neurotoxicology 2001;22:795–810. https://doi.org/10.1016/s0161-813x(01)00062-6.Search in Google Scholar PubMed

129. Bessac, BF, Sivula, M, von Hehn, CA, Caceres, AI, Escalera, J, Jordt, S-E. Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J Off Publ Fed Am Soc Exp Biol 2009;23:1102–14. https://doi.org/10.1096/fj.08-117812.Search in Google Scholar PubMed PubMed Central

130. Lanosa, MJ, Willis, DN, Jordt, S, Morris, JB. Role of metabolic activation and the TRPA1 receptor in the sensory irritation response to styrene and naphthalene. Toxicol Sci Off J Soc Toxicol 2010;115:589–95. https://doi.org/10.1093/toxsci/kfq057.Search in Google Scholar PubMed PubMed Central

131. Talavera, K, Startek, JB, Alvarez-Collazo, J, Boonen, B, Alpizar, YA, Sanchez, A, et al.. Mammalian transient receptor potential TRPA1 channels: from structure to disease. Physiol Rev 2020;100:725–803. https://doi.org/10.1152/physrev.00005.2019.Search in Google Scholar PubMed

132. Finger, TE, St Jeor, VL, Kinnamon, JC, Silver, WL. Ultrastructure of substance P- and CGRP-immunoreactive nerve fibers in the nasal epithelium of rodents. J Comp Neurol 1990;294:293–305. https://doi.org/10.1002/cne.902940212.Search in Google Scholar PubMed

133. Zeliger, HI. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases. Interdiscipl Toxicol 2013;6:103–10. https://doi.org/10.2478/intox-2013-0018.Search in Google Scholar PubMed PubMed Central

134. Fernandes, E, Fernandes, M, Keeble, J. The functions of TRPA1 and TRPV1: moving away from sensory nerves. Br J Pharmacol 2012;166:510–21. https://doi.org/10.1111/j.1476-5381.2012.01851.x.Search in Google Scholar PubMed PubMed Central

135. Deering-Rice, CE, Romero, EG, Shapiro, D, Hughen, RW, Light, AR, Yost, GS, et al.. Electrophilic components of diesel exhaust particles (DEP) activate transient receptor potential ankyrin-1 (TRPA1): a probable mechanism of acute pulmonary toxicity for DEP. Chem Res Toxicol 2011;24:950–9. https://doi.org/10.1021/tx200123z.Search in Google Scholar PubMed PubMed Central

136. Deering-Rice, CE, Johansen, ME, Roberts, JK, Thomas, KC, Romero, EG, Lee, J, et al.. Transient receptor potential vanilloid-1 (TRPV1) is a mediator of lung toxicity for coal fly ash particulate material. Mol Pharmacol 2012;81:411–9. https://doi.org/10.1124/mol.111.076067.Search in Google Scholar PubMed PubMed Central

137. Robertson, S, Thomson, AL, Carter, R, Stott, HR, Shaw, CA, Hadoke, PWF, et al.. Pulmonary diesel particulate increases susceptibility to myocardial ischemia/reperfusion injury via activation of sensory TRPV1 and β1 adrenoreceptors. Part Fibre Toxicol 2014;11:12. https://doi.org/10.1186/1743-8977-11-12.Search in Google Scholar PubMed PubMed Central

138. Furuta, A, Suzuki, Y, Hayashi, N, Egawa, S, Yoshimura, N. Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: implication for the pathogenesis of interstitial cystitis/bladder pain syndrome. Int J Urol 2012;19:429–36. https://doi.org/10.1111/j.1442-2042.2012.02966.x.Search in Google Scholar PubMed

139. Sawada, Y, Hosokawa, H, Matsumura, K, Kobayashi, S. Activation of transient receptor potential ankyrin 1 by hydrogen peroxide. Eur J Neurosci 2008;27:1131–42. https://doi.org/10.1111/j.1460-9568.2008.06093.x.Search in Google Scholar PubMed

140. Chuang, H, Lin, S. Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification. Proc Natl Acad Sci U S A 2009;106:20097–102. https://doi.org/10.1073/pnas.0902675106.Search in Google Scholar PubMed PubMed Central

141. Susankova, K, Tousova, K, Vyklicky, L, Teisinger, J, Vlachova, V. Reducing and oxidizing agents sensitize heat-activated vanilloid receptor (TRPV1) current. Mol Pharmacol 2006;70:383–94. https://doi.org/10.1124/mol.106.023069.Search in Google Scholar PubMed

142. Kistner, K, Siklosi, N, Babes, A, Khalil, M, Selescu, T, Zimmermann, K, et al.. Systemic desensitization through TRPA1 channels by capsazepine and mustard oil – a novel strategy against inflammation and pain. Sci Rep 2016;6:28621. https://doi.org/10.1038/srep28621.Search in Google Scholar PubMed PubMed Central

143. Bujak, JK, Kosmala, D, Szopa, IM, Majchrzak, K, Bednarczyk, P. Inflammation, cancer and immunity-implication of TRPV1 channel. Front Oncol 2019;9:1087. https://doi.org/10.3389/fonc.2019.01087.Search in Google Scholar PubMed PubMed Central

144. Zhang, N, Inan, S, Inan, S, Cowan, A, Sun, R, Wang, JM, et al.. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. Proc Natl Acad Sci U S A 2005;102:4536–41. https://doi.org/10.1073/pnas.0406030102.Search in Google Scholar PubMed PubMed Central

145. Breese, NM, George, AC, Pauers, LE, Stucky, CL. Peripheral inflammation selectively increases TRPV1 function in IB4-positive sensory neurons from adult mouse. Pain 2005;115:37–49. https://doi.org/10.1016/j.pain.2005.02.010.Search in Google Scholar PubMed

146. Ogawa, N, Kurokawa, T, Fujiwara, K, Polat, OK, Badr, H, Takahashi, N, et al.. Functional and structural divergence in human TRPV1 channel subunits by oxidative cysteine modification. J Biol Chem 2016;291:4197–210. https://doi.org/10.1074/jbc.m115.700278.Search in Google Scholar

147. Straub, RH. Evolutionary medicine and chronic inflammatory state – known and new concepts in pathophysiology. J Mol Med Berl Ger 2012;90:523–34. https://doi.org/10.1007/s00109-012-0861-8.Search in Google Scholar PubMed PubMed Central

148. Story, GM, Peier, AM, Reeve, AJ, Eid, SR, Mosbacher, J, Hricik, TR, et al.. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 2003;112:819–29. https://doi.org/10.1016/s0092-8674(03)00158-2.Search in Google Scholar PubMed

149. Lee, L-Y, Hsu, C-C, Lin, Y-J, Lin, R-L, Khosravi, M. Interaction between TRPA1 and TRPV1: synergy on pulmonary sensory nerves. Pulm Pharmacol Therapeut 2015;35:87–93. https://doi.org/10.1016/j.pupt.2015.08.003.Search in Google Scholar PubMed PubMed Central

150. Sadofsky, LR, Sreekrishna, KT, Lin, Y, Schinaman, R, Gorka, K, Mantri, Y, et al.. Unique responses are observed in transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1 and TRPV1) Co-expressing cells. Cells 2014;3:616–26. https://doi.org/10.3390/cells3020616.Search in Google Scholar PubMed PubMed Central

151. Spahn, V, Stein, C, Zöllner, C. Modulation of transient receptor vanilloid 1 activity by transient receptor potential ankyrin 1. Mol Pharmacol 2014;85:335–44. https://doi.org/10.1124/mol.113.088997.Search in Google Scholar PubMed

152. Gouin, O, L’Herondelle, K, Lebonvallet, N, Le Gall-Ianotto, C, Sakka, M, Buhé, V, et al.. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell 2017;8:644–61. https://doi.org/10.1007/s13238-017-0395-5.Search in Google Scholar PubMed PubMed Central

153. Patil, MJ, Salas, M, Bialuhin, S, Boyd, JT, Jeske, NA, Akopian, AN. Sensitization of small-diameter sensory neurons is controlled by TRPV1 and TRPA1 association. FASEB J Off Publ Fed Am Soc Exp Biol 2020;34:287–302. https://doi.org/10.1096/fj.201902026r.Search in Google Scholar PubMed PubMed Central

154. Nielsen, TA, Eriksen, MA, Gazerani, P, Andersen, HH. Psychophysical and vasomotor evidence for interdependency of TRPA1 and TRPV1-evoked nociceptive responses in human skin: an experimental study. Pain 2018;159:1989–2001. https://doi.org/10.1097/j.pain.0000000000001298.Search in Google Scholar PubMed

155. Hsu, C-C, Lee, L-Y. Role of calcium ions in the positive interaction between TRPA1 and TRPV1 channels in bronchopulmonary sensory neurons. J Appl Physiol 2015;118:1533–43. https://doi.org/10.1152/japplphysiol.00043.2015.Search in Google Scholar PubMed PubMed Central

156. Miao, F, Wang, R, Cui, G, Li, X, Wang, T, Li, X. Engagement of MicroRNA-155 in exaggerated oxidative stress signal and TRPA1 in the Dorsal Horn of the spinal cord and neuropathic pain during chemotherapeutic oxaliplatin. Neurotox Res 2019;36:712–23. https://doi.org/10.1007/s12640-019-00039-5.Search in Google Scholar PubMed

157. Giorgi, S, Nikolaeva-Koleva, M, Alarcón-Alarcón, D, Butrón, L, González-Rodríguez, S. Is TRPA1 burning down TRPV1 as druggable target for the treatment of chronic pain? Int J Mol Sci 2019;20:2906. https://doi.org/10.3390/ijms20122906.Search in Google Scholar PubMed PubMed Central

158. Gu, X, Yu, N, Pang, X, Zhang, W, Zhang, J, Zhang, Y. EXPRESS: products of oxidative stress and TRPA1 expression in the brainstem of rats after lung ischemia-reperfusion injury. Pulm Circ 2019:2045894019865169.10.1177/2045894019865169Search in Google Scholar PubMed PubMed Central

159. Yoshida, T, Inoue, R, Morii, T, Takahashi, N, Yamamoto, S, Hara, Y, et al.. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat Chem Biol 2006;2:596–607. https://doi.org/10.1038/nchembio821.Search in Google Scholar PubMed

160. Miller, BA, Zhang, W. TRP channels as mediators of oxidative stress. Adv Exp Med Biol 2011;704:531–44. https://doi.org/10.1007/978-94-007-0265-3_29.Search in Google Scholar PubMed

161. National Institutes of Health. Definition of upregulation – NCI dictionary of cancer terms – national cancer Institute [internet]; 2011. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/upregulation [Accessed 3 Jun 2021].Search in Google Scholar

162. Schumacher, MA. TRP channels in pain and inflammation: therapeutic opportunities. Pain Pract Off J World Inst Pain 2010;10:185–200. https://doi.org/10.1111/j.1533-2500.2010.00358.x.Search in Google Scholar PubMed PubMed Central

163. Meng, J, Wang, J, Steinhoff, M, Dolly, JO. TNFα induces co-trafficking of TRPV1/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18-1/syntaxin1/SNAP-25 mediated fusion. Sci Rep 2016;6:21226. https://doi.org/10.1038/srep21226.Search in Google Scholar PubMed PubMed Central

164. Moulton, PV, Yang, W. Air pollution, oxidative stress, and Alzheimer’s disease. J Environ Public Health 2012;2012:472751. https://doi.org/10.1155/2012/472751.Search in Google Scholar PubMed PubMed Central

165. Hodges, RE, Minich, DM. Modulation of metabolic detoxification pathways using foods and food-derived components: a scientific review with clinical application. J Nutr Metab 2015;2015:760689. https://doi.org/10.1155/2015/760689.Search in Google Scholar PubMed PubMed Central

166. Szyf, M. The dynamic epigenome and its implications in toxicology. Toxicol Sci Off J Soc Toxicol 2007;100:7–23. https://doi.org/10.1093/toxsci/kfm177.Search in Google Scholar PubMed

167. Shastry, B. Genetic diversity and new therapeutic concepts. J Hum Genet 2005;50:321–8. https://doi.org/10.1007/s10038-005-0264-6.Search in Google Scholar PubMed

168. Polimanti, R, Carboni, C, Baesso, I, Piacentini, S, Iorio, A, De Stefano, GF, et al.. Genetic variability of glutathione S-transferase enzymes in human populations: functional inter-ethnic differences in detoxification systems. Gene 2013;512:102–7. https://doi.org/10.1016/j.gene.2012.09.113.Search in Google Scholar PubMed

169. Manikandan, P, Nagini, S. Cytochrome P450 structure, function and clinical significance: a review. Curr Drug Targets 2018;19:38–54. https://doi.org/10.2174/1389450118666170125144557.Search in Google Scholar PubMed

170. Allen, JL, Klocke, C, Morris-Schaffer, K, Conrad, K, Sobolewski, M, Cory-Slechta, DA. Cognitive effects of air pollution exposures and potential mechanistic underpinnings. Curr Environ Health Rep 2017;4:180–91. https://doi.org/10.1007/s40572-017-0134-3.Search in Google Scholar PubMed PubMed Central

171. Block, ML, Elder, A, Auten, RL, Bilbo, SD, Chen, H, Chen, J-C, et al.. The outdoor air pollution and brain health workshop. Neurotoxicology 2012;33:972–84. https://doi.org/10.1016/j.neuro.2012.08.014.Search in Google Scholar PubMed PubMed Central

172. Kasdagli, M-I, Katsouyanni, K, Dimakopoulou, K, Samoli, E. Air pollution and Parkinson’s disease: a systematic review and meta-analysis up to 2018. Int J Hyg Environ Health 2019;222:402–9. https://doi.org/10.1016/j.ijheh.2018.12.006.Search in Google Scholar PubMed

173. Salimi, F, Hanigan, I, Jalaludin, B, Guo, Y, Rolfe, M, Heyworth, JS, et al.. Associations between long-term exposure to ambient air pollution and Parkinson’s disease prevalence: a cross-sectional study. Neurochem Int 2020;133:104615. https://doi.org/10.1016/j.neuint.2019.104615.Search in Google Scholar PubMed

174. Jung, C-R, Lin, Y-T, Hwang, B-F. Ozone, particulate matter, and newly diagnosed Alzheimer’s disease: a population-based cohort study in Taiwan. J Alzheimers Dis 2015;44:573–84. https://doi.org/10.3233/jad-140855.Search in Google Scholar PubMed

175. Oudin, A, Forsberg, B, Adolfsson, AN, Lind, N, Modig, L, Nordin, M, et al.. Traffic-related air pollution and dementia incidence in Northern Sweden: a longitudinal study. Environ Health Perspect 2016;124:306–12. https://doi.org/10.1289/ehp.1408322.Search in Google Scholar PubMed PubMed Central

176. Kilian, J, Kitazawa, M. The emerging risk of exposure to air pollution on cognitive decline and Alzheimer’s disease – evidence from epidemiological and animal studies. Biomed J 2018;41:141–62. https://doi.org/10.1016/j.bj.2018.06.001.Search in Google Scholar PubMed PubMed Central

177. Thomson, EM. Air pollution, stress, and Allostatic load: linking systemic and central nervous system impacts. J Alzheimers Dis 2019;69:597–614. https://doi.org/10.3233/jad-190015.Search in Google Scholar

178. Power, MC, Adar, SD, Yanosky, JD, Weuve, J. Exposure to air pollution as a potential contributor to cognitive function, cognitive decline, brain imaging, and dementia: a systematic review of epidemiologic research. Neurotoxicology 2016;56:235–53. https://doi.org/10.1016/j.neuro.2016.06.004.Search in Google Scholar PubMed PubMed Central

179. Erickson, LD, Gale, SD, Anderson, JE, Brown, BL, Hedges, DW. Association between exposure to air pollution and total gray matter and total white matter volumes in adults: a cross-sectional study. Brain Sci 2020;10. https://doi.org/10.3390/brainsci10030164.Search in Google Scholar PubMed PubMed Central

180. Power, MC, Lamichhane, AP, Liao, D, Xu, X, Jack, CR, Gottesman, RF, et al.. The association of long-term exposure to particulate matter air pollution with brain MRI findings: the ARIC study. Environ Health Perspect 2018;126:027009. https://doi.org/10.1289/ehp2152.Search in Google Scholar PubMed PubMed Central

181. Hedges, DW, Erickson, LD, Kunzelman, J, Brown, BL, Gale, SD. Association between exposure to air pollution and hippocampal volume in adults in the UK Biobank. Neurotoxicology 2019;74:108–20. https://doi.org/10.1016/j.neuro.2019.06.005.Search in Google Scholar PubMed

182. Hedges, DW, Erickson, LD, Gale, SD, Anderson, JE, Brown, BL. Association between exposure to air pollution and thalamus volume in adults: a cross-sectional study. PloS One 2020;15:e0230829. https://doi.org/10.1371/journal.pone.0230829.Search in Google Scholar PubMed PubMed Central

183. Gale, SD, Erickson, LD, Anderson, JE, Brown, BL, Hedges, DW. Association between exposure to air pollution and prefrontal cortical volume in adults: a cross-sectional study from the UK biobank. Environ Res 2020;185:109365. https://doi.org/10.1016/j.envres.2020.109365.Search in Google Scholar PubMed

184. Rodriguez-Oroz, MC, Gago, B, Clavero, P, Delgado-Alvarado, M, Garcia-Garcia, D, Jimenez-Urbieta, H. The relationship between atrophy and hypometabolism: is it regionally dependent in dementias? Curr Neurol Neurosci Rep 2015;15:44. https://doi.org/10.1007/s11910-015-0562-0.Search in Google Scholar PubMed

185. Whitwell, JL. Progression of atrophy in Alzheimer’s disease and related disorders. Neurotox Res 2010;18:339–46. https://doi.org/10.1007/s12640-010-9175-1.Search in Google Scholar PubMed

186. Jiménez-Jiménez, FJ, Alonso-Navarro, H, García-Martín, E, Agúndez, JAG. NAT2 polymorphisms and risk for Parkinson’s disease: a systematic review and meta-analysis. Expet Opin Drug Metabol Toxicol 2016;12:937–46. https://doi.org/10.1080/17425255.2016.1192127.Search in Google Scholar PubMed

187. Wang, M, Li, Y, Lin, L, Song, G, Deng, T. GSTM1 null genotype and GSTP1 Ile105Val polymorphism are associated with Alzheimer’s disease: a meta-analysis. Mol Neurobiol 2016;53:1355–64. https://doi.org/10.1007/s12035-015-9092-7.Search in Google Scholar PubMed

188. Cherbuin, N, Walsh, E, Baune, BT, Anstey, KJ. Oxidative stress, inflammation and risk of neurodegeneration in a population sample. Eur J Neurol 2019;26:1347–54. https://doi.org/10.1111/ene.13985.Search in Google Scholar PubMed

189. Wei, Z, Li, X, Li, X, Liu, Q, Cheng, Y. Oxidative stress in Parkinson’s disease: a systematic review and meta-analysis. Front Mol Neurosci 2018;11:236. https://doi.org/10.3389/fnmol.2018.00236.Search in Google Scholar PubMed PubMed Central

190. Haehner, A, Boesveldt, S, Berendse, HW, Mackay-Sim, A, Fleischmann, J, Silburn, PA, et al.. Prevalence of smell loss in Parkinson’s disease – a multicenter study. Park Relat Disord 2009;15:490–4. https://doi.org/10.1016/j.parkreldis.2008.12.005.Search in Google Scholar PubMed

191. Doty, RL. Olfactory dysfunction in Parkinson disease. Nat Rev Neurol 2012;8:329–39. https://doi.org/10.1038/nrneurol.2012.80.Search in Google Scholar PubMed

192. Mesholam, RI, Moberg, PJ, Mahr, RN, Doty, RL. Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases. Arch Neurol 1998;55:84–90. https://doi.org/10.1001/archneur.55.1.84.Search in Google Scholar PubMed

193. Pinto, JM. Olfaction. Proc Am Thorac Soc 2011;8:46–52. https://doi.org/10.1513/pats.201005-035rn.Search in Google Scholar PubMed PubMed Central

194. Dintica, CS, Marseglia, A, Rizzuto, D, Wang, R, Seubert, J, Arfanakis, K, et al.. Impaired olfaction is associated with cognitive decline and neurodegeneration in the brain. Neurology 2019;92:e700–9. https://doi.org/10.1212/wnl.0000000000006919.Search in Google Scholar

195. Hawkes, C. Olfaction in neurodegenerative disorder. Adv Oto-Rhino-Laryngol 2006;63:133–51. https://doi.org/10.1159/000093759.Search in Google Scholar PubMed

196. Marin, C, Vilas, D, Langdon, C, Alobid, I, López-Chacón, M, Haehner, A, et al.. Olfactory dysfunction in neurodegenerative diseases. Curr Allergy Asthma Rep 2018;18:42. https://doi.org/10.1007/s11882-018-0796-4.Search in Google Scholar PubMed

197. Hüttenbrink, K-B, Hummel, T, Berg, D, Gasser, T, Hähner, A. Olfactory dysfunction: common in later life and early warning of neurodegenerative disease. Dtsch Ärztebl Int. 2013;110:1–7. https://doi.org/10.3238/arztebl.2013.0001.Search in Google Scholar PubMed PubMed Central

198. Ross, GW, Petrovitch, H, Abbott, RD, Tanner, CM, Popper, J, Masaki, K, et al.. Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann Neurol 2008;63:167–73. https://doi.org/10.1002/ana.21291.Search in Google Scholar PubMed

199. Duitama, M, Vargas-López, V, Casas, Z, Albarracin, SL, Sutachan, J-J, Torres, YP. TRP channels role in pain associated with neurodegenerative diseases. Front Neurosci 2020;14:782. https://doi.org/10.3389/fnins.2020.00782.Search in Google Scholar PubMed PubMed Central

200. Young Blood, MR, Ferro, MM, Munhoz, RP, Teive, HAG, Camargo, CHF. Classification and characteristics of pain associated with Parkinson’s disease. Park Dis 2016;2016:6067132. https://doi.org/10.1155/2016/6067132.Search in Google Scholar PubMed PubMed Central

201. Pont-Sunyer, C, Hotter, A, Gaig, C, Seppi, K, Compta, Y, Katzenschlager, R, et al.. The onset of nonmotor symptoms in Parkinson’s disease (the ONSET PD study). Mov Disord Off J Mov Disord Soc 2015;30:229–37. https://doi.org/10.1002/mds.26077.Search in Google Scholar PubMed

202. de Tommaso, M, Arendt-Nielsen, L, Defrin, R, Kunz, M, Pickering, G, Valeriani, M. Pain in neurodegenerative disease: current knowledge and future perspectives. Behav Neurol 2016;2016:7576292. https://doi.org/10.1155/2016/7576292.Search in Google Scholar PubMed PubMed Central

203. Rukavina, K, Leta, V, Sportelli, C, Buhidma, Y, Duty, S, Malcangio, M, et al.. Pain in Parkinson’s disease: new concepts in pathogenesis and treatment. Curr Opin Neurol 2019;32:579–88. https://doi.org/10.1097/wco.0000000000000711.Search in Google Scholar

204. Wasner, G, Deuschl, G. Pains in Parkinson disease – many syndromes under one umbrella. Nat Rev Neurol 2012;8:284–94. https://doi.org/10.1038/nrneurol.2012.54.Search in Google Scholar PubMed

205. Mylius, V, Pee, S, Pape, H, Teepker, M, Stamelou, M, Eggert, K, et al.. Experimental pain sensitivity in multiple system atrophy and Parkinson’s disease at an early stage. Eur J Pain Lond Engl 2016;20:1223–8. https://doi.org/10.1002/ejp.846.Search in Google Scholar PubMed

206. Defazio, G, Tinazzi, M, Berardelli, A. How pain arises in Parkinson’s disease? Eur J Neurol 2013;20:1517–23. https://doi.org/10.1111/ene.12260.Search in Google Scholar PubMed

207. Crivelaro do Nascimento, G, Ferrari, DP, Guimaraes, FS, Del Bel, EA, Bortolanza, M, Ferreira-Junior, NC. Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson’s disease. Neuropharmacology 2020;163:107808. https://doi.org/10.1016/j.neuropharm.2019.107808.Search in Google Scholar PubMed

208. Tseng, M-T, Lin, C-H. Pain in early-stage Parkinson’s disease: implications from clinical features to pathophysiology mechanisms. J Formos Med Assoc 2017;116:571–81. https://doi.org/10.1016/j.jfma.2017.04.024.Search in Google Scholar PubMed

209. Weng, H-J, Patel, KN, Jeske, NA, Bierbower, SM, Zou, W, Tiwari, V, et al.. Tmem100 is a regulator of TRPA1-TRPV1 complex and contributes to persistent pain. Neuron 2015;85:833–46. https://doi.org/10.1016/j.neuron.2014.12.065.Search in Google Scholar PubMed PubMed Central

210. Li, M, Zhu, M, Xu, Q, Ding, F, Tian, Y, Zhang, M. Sensation of TRPV1 via 5-hydroxytryptamine signaling modulates pain hypersensitivity in a 6-hydroxydopamine induced mice model of Parkinson’s disease. Biochem Biophys Res Commun 2020;521:868–73. https://doi.org/10.1016/j.bbrc.2019.10.204.Search in Google Scholar PubMed

211. Defrin, R, Amanzio, M, de Tommaso, M, Dimova, V, Filipovic, S, Finn, DP, et al.. Experimental pain processing in individuals with cognitive impairment: current state of the science. Pain 2015;156:1396–408. https://doi.org/10.1097/j.pain.0000000000000195.Search in Google Scholar PubMed

212. Lee, Z-F, Huang, T-H, Chen, S-P, Cheng, IH. Altered nociception in Alzheimer’s disease is associated with STEP signaling. Pain 2021;162:1669–80.10.1097/j.pain.0000000000002180Search in Google Scholar PubMed

213. Zhai, K, Liskova, A, Kubatka, P, Büsselberg, D. Calcium entry through TRPV1: a potential target for the regulation of proliferation and apoptosis in cancerous and healthy cells. Int J Mol Sci 2020;21:4177. https://doi.org/10.3390/ijms21114177.Search in Google Scholar PubMed PubMed Central

214. Caraballo, JC, Borcherding, J, Thorne, PS, Comellas, AP. Protein kinase C–ζ mediates lung injury induced by diesel exhaust particles. Am J Respir Cell Mol Biol 2013;48:306–13. https://doi.org/10.1165/rcmb.2012-0056oc.Search in Google Scholar PubMed PubMed Central

215. Planells-Cases, R, Valente, P, Ferrer-Montiel, A, Qin, F, Szallasi, A. Complex regulation of TRPV1 and related thermo-TRPs: implications for therapeutic intervention. Adv Exp Med Biol 2011;704:491–515. https://doi.org/10.1007/978-94-007-0265-3_27.Search in Google Scholar PubMed

216. Ho, KW, Ward, NJ, Calkins, DJ. TRPV1: a stress response protein in the central nervous system. Am J Neurodegener Dis 2012;1:1–14.Search in Google Scholar

217. Ramírez-Barrantes, R, Córdova, C, Gatica, S, Rodriguez, B, Lozano, C, Marchant, I, et al.. Transient receptor potential vanilloid 1 expression mediates capsaicin-induced cell death. Front Physiol 2018;9:682. https://doi.org/10.3389/fphys.2018.00682.Search in Google Scholar PubMed PubMed Central

218. Gleichmann, M, Mattson, MP. Neuronal calcium homeostasis and dysregulation. Antioxidants Redox Signal 2011;14:1261–73. https://doi.org/10.1089/ars.2010.3386.Search in Google Scholar PubMed PubMed Central

219. Bano, D, Ankarcrona, M. Beyond the critical point: an overview of excitotoxicity, calcium overload and the downstream consequences. Neurosci Lett 2018;663:79–85. https://doi.org/10.1016/j.neulet.2017.08.048.Search in Google Scholar PubMed

220. Khariv, V, Elkabes, S. Contribution of Plasma Membrane Calcium ATPases to neuronal maladaptive responses: focus on spinal nociceptive mechanisms and neurodegeneration. Neurosci Lett 2018;663:60–5. https://doi.org/10.1016/j.neulet.2017.08.003.Search in Google Scholar PubMed

221. Zaidi, A, Adewale, M, McLean, L, Ramlow, P. The plasma membrane calcium pumps-The old and the new. Neurosci Lett 2018;663:12–7. https://doi.org/10.1016/j.neulet.2017.09.066.Search in Google Scholar PubMed

222. Khariv, V, Ni, L, Ratnayake, A, Sampath, S, Lutz, BM, Tao, X-X, et al.. Impaired sensitivity to pain stimuli in plasma membrane calcium ATPase 2 (PMCA2) heterozygous mice: a possible modality- and sex-specific role for PMCA2 in nociception. FASEB J 2017;31:224–37. https://doi.org/10.1096/fj.201600541r.Search in Google Scholar

223. Anjum, I, Jaffery, SS, Fayyaz, M, Samoo, Z, Anjum, S. The role of vitamin D in brain health: a mini literature review. Cureus 2018;10:e2960. https://doi.org/10.7759/cureus.2960.Search in Google Scholar PubMed PubMed Central

224. Sempos, CT, Heijboer, AC, Bikle, DD, Bollerslev, J, Bouillon, R, Brannon, PM, et al.. Vitamin D assays and the definition of hypovitaminosis D: results from the first international conference on controversies in vitamin D. Br J Clin Pharmacol 2018;84;2194–207. https://doi.org/10.1111/bcp.13652.Search in Google Scholar PubMed PubMed Central

225. Zhou, Z, Zhou, R, Zhang, Z, Li, K. The association between vitamin D status, vitamin D supplementation, sunlight exposure, and Parkinson’s disease: a systematic review and meta-analysis. Med Sci Mon Int Med J Exp Clin Res 2019;25:666–74. https://doi.org/10.12659/msm.912840.Search in Google Scholar

226. Chai, B, Gao, F, Wu, R, Dong, T, Gu, C, Lin, Q, et al.. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol 2019;19:284. https://doi.org/10.1186/s12883-019-1500-6.Search in Google Scholar PubMed PubMed Central

227. Yong, WC, Sanguankeo, A, Upala, S. Effect of vitamin D supplementation in chronic widespread pain: a systematic review and meta-analysis. Clin Rheumatol 2017;36:2825–33. https://doi.org/10.1007/s10067-017-3754-y.Search in Google Scholar PubMed

228. Long, W, Fatehi, M, Soni, S, Panigrahi, R, Philippaert, K, Yu, Y, et al.. Vitamin D is an endogenous partial agonist of the transient receptor potential vanilloid 1 channel. J Physiol 2020;598:4321–38. https://doi.org/10.1113/jp279961.Search in Google Scholar

229. Bhave, G, Hu, H-J, Glauner, KS, Zhu, W, Wang, H, Brasier, DJ, et al.. Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Proc Natl Acad Sci U S A 2003;100:12480–5. https://doi.org/10.1073/pnas.2032100100.Search in Google Scholar PubMed PubMed Central

230. Callender, JA, Newton, AC. Conventional protein kinase C in the brain: 40 years later. Neuronal Signal 2017;1. https://doi.org/10.1042/NS20160005.Search in Google Scholar PubMed PubMed Central

231. Tripathy, B, Majhi, RK. TRPV1 channel as the membrane vitamin D receptor: solving part of the puzzle. J Physiol 2020;598:5601–3. https://doi.org/10.1113/jp280633.Search in Google Scholar PubMed

232. Wong, J, Magun, BE, Wood, LJ. Lung inflammation caused by inhaled toxicants: a review. Int J Chronic Obstr Pulm Dis 2016;11:1391–401. https://doi.org/10.2147/copd.s106009.Search in Google Scholar PubMed PubMed Central

233. Yan, Z, Jin, Y, An, Z, Liu, Y, Samet, JM, Wu, W. Inflammatory cell signaling following exposures to particulate matter and ozone. Biochim Biophys Acta 2016;1860:2826–34. https://doi.org/10.1016/j.bbagen.2016.03.030.Search in Google Scholar PubMed

234. Kodavanti, PRS. Cell signaling and neurotoxicity: protein kinase C in vitro and in vivo. Methods Mol Biol 2011;758:307–19. https://doi.org/10.1007/978-1-61779-170-3_21.Search in Google Scholar PubMed

235. Chico, LK, Van Eldik, LJ, Watterson, DM. Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov 2009;8:892–909. https://doi.org/10.1038/nrd2999.Search in Google Scholar PubMed PubMed Central

236. Manning, G, Whyte, DB, Martinez, R, Hunter, T, Sudarsanam, S. The protein kinase complement of the human genome. Science 2002;298:1912–34. https://doi.org/10.1126/science.1075762.Search in Google Scholar PubMed

237. Krahn, AI, Wells, C, Drewry, DH, Beitel, LK, Durcan, TM, Axtman, AD. Defining the neural kinome: strategies and opportunities for small molecule drug discovery to target neurodegenerative diseases. ACS Chem Neurosci 2020;11:1871–86. https://doi.org/10.1021/acschemneuro.0c00176.Search in Google Scholar PubMed

238. Sikand, P, Premkumar, LS. Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse. J Physiol 2007;581:631–47. https://doi.org/10.1113/jphysiol.2006.118620.Search in Google Scholar PubMed PubMed Central

239. Koda, K, Hyakkoku, K, Ogawa, K, Takasu, K, Imai, S, Sakurai, Y, et al.. Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain. Osteoarthritis Cartilage 2016;24:1254–62. https://doi.org/10.1016/j.joca.2016.02.010.Search in Google Scholar PubMed

240. Ji, R-R, Samad, TA, Jin, S-X, Schmoll, R, Woolf, CJ. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 2002;36:57–68. https://doi.org/10.1016/s0896-6273(02)00908-x.Search in Google Scholar PubMed

241. Meents, JE, Fischer, MJM, McNaughton, PA. Sensitization of TRPA1 by Protein Kinase A. Obukhov AG, editor. PLoS One 2017;12: e0170097. https://doi.org/10.1371/journal.pone.0170097.Search in Google Scholar PubMed PubMed Central

242. Koltzenburg, M. The role of TRP channels in sensory neurons. Novartis Found Symp 2004;260:206–13.10.1002/0470867639.ch14Search in Google Scholar

243. Staud, R, Smitherman, ML. Peripheral and central sensitization in fibromyalgia: pathogenetic role. Curr Pain Headache Rep 2002;6:259–66. https://doi.org/10.1007/s11916-002-0046-1.Search in Google Scholar PubMed

244. Mandadi, S, Roufogalis, BD. ThermoTRP channels in nociceptors: taking a lead from capsaicin receptor TRPV1. Curr Neuropharmacol 2008;6:21–38. https://doi.org/10.2174/157015908783769680.Search in Google Scholar PubMed PubMed Central

245. Latremoliere, A, Woolf, CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain Off J Am Pain Soc 2009;10:895–926. https://doi.org/10.1016/j.jpain.2009.06.012.Search in Google Scholar PubMed PubMed Central

246. IASP terminology – IASP. Available from: https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698#Centralsensitization [Accessed 21 Nov 2020].Search in Google Scholar

247. den Boer, C, Dries, L, Terluin, B, van der Wouden, JC, Blankenstein, AH, van Wilgen, CP, et al.. Central sensitization in chronic pain and medically unexplained symptom research: a systematic review of definitions, operationalizations and measurement instruments. J Psychosom Res 2019;117:32–40. https://doi.org/10.1016/j.jpsychores.2018.12.010.Search in Google Scholar PubMed

248. Fleming, KC, Volcheck, MM. Central sensitization syndrome and the initial evaluation of a patient with fibromyalgia: a review. Rambam Maimonides Med J 2015;6:e0020. https://doi.org/10.5041/rmmj.10204.Search in Google Scholar

249. Bourke, JH, Langford, RM, White, PD. The common link between functional somatic syndromes may be central sensitisation. J Psychosom Res 2015;78:228–36. https://doi.org/10.1016/j.jpsychores.2015.01.003.Search in Google Scholar PubMed

250. Dixon, EA, Benham, G, Sturgeon, JA, Mackey, S, Johnson, KA, Younger, J. Development of the Sensory Hypersensitivity Scale (SHS): a self-report tool for assessing sensitivity to sensory stimuli. J Behav Med 2016;39:537–50. https://doi.org/10.1007/s10865-016-9720-3.Search in Google Scholar PubMed PubMed Central

251. Yang, A, Wang, H, Zuo, X, Yang, J. Potassium chloride cotransporter 2 inhibits neuropathic pain and future development of neurodegeneration. J Alzheimers Dis 2020;74:875–81. https://doi.org/10.3233/jad-200027.Search in Google Scholar

252. Zengin-Toktas, Y, Ferrier, J, Durif, F, Llorca, P-M, Authier, N. Bilateral lesions of the nigrostriatal pathways are associated with chronic mechanical pain hypersensitivity in rats. Neurosci Res 2013;76:261–4. https://doi.org/10.1016/j.neures.2013.05.003.Search in Google Scholar PubMed

253. Steinemann, A. National prevalence and effects of multiple chemical sensitivities. J Occup Environ Med 2018;60:e152–6. https://doi.org/10.1097/jom.0000000000001272.Search in Google Scholar

254. Dantoft, TM, Andersson, L, Nordin, S, Skovbjerg, S. Chemical intolerance. Curr Rheumatol Rev 2015;11:167–84. https://doi.org/10.2174/157339711102150702111101.Search in Google Scholar PubMed

255. Haines, J, Chua, SHK, Smith, J, Slinger, C, Simpson, AJ, Fowler, SJ. Triggers of breathlessness in inducible laryngeal obstruction and asthma. Clin Exp Allergy J Br Soc Allergy Clin Immunol 2020;50:1230–7. https://doi.org/10.1111/cea.13715.Search in Google Scholar PubMed

256. Silva-Néto, RP, Peres, MFP, Valença, MM. Odorant substances that trigger headaches in migraine patients. Cephalalgia Int J Headache 2014;34:14–21. https://doi.org/10.1177/0333102413495969.Search in Google Scholar PubMed

257. Sayyah, M, Saki-Malehi, A, Javanmardi, F, Forouzan, A, Shirbandi, K, Rahim, F. Which came first, the risk of migraine or the risk of asthma? A systematic review. Neurol Neurochir Pol 2018;52:562–9. https://doi.org/10.1016/j.pjnns.2018.07.004.Search in Google Scholar PubMed

258. Guarnieri, M, Balmes, JR. Outdoor air pollution and asthma. Lancet 2014;383:1581–92. https://doi.org/10.1016/s0140-6736(14)60617-6.Search in Google Scholar PubMed PubMed Central

259. Lee, H, Myung, W, Cheong, H-K, Yi, S-M, Hong, Y-C, Cho, S-I, et al.. Ambient air pollution exposure and risk of migraine: synergistic effect with high temperature. Environ Int 2018;121:383–91. https://doi.org/10.1016/j.envint.2018.09.022.Search in Google Scholar PubMed

260. Benemei, S, Dussor, G. TRP channels and migraine: recent developments and new therapeutic opportunities. Pharm Basel Switz 2019;12. https://doi.org/10.3390/ph12020054.Search in Google Scholar PubMed PubMed Central

261. Xu, M, Zhang, Y, Wang, M, Zhang, H, Chen, Y, Adcock, IM, et al.. TRPV1 and TRPA1 in lung inflammation and airway hyperresponsiveness induced by fine particulate matter (PM2.5). Oxid Med Cell Longev 2019;2019:7450151. https://doi.org/10.1155/2019/7450151.Search in Google Scholar PubMed PubMed Central

262. McKeown-Eyssen, GE, Baines, CJ, Marshall, LM, Jazmaji, V, Sokoloff, ER. Multiple chemical sensitivity: discriminant validity of case definitions. Arch Environ Health 2001;56:406–12. https://doi.org/10.1080/00039890109604475.Search in Google Scholar PubMed

263. Cullen, MR. The worker with multiple chemical sensitivities: an overview. Occup Med Phila Pa 1987;2:655–61.Search in Google Scholar

264. Multiple chemical sensitivity: a 1999 consensus. Arch Environ Health. 1999;54:147–9. https://doi.org/10.1080/00039899909602251.Search in Google Scholar PubMed

265. McKeown-Eyssen, GE, Sokoloff, ER, Jazmaji, V, Marshall, LM, Baines, CJ. Reproducibility of the University of Toronto self-administered questionnaire used to assess environmental sensitivity. Am J Epidemiol 2000;151:1216–22. https://doi.org/10.1093/oxfordjournals.aje.a010172.Search in Google Scholar PubMed

266. Lacour, M, Zunder, T, Schmidtke, K, Vaith, P, Scheidt, C. Multiple chemical sensitivity syndrome (MCS) – suggestions for an extension of the US MCS-case definition. Int J Hyg Environ Health 2005;208:141–51. https://doi.org/10.1016/j.ijheh.2005.01.017.Search in Google Scholar PubMed

267. McKeown-Eyssen, G, Baines, C, Cole, DEC, Riley, N, Tyndale, RF, Marshall, L, et al.. Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR. Int J Epidemiol 2004;33:971–8. https://doi.org/10.1093/ije/dyh251.Search in Google Scholar PubMed

268. Schnakenberg, E, Fabig, K-R, Stanulla, M, Strobl, N, Lustig, M, Fabig, N, et al.. A cross-sectional study of self-reported chemical-related sensitivity is associated with gene variants of drug-metabolizing enzymes. Environ Health Glob Access Sci Source 2007;6:6. https://doi.org/10.1186/1476-069x-6-6.Search in Google Scholar PubMed PubMed Central

269. La Du, BN, Billecke, S, Hsu, C, Haley, RW, Broomfield, CA. Serum paraoxonase (PON1) isozymes: the quantitative analysis of isozymes affecting individual sensitivity to environmental chemicals. Drug Metab Dispos Biol Fate Chem 2001;29:566–9.Search in Google Scholar

270. Furlong, CE, Cole, TB, Jarvik, GP, Pettan-Brewer, C, Geiss, GK, Richter, RJ, et al.. Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants. Neurotoxicology 2005;26:651–9. https://doi.org/10.1016/j.neuro.2004.08.002.Search in Google Scholar PubMed

271. Caccamo, D, Cesareo, E, Mariani, S, Raskovic, D, Ientile, R, Currò, M, et al.. Xenobiotic sensor- and metabolism-related gene variants in environmental sensitivity-related illnesses: a survey on the Italian population. Oxid Med Cell Longev 2013;2013:831969. https://doi.org/10.1155/2013/831969.Search in Google Scholar PubMed PubMed Central

272. Cui, X, Lu, X, Hiura, M, Oda, M, Miyazaki, W, Katoh, T. Evaluation of genetic polymorphisms in patients with multiple chemical sensitivity. Pant AB, editor. PLoS One 2013;8:e73708. https://doi.org/10.1371/journal.pone.0073708.Search in Google Scholar PubMed PubMed Central

273. Berg, ND, Berg Rasmussen, H, Linneberg, A, Brasch-Andersen, C, Fenger, M, Dirksen, A, et al.. Genetic susceptibility factors for multiple chemical sensitivity revisited. Int J Hyg Environ Health 2010;213:131–9. https://doi.org/10.1016/j.ijheh.2010.02.001.Search in Google Scholar PubMed

274. Fujimori, S, Hiura, M, Yi, CX, Xi, L, Katoh, T. Factors in genetic susceptibility in a chemical sensitive population using QEESI. Environ Health Prev Med 2012;17:357–63. https://doi.org/10.1007/s12199-011-0260-8.Search in Google Scholar PubMed PubMed Central

275. Micarelli, A, Cormano, A, Caccamo, D, Alessandrini, M. Olfactory-related quality of life in multiple chemical sensitivity: a genetic-acquired factors model. Int J Mol Sci 2019;21. https://doi.org/10.3390/ijms21010156.Search in Google Scholar PubMed PubMed Central

276. De Luca, C, Scordo, MG, Cesareo, E, Pastore, S, Mariani, S, Maiani, G, et al.. Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes. Toxicol Appl Pharmacol 2010;248:285–92. https://doi.org/10.1016/j.taap.2010.04.017.Search in Google Scholar PubMed

277. Gugliandolo, A, Gangemi, C, Calabrò, C, Vecchio, M, Di Mauro, D, Renis, M, et al.. Assessment of glutathione peroxidase-1 polymorphisms, oxidative stress and DNA damage in sensitivity-related illnesses. Life Sci 2016;145:27–33. https://doi.org/10.1016/j.lfs.2015.12.028.Search in Google Scholar PubMed

278. Belpomme, D, Campagnac, C, Irigaray, P. Reliable disease biomarkers characterizing and identifying electrohypersensitivity and multiple chemical sensitivity as two etiopathogenic aspects of a unique pathological disorder. Rev Environ Health 2015;30:251–71. https://doi.org/10.1515/reveh-2015-0027.Search in Google Scholar PubMed

279. Miller, CS. Toxicant-induced loss of tolerance. Addiction 2001;96:115–37. https://doi.org/10.1046/j.1360-0443.2001.9611159.x.Search in Google Scholar PubMed

280. Ross, GH. Clinical characteristics of chemical sensitivity: an illustrative case history of asthma and MCS. Environ Health Perspect 1997;105:437–41. https://doi.org/10.2307/3433349.Search in Google Scholar

281. Chemical Exposures: Low Levels and High Stakes, 2nd ed. Wiley. Available from: https://www.wiley.com/en-us/Chemical+Exposures%3A+Low+Levels+and+High+Stakes%2C+2nd+Edition-p-9780471292401, https://www.Wiley.com, [Accessed 7 Dec 2020].Search in Google Scholar

282. Hojo, S, Ishikawa, S, Kumano, H, Miyata, M, Sakabe, K. Clinical characteristics of physician-diagnosed patients with multiple chemical sensitivity in Japan. Int J Hyg Environ Health 2008;211:682–9. https://doi.org/10.1016/j.ijheh.2007.09.007.Search in Google Scholar PubMed

283. Miller, CS, Prihoda, TJ. A controlled comparison of symptoms and chemical intolerances reported by Gulf War veterans, implant recipients and persons with multiple chemical sensitivity. Toxicol Ind Health 1999;15:386–97. https://doi.org/10.1177/074823379901500312.Search in Google Scholar PubMed

284. Millqvist, E. Cough provocation with capsaicin is an objective way to test sensory hyperreactivity in patients with asthma-like symptoms. Allergy 2000;55:546–50. https://doi.org/10.1111/j.1398-9995.2000.all2513.x.Search in Google Scholar

285. Cone, JE, Harrison, R, Reiter, R. Patients with multiple chemical sensitivities: clinical diagnostic subsets among an occupational health clinic population. Occup Med Phila Pa 1987;2:721–38.Search in Google Scholar

286. Cullen, MR, Pace, PE, Redlich, CA. The experience of the Yale occupational and environmental medicine clinics with multiple chemical sensitivities, 1986–1991. Toxicol Ind Health 1992;8:15–9. https://doi.org/10.1177/074823379200800402.Search in Google Scholar

287. Simon, GE. Epidemic multiple chemical sensitivity in an industrial setting. Toxicol Ind Health 1992;8:41–6. https://doi.org/10.1177/074823379200800405.Search in Google Scholar

288. Nethercott, JR, Davidoff, LL, Curbow, B, Abbey, H. Multiple chemical sensitivities syndrome: toward a working case definition. Arch Environ Health 1993;48:19–26. https://doi.org/10.1080/00039896.1993.9938389.Search in Google Scholar PubMed

289. Lax, MB, Henneberger, PK. Patients with multiple chemical sensitivities in an occupational health clinic: presentation and follow-up. Arch Environ Health 1995;50:425–31. https://doi.org/10.1080/00039896.1995.9935978.Search in Google Scholar PubMed

290. Davidoff, AL, Keyl, PM. Symptoms and health status in individuals with multiple chemical sensitivities syndrome from four reported sensitizing exposures and a general population comparison group. Arch Environ Health 1996;51:201–13. https://doi.org/10.1080/00039896.1996.9936017.Search in Google Scholar PubMed

291. Conway, SJ. TRPing the switch on pain: an introduction to the chemistry and biology of capsaicin and TRPV1. Chem Soc Rev 2008;37:1530–45. https://doi.org/10.1039/b610226n.Search in Google Scholar PubMed

292. Caterina, MJ, Schumacher, MA, Tominaga, M, Rosen, TA, Levine, JD, Julius, D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389:816–24. https://doi.org/10.1038/39807.Search in Google Scholar PubMed

293. Dicpinigaitis, PV. Short- and long-term reproducibility of capsaicin cough challenge testing. Pulm Pharmacol Therapeut 2003;16:61–5. https://doi.org/10.1016/s1094-5539(02)00149-9.Search in Google Scholar

294. Banner, KH, Igney, F, Poll, C. TRP channels: emerging targets for respiratory disease. Pharmacol Ther 2011;130:371–84. https://doi.org/10.1016/j.pharmthera.2011.03.005.Search in Google Scholar PubMed

295. Millqvist, E. TRP channels and temperature in airway disease-clinical significance. Temperature 2015;2:172–7. https://doi.org/10.1080/23328940.2015.1012979.Search in Google Scholar PubMed PubMed Central

296. Dicpinigaitis, PV. Review: effect of drugs on human cough reflex sensitivity to inhaled capsaicin. Cough 2012;8:10. https://doi.org/10.1186/1745-9974-8-10.Search in Google Scholar PubMed PubMed Central

297. Millqvist, E, Löwhagen, O. Placebo-controlled challenges with perfume in patients with asthma-like symptoms. Allergy 1996;51:434–9. https://doi.org/10.1111/j.1398-9995.1996.tb04644.x.Search in Google Scholar PubMed

298. Millqvist, E, Bende, M, Löwhagen, O. Sensory hyperreactivity – a possible mechanism underlying cough and asthma-like symptoms. Allergy 1998;53:1208–12. https://doi.org/10.1111/j.1398-9995.1998.tb03843.x.Search in Google Scholar PubMed

299. Millqvist, E, Löwhagen, O, Bende, M. Quality of life and capsaicin sensitivity in patients with sensory airway hyperreactivity. Allergy 2000;55:540–5. https://doi.org/10.1034/j.1398-9995.2000.00514.x.Search in Google Scholar PubMed

300. Ternesten-Hasséus, E, Bende, M, Millqvist, E. Increased capsaicin cough sensitivity in patients with multiple chemical sensitivity. J Occup Environ Med 2002;44:1012–7. https://doi.org/10.1097/00043764-200211000-00006.Search in Google Scholar PubMed

301. Millqvist, E, Ternesten-Hasséus, E, Ståhl, A, Bende, M. Changes in levels of nerve growth factor in nasal secretions after capsaicin inhalation in patients with airway symptoms from scents and chemicals. Environ Health Perspect 2005;113:849–52. https://doi.org/10.1289/ehp.7657.Search in Google Scholar PubMed PubMed Central

302. Ternesten-Hasséus, E, Johansson, K, Löwhagen, O, Millqvist, E. Inhalation method determines outcome of capsaicin inhalation in patients with chronic cough due to sensory hyperreactivity. Pulm Pharmacol Therapeut 2006;19:172–8. https://doi.org/10.1016/j.pupt.2005.04.010.Search in Google Scholar PubMed

303. Millqvist, E, Ternesten-Hasséus, E, Bende, M. Inhaled ethanol potentiates the cough response to capsaicin in patients with airway sensory hyperreactivity. Pulm Pharmacol Therapeut 2008;21:794–7. https://doi.org/10.1016/j.pupt.2008.06.002.Search in Google Scholar PubMed

304. Ternesten-Hasséus, E, Lowhagen, O, Millqvist, E. Quality of life and capsaicin sensitivity in patients with airway symptoms induced by chemicals and scents: a longitudinal study. Environ Health Perspect 2007;115:425–9. https://doi.org/10.1289/ehp.9624.Search in Google Scholar PubMed PubMed Central

305. Ternesten-Hasséus, E. Long-term follow-up in patients with airway chemical intolerance. J Occup Environ Med 2016;58:421–6. https://doi.org/10.1097/jom.0000000000000695.Search in Google Scholar PubMed

306. Holst, H, Arendt-Nielsen, L, Mosbech, H, Vesterhauge, S, Elberling, J. The capsaicin cough reflex in patients with symptoms eliAccessed by odorous chemicals. Int J Hyg Environ Health 2010;213:66–71. https://doi.org/10.1016/j.ijheh.2009.08.005.Search in Google Scholar PubMed

307. Nogami, H, Odajima, H, Shoji, S, Shimoda, T, Nishima, S. Capsaicin provocation test as a diagnostic method for determining multiple chemical sensitivity. Allergol Int 2004;53:153–7. https://doi.org/10.1111/j.1440-1592.2004.00317.x.Search in Google Scholar

308. Claeson, A-S, Andersson, L. Symptoms from masked acrolein exposure suggest altered trigeminal reactivity in chemical intolerance. NeuroToxicology 2017;60:92–8. https://doi.org/10.1016/j.neuro.2017.03.007.Search in Google Scholar PubMed

309. Miller, CS, Mitzel, HC. Chemical sensitivity attributed to pesticide exposure versus remodeling. Arch Environ Health 1995;50:119–29. https://doi.org/10.1080/00039896.1995.9940889.Search in Google Scholar PubMed

310. Doty, RL, Deems, DA, Frye, RE, Pelberg, R, Shapiro, A. Olfactory sensitivity, nasal resistance, and autonomic function in patients with multiple chemical sensitivities. Arch Otolaryngol Head Neck Surg 1988;114:1422–7. https://doi.org/10.1001/archotol.1988.01860240072027.Search in Google Scholar PubMed

311. Fernandez, M, Bell, IR, Schwartz, GE. EEG sensitization during chemical exposure in women with and without chemical sensitivity of unknown etiology. Toxicol Ind Health 1999;15:305–12. https://doi.org/10.1191/074823399678846835.Search in Google Scholar

312. Dalton, P, Hummel, T. Chemosensory function and response in idiopathic environmental intolerance. Occup Med Phila Pa 2000;15:539–56.Search in Google Scholar

313. Osterberg, K, Orbaek, P, Karlson, B, Akesson, B, Bergendorf, U. Annoyance and performance during the experimental chemical challenge of subjects with multiple chemical sensitivity. Scand J Work Environ Health 2003;29:40–50. https://doi.org/10.5271/sjweh.703.Search in Google Scholar

314. Hillert, L, Musabasic, V, Berglund, H, Ciumas, C, Savic, I. Odor processing in multiple chemical sensitivity. Hum Brain Mapp 2007;28:172–82. https://doi.org/10.1002/hbm.20266.Search in Google Scholar PubMed PubMed Central

315. Doty, RL. Olfaction and multiple chemical sensitivity. Toxicol Ind Health 1994;10:359–68. https://doi.org/10.1177/074823379401000510.Search in Google Scholar

316. Nordin, S, Martinkauppi, M, Olofsson, J, Hummel, T, Millqvist, E, Bende, M. Chemosensory perception and event-related potentials in self-reported chemical hypersensitivity. Int J Psychophysiol 2005;55:243–55. https://doi.org/10.1016/j.ijpsycho.2004.08.003.Search in Google Scholar PubMed

317. Caccappolo, E, Kipen, H, Kelly-McNeil, K, Knasko, S, Hamer, RM, Natelson, B, et al.. Odor perception: multiple chemical sensitivities, chronic fatigue, and asthma. J Occup Environ Med 2000;42:629–38. https://doi.org/10.1097/00043764-200006000-00012.Search in Google Scholar PubMed

318. Azuma, K, Uchiyama, I, Tanigawa, M, Bamba, I, Azuma, M, Takano, H, et al.. Association of odor thresholds and responses in cerebral blood flow of the prefrontal area during olfactory stimulation in patients with multiple chemical sensitivity. Matsunami H, editor. PLoS One 2016;11:e0168006. https://doi.org/10.1371/journal.pone.0168006.Search in Google Scholar PubMed PubMed Central

319. Frasnelli, J, Schuster, B, Hummel, T. Interactions between olfaction and the trigeminal system: what can be learned from olfactory loss. Cerebr Cortex 2007;17:2268–75. https://doi.org/10.1093/cercor/bhl135.Search in Google Scholar PubMed

320. Boukalova, S, Touska, F, Marsakova, L, Hynkova, A, Sura, L, Chvojka, S, et al.. Gain-of-function mutations in the transient receptor potential channels TRPV1 and TRPA1: how painful? Physiol Res 2014;63:S205–13. https://doi.org/10.33549/physiolres.932658.Search in Google Scholar PubMed

321. Brand, G. Olfactory/trigeminal interactions in nasal chemoreception. Neurosci Biobehav Rev 2006;30:908–17. https://doi.org/10.1016/j.neubiorev.2006.01.002.Search in Google Scholar PubMed

322. Boyle, JA, Frasnelli, J, Gerber, J, Heinke, M, Hummel, T. Cross-modal integration of intranasal stimuli: a functional magnetic resonance imaging study. Neuroscience 2007;149:223–31. https://doi.org/10.1016/j.neuroscience.2007.06.045.Search in Google Scholar PubMed

323. Das-Munshi, J, Rubin, GJ, Wessely, S. Multiple chemical sensitivities: a systematic review of provocation studies. J Allergy Clin Immunol 2006;118:1257–64. https://doi.org/10.1016/j.jaci.2006.07.046.Search in Google Scholar PubMed

324. Joffres, MR, Sampalli, T, Fox, RA. Physiologic and symptomatic responses to low-level substances in individuals with and without chemical sensitivities: a randomized controlled blinded pilot booth study. Environ Health Perspect 2005;113:1178–83. https://doi.org/10.1289/ehp.7198.Search in Google Scholar PubMed PubMed Central

325. Berg, ND, Linneberg, A, Dirksen, A, Elberling, J. Phenotypes of individuals affected by airborne chemicals in the general population. Int Arch Occup Environ Health 2009;82:509–17. https://doi.org/10.1007/s00420-008-0352-y.Search in Google Scholar PubMed

326. Orriols, R, Costa, R, Cuberas, G, Jacas, C, Castell, J, Sunyer, J. Brain dysfunction in multiple chemical sensitivity. J Neurol Sci 2009;287:72–8. https://doi.org/10.1016/j.jns.2009.09.003.Search in Google Scholar PubMed

327. Simon, TR, Hickey, DC, Fincher, CE, Johnson, AR, Ross, GH, Rea, WJ. Single photon emission computed tomography of the brain in patients with chemical sensitivities. Toxicol Ind Health 1994;10:573–7. https://doi.org/10.1177/074823379401000526.Search in Google Scholar

328. Ross, GH, Rea, WJ, Johnson, AR, Hickey, DC, Simon, TR. Neurotoxicity in single photon emission computed tomography brain scans of patients reporting chemical sensitivities. Toxicol Ind Health 1999;15:415–20. https://doi.org/10.1191/074823399678846853.Search in Google Scholar

329. Heuser, G, Wu, JC. Deep subcortical (including limbic) hypermetabolism in patients with chemical intolerance: human PET studies. Ann N Y Acad Sci 2001;933:319–22. https://doi.org/10.1111/j.1749-6632.2001.tb05835.x.Search in Google Scholar PubMed

330. Bornschein, S, Hausteiner, C, Drzezga, A, Theml, T, Heldmann, B, Grimmer, T, et al.. Neuropsychological and positron emission tomography correlates in idiopathic environmental intolerances. Scand J Work Environ Health 2007;33:447–53. https://doi.org/10.5271/sjweh.1164.Search in Google Scholar PubMed

331. Hillert, L, Jovanovic, H, Åhs, F, Savic, I. Women with multiple chemical sensitivity have increased harm Avoidance and reduced 5-HT1A receptor binding potential in the anterior cingulate and amygdala. Herholz K, editor, PLoS One 2013;8:e54781. https://doi.org/10.1371/journal.pone.0054781.Search in Google Scholar PubMed PubMed Central

332. Chiaravalloti, A, Pagani, M, Micarelli, A, Di Pietro, B, Genovesi, G, Alessandrini, M, et al.. Cortical activity during olfactory stimulation in multiple chemical sensitivity: a 18F-FDG PET/CT study. Eur J Nucl Med Mol Imag 2015;42:733–40. https://doi.org/10.1007/s00259-014-2969-2.Search in Google Scholar PubMed

333. Azuma, K, Uchiyama, I, Tanigawa, M, Bamba, I, Azuma, M, Takano, H, et al.. Assessment of cerebral blood flow in patients with multiple chemical sensitivity using near-infrared spectroscopy—recovery after olfactory stimulation: a case–control study. Environ Health Prev Med 2015;20:185–94. https://doi.org/10.1007/s12199-015-0448-4.Search in Google Scholar PubMed PubMed Central

334. Azuma, K, Uchiyama, I, Takano, H, Tanigawa, M, Azuma, M, Bamba, I, et al.. Changes in cerebral blood flow during olfactory stimulation in patients with multiple chemical sensitivity: a multi-channel near-infrared spectroscopic study. PloS One 2013;8:e80567. https://doi.org/10.1371/journal.pone.0080567.Search in Google Scholar PubMed PubMed Central

335. Miki, T, Inoue, Y, Miyajima, E, Kudo, Y, Tsunoda, M, Kan, S, et al.. Enhanced brain images in the limbic system by functional magnetic resonance imaging (fMRI) during chemical exposures to patients with multiple chemical sensitivities. Kitasato Med J 2010;40:27–34.Search in Google Scholar

336. Andersson, L, Claeson, A-S, Nyberg, L, Stenberg, B, Nordin, S. Brain responses to olfactory and trigeminal exposure in idiopathic environmental illness (IEI) attributed to smells — an fMRI study. J Psychosom Res 2014;77:401–8. https://doi.org/10.1016/j.jpsychores.2014.09.014.Search in Google Scholar PubMed

337. Andersson, L, Claeson, A-S, Nyberg, L, Nordin, S. Short-term olfactory sensitization involves brain networks relevant for pain, and indicates chemical intolerance. Int J Hyg Environ Health 2017;220:503–9. https://doi.org/10.1016/j.ijheh.2017.02.002.Search in Google Scholar PubMed

338. Viziano, A, Micarelli, A, Pasquantonio, G, Della-Morte, D, Alessandrini, M. Perspectives on multisensory perception disruption in idiopathic environmental intolerance: a systematic review. Int Arch Occup Environ Health 2018;91:923–35. https://doi.org/10.1007/s00420-018-1346-z.Search in Google Scholar PubMed

339. Azuma, K, Uchiyama, I, Tanigawa, M, Bamba, I, Azuma, M, Takano, H, et al.. Chemical intolerance: involvement of brain function and networks after exposure to extrinsic stimuli perceived as hazardous. Environ Health Prev Med 2019;24:61. https://doi.org/10.1186/s12199-019-0816-6.Search in Google Scholar PubMed PubMed Central

340. Andersson, L, Nordin, S, Millqvist, E, Bende, M. On the relation between capsaicin sensitivity and responsiveness to CO2: detection sensitivity and event-related brain potentials. Int Arch Occup Environ Health 2009;82:285–90. https://doi.org/10.1007/s00420-008-0333-1.Search in Google Scholar PubMed

341. Poonai, N, Antony, MM, Binkley, KE, Stenn, P, Swinson, RP, Corey, P, et al.. Carbon dioxide inhalation challenges in idiopathic environmental intolerance. J Allergy Clin Immunol 2000;105:358–63. https://doi.org/10.1016/s0091-6749(00)90088-5.Search in Google Scholar PubMed

342. Tran, MTD, Arendt-Nielsen, L, Kupers, R, Elberling, J. Multiple chemical sensitivity: on the scent of central sensitization. Int J Hyg Environ Health 2013;216:202–10. https://doi.org/10.1016/j.ijheh.2012.02.010.Search in Google Scholar PubMed

343. Lavergne, MR, Cole, DC, Kerr, K, Marshall, LM. Functional impairment in chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity. Can Fam Physician Med Fam Can 2010;56:e57–65.Search in Google Scholar

344. Aaron, LA, Buchwald, D. Chronic diffuse musculoskeletal pain, fibromyalgia and co-morbid unexplained clinical conditions. Best Pract Res Clin Rheumatol 2003;17:563–74. https://doi.org/10.1016/s1521-6942(03)00033-0.Search in Google Scholar PubMed

345. Holst, H, Arendt-Nielsen, L, Mosbech, H, Elberling, J. Increased capsaicin-induced secondary hyperalgesia in patients with multiple chemical sensitivity. Clin J Pain 2011;27:156–62. https://doi.org/10.1097/ajp.0b013e3181f9d60c.Search in Google Scholar PubMed

346. Government of Canada, SC. Canadian community health survey (CCHS) – 2016. 2015. Available from: https://www23.statcan.gc.ca/imdb/p3Instr.pl?Function=assembleInstr&lang=en&Item_Id=260675 [Accessed 17 Jan 2021].Search in Google Scholar

347. Mori, F, Ribolsi, M, Kusayanagi, H, Monteleone, F, Mantovani, V, Buttari, F, et al.. TRPV1 channels regulate cortical excitability in humans. J Neurosci 2012;32:873–9. https://doi.org/10.1523/jneurosci.2531-11.2012.Search in Google Scholar

348. Xu, H, Tian, W, Fu, Y, Oyama, TT, Anderson, S, Cohen, DM. Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Am J Physiol Ren Physiol 2007;293:F1865–76. https://doi.org/10.1152/ajprenal.00347.2007.Search in Google Scholar PubMed

349. Vanden Abeele, F, Lotteau, S, Ducreux, S, Dubois, C, Monnier, N, Hanna, A, et al.. TRPV1 variants impair intracellular Ca2+ signaling and may confer susceptibility to malignant hyperthermia. Genet Med 2019;21:441–50. https://doi.org/10.1038/s41436-018-0066-9.Search in Google Scholar PubMed PubMed Central

350. Deering-Rice, CE, Stockmann, C, Romero, EG, Lu, Z, Shapiro, D, Stone, BL, et al.. Characterization of transient receptor potential vanilloid-1 (TRPV1) variant activation by coal fly ash particles and associations with altered transient receptor potential ankyrin-1 (TRPA1) expression and asthma. J Biol Chem 2016;291:24866–79. https://doi.org/10.1074/jbc.m116.746156.Search in Google Scholar PubMed PubMed Central

351. Naert, R, Talavera, A, Startek, JB, Talavera, K. TRPA1 gene variants hurting our feelings. Pflügers Archiv 2020;472:953–60. https://doi.org/10.1007/s00424-020-02397-y.Search in Google Scholar PubMed


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/reveh-2021-0043).


Received: 2021-04-06
Accepted: 2021-08-13
Published Online: 2021-09-16
Published in Print: 2022-12-16

© 2021 John Molot et al., published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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