Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter February 2, 2019

Early life exposure to lead (Pb) and changes in DNA methylation: relevance to Alzheimer’s disease

Syed Waseem Bihaqi

Abstract

Recent advances in neuroepigenetics have revealed its essential role in governing body function and disease. Epigenetics regulates an array of mechanisms that are susceptible to undergoing alteration by intracellular or extracellular factors. DNA methylation, one of the most extensively studied epigenetic markers is involved in the regulation of gene expression and also plays a vital role in neuronal development. The epigenome is most vulnerable during early the embryonic stage and perturbation in DNA methylation during this period can result in a latent outcome which can persist during the entire lifespan. Accumulating evidence suggests that environmental insults during the developmental phase can impart changes in the DNA methylation landscape. Based on reports on human subjects and animal models this review will explore the evidence on how developmental exposure of the known environmental pollutant, lead (Pb), can induce changes in the DNA methylation of genes which later can induce development of neurodegenerative disorders like Alzheimer’s disease (AD).


Corresponding author: Syed Waseem Bihaqi, PhD, George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Avedisian Hall, Lab: 390, 7 Greenhouse Road, Kingston, RI 02881, USA

  1. Research funding: Author states no funding involved.

  2. Conflict of interest: Author states no conflict of interest.

  3. Informed consent: Informed consent is not applicable.

  4. Ethical approval: The conducted research is not related to either human or animal use.

References

1. Needleman H. Low level lead exposure: history and discovery. Ann Epidemiol 2009;19(4):235–8.10.1016/j.annepidem.2009.01.022Search in Google Scholar PubMed

2. Needleman HL, Riess JA, Tobin MJ, Biesecker GE, Greenhouse JB. Bone lead levels and delinquent behavior. J Am Med Assoc 1996;275(5):363–9.10.1001/jama.1996.03530290033034Search in Google Scholar

3. Senut MC, Cingolani P, Sen A, Kruger A, Shaik A, Hirsch H, et al. Epigenetics of early-life lead exposure and effects on brain development. Epigenomics 2012;4(6):665–74.10.2217/epi.12.58Search in Google Scholar PubMed PubMed Central

4. Sanders T, Liu Y, Buchner V, Tchounwou PB. Neurotoxic effects and biomarkers of lead exposure: a review. Rev Environ Health 2009;24(1):15–45.10.1515/REVEH.2009.24.1.15Search in Google Scholar PubMed PubMed Central

5. White LD, Cory-Slechta DA, Gilbert ME, Tiffany-Castiglioni E, Zawia NH, Virgolini M, et al. New and evolving concepts in the neurotoxicology of lead. Toxicol Appl Pharmacol 2007;225(1):1–27.10.1016/j.taap.2007.08.001Search in Google Scholar PubMed

6. Bellinger DC. The protean toxicities of lead: new chapters in a familiar story. Int J Environ Res Public Health 2011;8(7): 2593–628.10.3390/ijerph8072593Search in Google Scholar PubMed PubMed Central

7. Grosse SD, Matte TD, Schwartz J, Jackson RJ. Economic gains resulting from the reduction in children’s exposure to lead in the United States. Environ Health Perspect 2002;110(6):563–9.10.1289/ehp.02110563Search in Google Scholar PubMed PubMed Central

8. Kuehn BM. Panel advises tougher limits on lead exposure. J Am Med Assoc 2012;307(5):445.10.1001/jama.2012.50Search in Google Scholar PubMed

9. van Wijngaarden E, Winters PC, Cory-Slechta DA. Blood lead levels in relation to cognitive function in older U.S. adults. Neurotoxicology 2011;32(1):110–5.10.1016/j.neuro.2010.11.002Search in Google Scholar PubMed

10. Santibanez M, Bolumar F, Garcia AM. Occupational risk factors in Alzheimer’s disease: a review assessing the quality of published epidemiological studies. Occup Environ Med 2007;64(11):723–32.10.1136/oem.2006.028209Search in Google Scholar PubMed PubMed Central

11. Schmidtke K, Hermeneit S. High rate of conversion to Alzheimer’s disease in a cohort of amnestic MCI patients. Int Psychogeriatr 2008;20(1):96–108.10.1017/S1041610207005509Search in Google Scholar

12. Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, et al. The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 2005;25(4):823–9.10.1523/JNEUROSCI.4335-04.2005Search in Google Scholar

13. Liu KS, Hao JH, Zeng Y, Dai FC, Gu PQ. Neurotoxicity and biomarkers of lead exposure: a review. Chin Med Sci J 2013;28(3):178–88.10.1016/S1001-9294(13)60045-0Search in Google Scholar

14. Guidotti TL, Ragain L. Protecting children from toxic exposure: three strategies. Pediatr Clin North Am 2007;54(2):227–35, vii.10.1016/j.pcl.2007.02.002Search in Google Scholar

15. Lanphear BP, Byrd RS, Auinger P, Schaffer SJ. Community characteristics associated with elevated blood lead levels in children. Pediatrics 1998;101(2):264–71.10.1542/peds.101.2.264Search in Google Scholar

16. Rabito FA, Shorter C, White LE. Lead levels among children who live in public housing. Epidemiology 2003;14(3):263–8.10.1097/01.EDE.0000060458.28457.E2Search in Google Scholar

17. Patrick L. Lead toxicity, a review of the literature. Part 1: Exposure, evaluation, and treatment. Altern Med Rev 2006;11(1):2–22.Search in Google Scholar

18. Russell Jones R. The continuing hazard of lead in drinking water. Lancet 1989;2(8664):669–70.10.1016/S0140-6736(89)90906-9Search in Google Scholar

19. Hu H. Bone lead as a new biologic marker of lead dose: recent findings and implications for public health. Environ Health Perspect 1998;106(Suppl 4):961–7.10.1289/ehp.98106s4961Search in Google Scholar

20. Philip AT, Gerson B. Lead poisoning – Part I. Incidence, etiology, and toxicokinetics. Clin Lab Med 1994;14(2):423–44.10.1016/S0272-2712(18)30386-XSearch in Google Scholar

21. Hu H, Rabinowitz M, Smith D. Bone lead as a biological marker in epidemiologic studies of chronic toxicity: conceptual paradigms. Environ Health Perspect 1998;106(1):1–8.10.1289/ehp.981061Search in Google Scholar PubMed PubMed Central

22. Rabinowitz MB. Toxicokinetics of bone lead. Environ Health Perspect 1991;91:33–7.10.1289/ehp.919133Search in Google Scholar

23. Silbergeld EK, Schwartz J, Mahaffey K. Lead and osteoporosis: mobilization of lead from bone in postmenopausal women. Environ Res 1988;47(1):79–94.10.1016/S0013-9351(88)80023-9Search in Google Scholar

24. Fewtrell LJ, Pruss-Ustun A, Landrigan P, Ayuso-Mateos JL. Estimating the global burden of disease of mild mental retardation and cardiovascular diseases from environmental lead exposure. Environ Res 2004;94(2):120–33.10.1016/S0013-9351(03)00132-4Search in Google Scholar

25. Gorell JM, Rybicki BA, Cole Johnson C, Peterson EL. Occupational metal exposures and the risk of Parkinson’s disease. Neuroepidemiology 1999;18(6):303–8.10.1159/000026225Search in Google Scholar

26. Stewart WF, Schwartz BS, Simon D, Kelsey K, Todd AC. ApoE genotype, past adult lead exposure, and neurobehavioral function. Environ Health Perspect 2002;110(5):501–5.10.1289/ehp.02110501Search in Google Scholar

27. Payton M, Riggs KM, Spiro 3rd A, Weiss ST, Hu H. Relations of bone and blood lead to cognitive function: the VA Normative Aging Study. Neurotoxicol Teratol 1998;20(1):19–27.10.1016/S0892-0362(97)00075-5Search in Google Scholar

28. Weisskopf MG, Wright RO, Schwartz J, Spiro 3rd A, Sparrow D, Aro A, et al. Cumulative lead exposure and prospective change in cognition among elderly men: the VA Normative Aging Study. Am J Epidemiol 2004;160(12):1184–93.10.1093/aje/kwh333Search in Google Scholar PubMed

29. Weisskopf MG, Proctor SP, Wright RO, Schwartz J, Spiro 3rd A, Sparrow D, et al. Cumulative lead exposure and cognitive performance among elderly men. Epidemiology 2007;18(1): 59–66.10.1097/01.ede.0000248237.35363.29Search in Google Scholar PubMed

30. Selkoe DJ. Amyloid protein and Alzheimer’s disease. Sci Am 1991;265(5):68–71, 4–6, 78.10.1038/scientificamerican1191-68Search in Google Scholar PubMed

31. Tanzi RE, Bertram L. Alzheimer’s disease: the latest suspect. Nature 2008;454(7205):706–8.Search in Google Scholar

32. Zawia NH, Lahiri DK, Cardozo-Pelaez F. Epigenetics, oxidative stress, and Alzheimer disease. Free Radic Biol Med 2009;46(9):1241–9.10.1016/j.freeradbiomed.2009.02.006Search in Google Scholar PubMed PubMed Central

33. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989;2(8663):577–80.10.1016/S0140-6736(89)90710-1Search in Google Scholar

34. Barker DJ. Fetal origins of cardiovascular disease. Ann Med 1999;31(Suppl 1):3–6.10.1080/07853890.1999.11904392Search in Google Scholar PubMed

35. Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, et al. Alzheimer’s disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 2008;28(1):3–9.10.1523/JNEUROSCI.4405-07.2008Search in Google Scholar PubMed PubMed Central

36. Bihaqi SW, Bahmani A, Subaiea GM, Zawia NH. Infantile exposure to lead and late-age cognitive decline: relevance to AD. Alzheimers Dement 2014;10(2):187–95.10.1016/j.jalz.2013.02.012Search in Google Scholar PubMed PubMed Central

37. Bihaqi SW, Bahmani A, Adem A, Zawia NH. Infantile postnatal exposure to lead (Pb) enhances tau expression in the cerebral cortex of aged mice: relevance to AD. Neurotoxicology 2014;44:114–20.10.1016/j.neuro.2014.06.008Search in Google Scholar PubMed PubMed Central

38. Bihaqi SW, Zawia NH. Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb). Neurotoxicology 2013;39:95–101.10.1016/j.neuro.2013.07.010Search in Google Scholar PubMed PubMed Central

39. Kanherkar RR, Bhatia-Dey N, Makarev E, Csoka AB. Cellular reprogramming for understanding and treating human disease. Front Cell Dev Biol 2014;2:67.10.3389/fcell.2014.00067Search in Google Scholar PubMed PubMed Central

40. Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986;321(6067):209–13.10.1038/321209a0Search in Google Scholar PubMed

41. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003;33(Suppl):245–54.10.1038/ng1089Search in Google Scholar PubMed

42. Robert L. Epigenetic post-transcriptional mechanisms for regulating physiological functions, and their decline during aging. J Soc Biol 2004;198(3):257–62.10.1051/jbio/2004198030257Search in Google Scholar

43. Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE. Maternal nutrition and fetal development. J Nutr 2004;134(9):2169–72.10.1093/jn/134.9.2169Search in Google Scholar

44. Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD. Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PLoS One 2009;4(8):e6617.10.1371/journal.pone.0006617Search in Google Scholar

45. Martin GM. Epigenetic drift in aging identical twins. Proc Natl Acad Sci USA 2005;102(30):10413–4.10.1073/pnas.0504743102Search in Google Scholar

46. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology 2013;38(1):23–38.10.1038/npp.2012.112Search in Google Scholar

47. Niculescu MD, Craciunescu CN, Zeisel SH. Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. FASEB J 2006;20(1):43–9.10.1096/fj.05-4707comSearch in Google Scholar

48. Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 1990;53(12):1096–8.10.1136/jnnp.53.12.1096Search in Google Scholar

49. Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem 1996;67(3):1328–31.10.1046/j.1471-4159.1996.67031328.xSearch in Google Scholar

50. Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer’s disease. FEBS Lett 2002;518(1–3):1–4.10.1016/S0014-5793(02)02702-3Search in Google Scholar

51. Obeid R, Kasoha M, Knapp JP, Kostopoulos P, Becker G, Fassbender K, et al. Folate and methylation status in relation to phosphorylated tau protein(181P) and beta-amyloid(1-42) in cerebrospinal fluid. Clin Chem 2007;53(6):1129–36.10.1373/clinchem.2006.085241Search in Google Scholar PubMed

52. Snowdon DA, Tully CL, Smith CD, Riley KP, Markesbery WR. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study. Am J Clin Nutr 2000;71(4):993–8.10.1093/ajcn/71.4.993Search in Google Scholar PubMed

53. Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer’s disease. J Neurosci 2002;22(5):1752–62.10.1523/JNEUROSCI.22-05-01752.2002Search in Google Scholar

54. Coppede F. One-carbon metabolism and Alzheimer’s disease: focus on epigenetics. Curr Genomics 2010;11(4):246–60.10.2174/138920210791233090Search in Google Scholar PubMed PubMed Central

55. Roth TL. Epigenetic mechanisms in the development of behavior: advances, challenges, and future promises of a new field. Dev Psychopathol 2013;25(4 Pt 2):1279–91.10.1017/S0954579413000618Search in Google Scholar PubMed PubMed Central

56. Motta V, Bonzini M, Grevendonk L, Iodice S, Bollati V. Epigenetics applied to epidemiology: investigating environmental factors and lifestyle influence on human health. Med Lav 2017;108(1):10–23.Search in Google Scholar

57. Cheng TF, Choudhuri S, Muldoon-Jacobs K. Epigenetic targets of some toxicologically relevant metals: a review of the literature. J Appl Toxicol 2012;32(9):643–53.10.1002/jat.2717Search in Google Scholar PubMed

58. Fragou D, Fragou A, Kouidou S, Njau S, Kovatsi L. Epigenetic mechanisms in metal toxicity. Toxicol Mech Methods 2011;21(4):343–52.10.3109/15376516.2011.557878Search in Google Scholar PubMed

59. Martinez-Zamudio R, Ha HC. Environmental epigenetics in metal exposure. Epigenetics 2011;6(7):820–7.10.4161/epi.6.7.16250Search in Google Scholar PubMed PubMed Central

60. Fuso A, Scarpa S. One-carbon metabolism and Alzheimer’s disease: is it all a methylation matter? Neurobiol Aging 2011;32(7):1192–5.10.1016/j.neurobiolaging.2011.01.012Search in Google Scholar PubMed

61. Cao XJ, Huang SH, Wang M, Chen JT, Ruan DY. S-adenosyl-L-methionine improves impaired hippocampal long-term potentiation and water maze performance induced by developmental lead exposure in rats. Eur J Pharmacol 2008;595(1–3):30–4.10.1016/j.ejphar.2008.07.061Search in Google Scholar PubMed

62. Chen T, Li YY, Zhang JL, Xu B, Lin Y, Wang CX, et al. Protective effect of C(60)-methionine derivate on lead-exposed human SH-SY5Y neuroblastoma cells. J Appl Toxicol 2011;31(3):255–61.10.1002/jat.1588Search in Google Scholar PubMed

63. Pilsner JR, Hu H, Ettinger A, Sanchez BN, Wright RO, Cantonwine D, et al. Influence of prenatal lead exposure on genomic methylation of cord blood DNA. Environ Health Perspect 2009;117(9):1466–71.10.1289/ehp.0800497Search in Google Scholar PubMed PubMed Central

64. Bihaqi SW, Huang H, Wu J, Zawia NH. Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: implications for Alzheimer’s disease. J Alzheimers Dis 2011;27(4):819–33.10.3233/JAD-2011-111013Search in Google Scholar PubMed

65. Bihaqi SW, Zawia NH. Alzheimer’s disease biomarkers and epigenetic intermediates following exposure to Pb in vitro. Curr Alzheimer Res 2012;9(5):555–62.10.2174/156720512800617964Search in Google Scholar PubMed

66. Dosunmu R, Alashwal H, Zawia NH. Genome-wide expression and methylation profiling in the aged rodent brain due to early-life Pb exposure and its relevance to aging. Mech Ageing Dev 2012;133(6):435–43.10.1016/j.mad.2012.05.003Search in Google Scholar PubMed PubMed Central

67. Alashwal H, Dosunmu R, Zawia NH. Integration of genome-wide expression and methylation data: relevance to aging and Alzheimer’s disease. Neurotoxicology 2012;33(6):1450–3.10.1016/j.neuro.2012.06.008Search in Google Scholar PubMed PubMed Central

68. Obeng-Gyasi E. Lead exposure and oxidative stress-a life course approach in U.S. adults. Toxics 2018;6(3):E42.10.3390/toxics6030042Search in Google Scholar PubMed PubMed Central

69. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001;60(8):759–67.10.1093/jnen/60.8.759Search in Google Scholar PubMed

70. Kuchino Y, Mori F, Kasai H, Inoue H, Iwai S, Miura K, et al. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature 1987;327(6117):77–9.10.1038/327077a0Search in Google Scholar PubMed

71. Xiao W, Samson L. In vivo evidence for endogenous DNA alkylation damage as a source of spontaneous mutation in eukaryotic cells. Proc Natl Acad Sci USA 1993;90(6):2117–21.10.1073/pnas.90.6.2117Search in Google Scholar PubMed PubMed Central

72. Bolin C, Stedeford T, Cardozo-Pelaez F. Single extraction protocol for the analysis of 8-hydroxy-2′-deoxyguanosine (oxo8dG) and the associated activity of 8-oxoguanine DNA glycosylase. J Neurosci Methods 2004;136(1):69–76.10.1016/j.jneumeth.2003.12.025Search in Google Scholar PubMed

73. Bihaqi SW, Schumacher A, Maloney B, Lahiri DK, Zawia NH. Do epigenetic pathways initiate late onset alzheimer disease (LOAD): towards a new paradigm. Curr Alzheimer Res 2012;9(5):574–88.10.2174/156720512800617982Search in Google Scholar PubMed

74. Weitzman SA, Turk PW, Milkowski DH, Kozlowski K. Free radical adducts induce alterations in DNA cytosine methylation. Proc Natl Acad Sci USA 1994;91(4):1261–4.10.1073/pnas.91.4.1261Search in Google Scholar PubMed PubMed Central

75. Castellani RJ, Lee HG, Perry G, Smith MA. Antioxidant protection and neurodegenerative disease: the role of amyloid-beta and tau. Am J Alzheimers Dis Other Demen 2006;21(2):126–30.10.1177/153331750602100213Search in Google Scholar PubMed

76. Bolin CM, Basha R, Cox D, Zawia NH, Maloney B, Lahiri DK, et al. Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain. FASEB J 2006;20(6):788–90.10.1096/fj.05-5091fjeSearch in Google Scholar PubMed

77. Chia N, Wang L, Lu X, Senut MC, Brenner C, Ruden DM. Hypothesis: environmental regulation of 5-hydroxymethylcytosine by oxidative stress. Epigenetics 2011;6(7):853–6.10.4161/epi.6.7.16461Search in Google Scholar PubMed

78. Bakulski KM, Rozek LS, Dolinoy DC, Paulson HL, Hu H. Alzheimer’s disease and environmental exposure to lead: the epidemiologic evidence and potential role of epigenetics. Curr Alzheimer Res 2012;9(5):563–73.10.2174/156720512800617991Search in Google Scholar PubMed PubMed Central

Received: 2018-11-20
Accepted: 2019-01-09
Published Online: 2019-02-02
Published in Print: 2019-06-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

Scroll Up Arrow