Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter September 29, 2021

Health effects associated with phthalate activity on nuclear receptors

  • Thoin Farzana Begum ORCID logo EMAIL logo and David Carpenter

Abstract

Phthalates are endocrine disruptors, widely used as plasticizers to impart flexibility in plastics, and as solvents in personal care products. Due to their nearly ubiquitous use in consumer products, most humans are exposed to phthalates daily. There has been extensive research on the reproductive health effects associated with phthalate exposure, but less attention has been paid to other actions. This review aims to summarize the known action of phthalates on different nuclear receptors. Some phthalates bind to and activate the estrogen receptor, making them weakly estrogenic. However, other phthalates antagonize androgen receptors. Some high molecular weight phthalates antagonize thyroid receptors, affecting metabolism. Several phthalates activate and interfere with the normal function of different peroxisome proliferator-activated receptors (PPARs), receptors that have critical roles in lipid metabolism and energy homeostasis. Some phthalates activate the aryl hydrocarbon receptor, which is critical for xenobiotic metabolism. Although phthalates have a short half-life in vivo, because people are continuously exposed, studies should examine the health effects of phthalates associated with long-term exposure. There is limited research on the effects of phthalates on health outcomes aside from reproductive function, particularly concerning are childhood adiposity, behavior, and learning. There is also limited information on actions of phthalates not mediated via nuclear receptors. Humans are exposed to multiple chemicals simultaneously, and how chemical mixtures act on nuclear receptor activity needs study. Although we know a great deal about phthalates, there is still much that remains uncertain. Future studies need to further examine their other potential health effects.


Corresponding author: Thoin Farzana Begum, MS, Department of Environmental Health Sciences, School of Public Health, University at Albany, 1 University Place, Rensselaer, NY 12144, USA, Phone: +1 518 402 0401, Fax: +1 51 525 2665, E-mail:

Funding source: University at Albany

  1. Research funding: Internal funding from the Institute for Health and the Environment, University at Albany.

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

  3. Competing interests: Authors state no conflict of interest.

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

References

1. Takeuchi, S, Iida, M, Kobayashi, S, Jin, K, Matsuda, T, Kojima, H. Differential effects of phthalate esters on transcriptional activities via human estrogen receptors α and β, and androgen receptor. Toxicology 2005;210:223–33. https://doi.org/10.1016/j.tox.2005.02.002.Search in Google Scholar PubMed

2. Frye, C, Bo, E, Calamandrei, G, Calza, L, Dessì‐Fulgheri, F, Fernández, M, et al.. Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems. J Neuroendocrinol 2012;24:144–59. https://doi.org/10.1111/j.1365-2826.2011.02229.x.Search in Google Scholar PubMed PubMed Central

3. Toporova, L, Balaguer, P. Nuclear receptors are the major targets of endocrine disrupting chemicals. Mol Cell Endocrinol 2020;502:110665. https://doi.org/10.1016/j.mce.2019.110665.Search in Google Scholar PubMed

4. Cooke, PS, Nanjappa, MK, Ko, C, Prins, GS, Hess, RA. Estrogens in male physiology. Physiol Rev 2017;97:995–1043. https://doi.org/10.1152/physrev.00018.2016.Search in Google Scholar PubMed PubMed Central

5. Yaşar, P, Ayaz, G, User, SD, Güpür, G, Muyan, M. Molecular mechanism of estrogen–estrogen receptor signaling. Reprod Med Biol 2017;16:4–20. https://doi.org/10.1002/rmb2.12006.Search in Google Scholar PubMed PubMed Central

6. Welboren, WJ, Stunnenberg, HG, Sweep, FC, Span, PN. Identifying estrogen receptor target genes. Mol Oncol 2007;1:138–43. https://doi.org/10.1016/j.molonc.2007.04.001.Search in Google Scholar PubMed PubMed Central

7. Nilsson, S, Gustafsson, JÅ. Estrogen receptor transcription and transactivation: basic aspects of estrogen action. Breast Canc Res 2000;2:360. https://doi.org/10.1186/bcr81.Search in Google Scholar PubMed PubMed Central

8. Lee, HR, Kim, TH, Choi, KC. Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab Anim Res 2012;28:71–6. https://doi.org/10.5625/lar.2012.28.2.71.Search in Google Scholar PubMed PubMed Central

9. Simpson, E, Rubin, G, Clyne, C, Robertson, K, O’Donnell, L, Jones, M, et al.. The role of local estrogen biosynthesis in males and females. Trends Endrocrinol Metab 2000;11:184–8. https://doi.org/10.1016/s1043-2760(00)00254-x.Search in Google Scholar PubMed

10. Saji, S, Jensen, EV, Nilsson, S, Rylander, T, Warner, M, Gustafsson, JÅ. Estrogen receptors α and β in the rodent mammary gland. Breast Canc Res 2000;2:1. https://doi.org/10.1073/pnas.97.1.337.Search in Google Scholar PubMed PubMed Central

11. Mitchner, NA, Garlick, C, Ben-Jonathan, N. Cellular distribution and gene regulation of estrogen receptorsα and β in the rat pituitary gland. Endocrinology 1998;139:3976–83. https://doi.org/10.1210/endo.139.9.6181.Search in Google Scholar PubMed

12. Gao, W, Bohl, CE, Dalton, JT. Chemistry and structural biology of androgen receptor. Chem Rev 2005;105:3352–70. https://doi.org/10.1021/cr020456u.Search in Google Scholar PubMed PubMed Central

13. Tóth, M, Zakár, T. Relative binding affinities of testosterone, 19-nortestosterone and their 5α-reduced derivatives to the androgen receptor and to other androgen-binding proteins: a suggested role of 5α-reductive steroid metabolism in the dissociation of “myotropic” and “androgenic” activities of 19-nortestosterone. J Steroid Biochem 1982;17:653–60. https://doi.org/10.1016/0022-4731(82)90567-2.Search in Google Scholar PubMed

14. Massie, CE, Lynch, A, Ramos‐Montoya, A, Boren, J, Stark, R, Fazli, L, et al.. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J 2011;30:2719–33. https://doi.org/10.1038/emboj.2011.158.Search in Google Scholar PubMed PubMed Central

15. Jin, HJ, Kim, J, Yu, J. Androgen receptor genomic regulation. Transl Androl Urol 2013;2:158. https://doi.org/10.3978/j.issn.2223-4683.2013.09.01.Search in Google Scholar PubMed PubMed Central

16. Kay, VR, Bloom, MS, Foster, WG. Reproductive and developmental effects of phthalate diesters in males. Crit Rev Toxicol 2014;44:467–98. https://doi.org/10.3109/10408444.2013.875983.Search in Google Scholar PubMed

17. Dalton, JT, Miller, DD, Steiner, MS, Veverka, KA, inventors. University of Tennessee Research Foundation, assignee. Halogenated selective androgen receptor modulators and methods of use thereof. United States patent US 7,026,500, 2006.Search in Google Scholar

18. Aranda, A, Martínez-Iglesias, O, Ruiz-Llorente, L, García-Carpizo, V, Zambrano, A. Thyroid receptor: roles in cancer. Trends Endocrinol Metabol 2009;20:318–24. https://doi.org/10.1016/j.tem.2009.03.011.Search in Google Scholar PubMed

19. Gouveia, C, Capelo, L, Neofiti-Papi, B, Zallone, A. Thyroid and bone, encyclopedia of bone biology. Amsterdam, Netherlands: Elsevier; 2020:558–82 pp.10.1016/B978-0-12-801238-3.11227-9Search in Google Scholar

20. Huang, YH, Tsai, MM, Lin, KH. Thyroid hormone dependent regulation of target genes and their physiological significance. Chang Gung Med J 2008;31:325–34.Search in Google Scholar

21. Zoeller, TR. Environmental chemicals targeting thyroid. Hormones 2010;9:28–40. https://doi.org/10.14310/horm.2002.1250.Search in Google Scholar PubMed

22. Shi, W, Hu, X, Zhang, F, Hu, G, Hao, Y, Zhang, X, et al.. Occurrence of thyroid hormone activities in drinking water from eastern China: contributions of phthalate esters. Environ Sci Technol 2012;46:1811–8. https://doi.org/10.1021/es202625r.Search in Google Scholar PubMed

23. Boas, M, Feldt-Rasmussen, U, Main, KM. Thyroid effects of endocrine disrupting chemicals. Mol Cell Endocrinol 2012;355:240–8. https://doi.org/10.1016/j.mce.2011.09.005.Search in Google Scholar PubMed

24. Kojima, H, Takeuchi, S, Uramaru, N, Sugihara, K, Yoshida, T, Kitamura, S. Nuclear hormone receptor activity of polybrominated diphenyl ethers and their hydroxylated and methoxylated metabolites in transactivation assays using Chinese hamster ovary cells. Environ Health Perspect 2009;117:1210–8. https://doi.org/10.1289/ehp.0900753.Search in Google Scholar PubMed PubMed Central

25. Ren, XM, Guo, LH. Assessment of the binding of hydroxylated polybrominated diphenyl ethers to thyroid hormone transport proteins using a site-specific fluorescence probe. Environ Sci Technol 2012;46:4633–40. https://doi.org/10.1021/es2046074.Search in Google Scholar PubMed

26. Tyagi, S, Gupta, P, Saini, AS, Kaushal, C, Sharma, S. The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases. J Adv Pharm Technol Res 2011;2:236–40. https://doi.org/10.4103%2F2231-4040.90879.10.4103/2231-4040.90879Search in Google Scholar PubMed PubMed Central

27. Kersten, S, Desvergne, B, Wahli, W. Roles of PPARs in health and disease. Nature 2000;405:421–4. https://doi.org/10.1038/35013000.Search in Google Scholar PubMed

28. Schoonjans, K, Peinado‐Onsurbe, J, Lefebvre, AM, Heyman, RA, Briggs, M, Deeb, S, et al.. PPARalpha and PPARgamma activators direct a distinct tissue‐specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 1996;15:5336–48. https://doi.org/10.1002/j.1460-2075.1996.tb00918.x.Search in Google Scholar

29. Peters, JM, Cattley, RC, Gonzalez, FJ. Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis 1997;18:2029–33. https://doi.org/10.1093/carcin/18.11.2029.Search in Google Scholar PubMed

30. Johns, LE, Ferguson, KK, McElrath, TF, Mukherjee, B, Meeker, JD. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 2016;124:1808–15. https://doi.org/10.1289/ehp170.Search in Google Scholar

31. Begum, TF, Gerona, R, Melamed, J, McGough, A, Lenhart, N, Wong, R, et al.. Sources of exposure to urinary phthalates among couples undergoing infertility treatment. Int J Hyg Environ Health 2020;229:113567. https://doi.org/10.1016/j.ijheh.2020.113567.Search in Google Scholar PubMed

32. Saravanabhavan, G, Guay, M, Langlois, É, Giroux, S, Murray, J, Haines, D. Biomonitoring of phthalate metabolites in the Canadian population through the Canadian Health Measures Survey (2007–2009). Int J Hyg Environ Health 2013;216:652–61. https://doi.org/10.1016/j.ijheh.2012.12.009.Search in Google Scholar PubMed

33. Saidi, SA, Holland, CM, Kreil, DP, MacKay, DJ, Charnock-Jones, DS, Print, CG, et al.. Independent component analysis of microarray data in the study of endometrial cancer. Oncogene 2004;23:6677–83. https://doi.org/10.1038/sj.onc.1207562.Search in Google Scholar PubMed

34. Saidi, SA, Holland, CM, Charnock-Jones, DS, Smith, SK. In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer. Mol Canc 2006;5:13. https://doi.org/10.1186/1476-4598-5-13.Search in Google Scholar PubMed PubMed Central

35. Yang, L, Zhou, J, Ma, Q, Wang, C, Chen, K, Meng, W, et al.. Knockdown of PPAR δ gene promotes the growth of colon cancer and reduces the sensitivity to bevacizumab in nude mice model. PLoS One 2013;8:e60715. https://doi.org/10.1371/journal.pone.0060715.Search in Google Scholar PubMed PubMed Central

36. Lim, H, Gupta, RA, Ma, WG, Paria, BC, Moller, DE, Morrow, JD, et al.. Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARδ. Genes Dev 1999;13:1561–74. https://doi.org/10.1101/gad.13.12.1561.Search in Google Scholar PubMed PubMed Central

37. Fajas, L, Schoonjans, K, Gelman, L, Kim, JB, Najib, J, Martin, G, et al.. Regulation of peroxisome proliferator-activated receptor γ expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism. Mol Cell Biol 1999;19:5495–503. https://doi.org/10.1128/mcb.19.8.5495.Search in Google Scholar PubMed PubMed Central

38. Ayed-Boussema, I, Pascussi, JM, Maurel, P, Bacha, H, Hassen, W. Effect of aflatoxin B1 on nuclear receptors PXR, CAR, and AhR and their target cytochromes P450 mRNA expression in primary cultures of human hepatocytes. Int J Toxicol 2012;31:86–93. https://doi.org/10.1177/1091581811422453.Search in Google Scholar PubMed

39. Johnson, CD, Balagurunathan, Y, Tadesse, MG, Falahatpisheh, MH, Brun, M, Walker, MK, et al.. Unraveling gene-gene interactions regulated by ligands of the aryl hydrocarbon receptor. Environ Health Perspect 2004;112:403–12. https://doi.org/10.1289/ehp.6758.Search in Google Scholar PubMed PubMed Central

40. Krüger, T, Long, M, Bonefeld-Jørgensen, EC. Plastic components affect the activation of the aryl hydrocarbon and the androgen receptor. Toxicology 2008;246:112–23. https://doi.org/10.1016/j.tox.2007.12.028.Search in Google Scholar PubMed

41. Kay, VR, Chambers, C, Foster, WG. Reproductive and developmental effects of phthalate diesters in females. Crit Rev Toxicol 2013;43:200–19. https://doi.org/10.3109/10408444.2013.766149.Search in Google Scholar PubMed PubMed Central

42. Rusyn, I, Corton, JC. Mechanistic considerations for human relevance of cancer hazard of di (2-ethylhexyl) phthalate. Mutat Res Rev Mutat Res 2012;750:141–58. https://doi.org/10.1016/j.mrrev.2011.12.004.Search in Google Scholar PubMed PubMed Central

43. Peijnenburg, WJ, Sven, EJ, Brian, F. Phthalates. In: Jørgensen, SE, Fath, BD, editors. Encycl Ecol. Oxford: Academic Press; 2008:2733–8 pp.10.1016/B978-008045405-4.00419-5Search in Google Scholar

44. U.S. Environmental Protection Agency. Assessing and Managing chemicals under TSCA: phthalates. Available from: https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/phthalates .Search in Google Scholar

45. Hauser, R, Calafat, AM. Phthalates and human health. Occup Environ Med 2005;62:806–18. https://doi.org/10.1136/oem.2004.017590.Search in Google Scholar PubMed PubMed Central

46. Pacyga, DC, Sathyanarayana, S, Strakovsky, RS. Dietary predictors of phthalate and bisphenol exposures in pregnant women. Adv Nutr 2019;10:803–15. https://doi.org/10.1093/advances/nmz029.Search in Google Scholar PubMed PubMed Central

47. 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

48. Meeker, JD, Calafat, AM, Hauser, R. Urinary phthalate metabolites and their biotransformation products: predictors and temporal variability among men and women. J Expo Sci Environ Epidemiol 2012;22:376–85. https://doi.org/10.1038/jes.2012.7.Search in Google Scholar PubMed PubMed Central

49. Begum, TF, Fujimoto, VY, Gerona, R, McGough, A, Lenhart, N, Wong, R, et al.. A pilot investigation of couple-level phthalates exposure and in vitro fertilization (IVF) outcomes. Reprod Toxicol 2021;99:56–64. https://doi.org/10.1016/j.reprotox.2020.11.014.Search in Google Scholar PubMed PubMed Central

50. Corton, JC, Lapinskas, PJ. Peroxisome proliferator-activated receptors: mediators of phthalate ester-induced effects in the male reproductive tract? Toxicol Sci 2005;83:4–17. https://doi.org/10.1093/toxsci/kfi011.Search in Google Scholar PubMed

51. Huang, Q, Chen, Q. Mediating roles of PPARs in the effects of environmental chemicals on sex steroids. PPAR Res 2017;2017:8. https://doi.org/10.1155/2017/3203161.Search in Google Scholar PubMed PubMed Central

52. Park, C, Lee, J, Kong, B, Park, J, Song, H, Choi, K, et al.. The effects of bisphenol A, benzyl butyl phthalate, and di (2-ethylhexyl) phthalate on estrogen receptor alpha in estrogen receptor-positive cells under hypoxia. Environ Pollut 2019;248:774–81. https://doi.org/10.1016/j.envpol.2019.02.069.Search in Google Scholar PubMed

53. Wang, SW, Wang, SS, Wu, DC, Lin, YC, Ku, CC, Wu, CC, et al.. Androgen receptor-mediated apoptosis in bovine testicular induced pluripotent stem cells in response to phthalate esters. Cell Death Dis 2013;4:e907. https://doi.org/10.1038/cddis.2013.420.Search in Google Scholar PubMed PubMed Central

54. Martinez-Arguelles, DB. In utero exposure to di-(2-ethylhexyl) phthalate reveals the presence of an adrenal-testis axis regulating androgen formation [PhD diss.]. Georgetown University; 2011.Search in Google Scholar

55. Wang, Y, Wang, T, Ban, Y, Shen, C, Shen, Q, Chai, X, et al.. Di-(2-ethylhexyl) phthalate exposure modulates antioxidant enzyme activity and gene expression in juvenile and adult Daphnia magna. Arch Environ Contam Toxicol 2018;75:145–56. https://doi.org/10.1007/s00244-018-0535-9.Search in Google Scholar PubMed

56. Zhang, T, Shen, W, De Felici, M, Zhang, XF. Di (2‐ethylhexyl) phthalate: adverse effects on folliculogenesis that cannot be neglected. Environ Mol Mutagen 2016;57:579–88. https://doi.org/10.1002/em.22037.Search in Google Scholar PubMed

57. Harris, CA, Henttu, P, Parker, MG, Sumpter, JP. The estrogenic activity of phthalate esters in vitro. Environ Health Perspect 1997;105:802–11. https://doi.org/10.1289/ehp.97105802.Search in Google Scholar PubMed PubMed Central

58. Wakui, S, Shirai, M, Motohashi, M, Mutou, T, Oyama, N, Wempe, MF, et al.. Effects of in utero exposure to di (n-butyl) phthalate for estrogen receptors α, β, and androgen receptor of Leydig cell on rats. Toxicol Pathol 2014;42:877–87. https://doi.org/10.1177/0192623313502879.Search in Google Scholar PubMed

59. Wójtowicz, AK, Szychowski, KA, Wnuk, A, Kajta, M. Dibutyl phthalate (DBP)-induced apoptosis and neurotoxicity are mediated via the aryl hydrocarbon receptor (AhR) but not by estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), or peroxisome proliferator-activated receptor gamma (PPARγ) in mouse cortical neurons. Neurotox Res 2017;31:77–89. https://doi.org/10.1007/s12640-016-9665-x.Search in Google Scholar PubMed PubMed Central

60. Zhang, Z, Hu, Y, Zhao, L, Li, J, Bai, H, Zhu, D, et al.. Estrogen agonist/antagonist properties of dibenzyl phthalate (DBzP) based on in vitro and in vivo assays. Toxicol Lett 2011;207:7–11. https://doi.org/10.1016/j.toxlet.2011.08.017.Search in Google Scholar PubMed

61. Jobling, S, Reynolds, T, White, R, Parker, MG, Sumpter, JP. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ Health Perspect 1995;103:582–7. https://doi.org/10.1289/ehp.95103582.Search in Google Scholar PubMed PubMed Central

62. Lin, LC, Wang, SL, Chang, YC, Huang, PC, Cheng, JT, Su, PH, et al.. Associations between maternal phthalate exposure and cord sex hormones in human infants. Chemosphere 2011;83:1192–9. https://doi.org/10.1016/j.chemosphere.2010.12.079.Search in Google Scholar PubMed

63. Ghisari, M, Bonefeld-Jorgensen, EC. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol Lett 2009;189:67–77. https://doi.org/10.1016/j.toxlet.2009.05.004.Search in Google Scholar PubMed

64. López-Carrillo, L, Hernández-Ramírez, RU, Calafat, AM, Torres-Sánchez, L, Galván-Portillo, M, Needham, LL, et al.. Exposure to phthalates and breast cancer risk in northern Mexico. Environ Health Perspect 2010;118:539–44. https://doi.org/10.1289/ehp.0901091.Search in Google Scholar PubMed PubMed Central

65. Christen, V, Crettaz, P, Oberli-Schrämmli, A, Fent, K. Antiandrogenic activity of phthalate mixtures: validity of concentration addition. Toxicol Appl Pharmacol 2012;259:169–76. https://doi.org/10.1016/j.taap.2011.12.021.Search in Google Scholar PubMed

66. Alam, MS, Ohsako, S, Matsuwaki, T, Zhu, XB, Tsunekawa, N, Kanai, Y, et al.. Induction of spermatogenic cell apoptosis in prepubertal rat testes irrespective of testicular steroidogenesis: a possible estrogenic effect of di (n-butyl) phthalate. Reproduction 2010;139:427. https://doi.org/10.1530/rep-09-0226.Search in Google Scholar

67. Mankidy, R, Wiseman, S, Ma, H, Giesy, JP. Biological impact of phthalates. Toxicol Lett 2013;217:50–8. https://doi.org/10.1016/j.toxlet.2012.11.025.Search in Google Scholar PubMed

68. Main, KM, Mortensen, GK, Kaleva, MM, Boisen, KA, Damgaard, IN, Chellakooty, M, et al.. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ Health Perspect 2006;114:270–6. https://doi.org/10.1289/ehp.8075.Search in Google Scholar PubMed PubMed Central

69. Martinez-Arguelles, DB, Campioli, E, Culty, M, Zirkin, BR, Papadopoulos, V. Fetal origin of endocrine dysfunction in the adult: the phthalate model. J Steroid Biochem Mol Biol 2013;137:5–17. https://doi.org/10.1016/j.jsbmb.2013.01.007.Search in Google Scholar PubMed

70. Martinez-Arguelles, DB, Culty, M, Zirkin, BR, Papadopoulos, V. In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis. Endocrinology 2009;150:5575–85. https://doi.org/10.1210/en.2009-0847.Search in Google Scholar PubMed PubMed Central

71. Martinez-Arguelles, DB, Guichard, T, Culty, M, Zirkin, BR, Papadopoulos, V. In utero exposure to the antiandrogen di-(2-ethylhexyl) phthalate decreases adrenal aldosterone production in the adult rat. Biol Reprod 2011;85:51–61. https://doi.org/10.1095/biolreprod.110.089920.Search in Google Scholar PubMed PubMed Central

72. Radke, EG, Braun, JM, Meeker, JD, Cooper, GS. Phthalate exposure and male reproductive outcomes: a systematic review of the human epidemiological evidence. Environ Int 2018;121:764–93. https://doi.org/10.1016/j.envint.2018.07.029.Search in Google Scholar PubMed

73. Bloom, MS, Whitcomb, BW, Chen, Z, Ye, A, Kannan, K, Buck-Louis, GM. Associations between urinary phthalate concentrations and semen quality parameters in a general population. Hum Reprod 2015;30:2645–57. https://doi.org/10.1093/humrep/dev219.Search in Google Scholar PubMed PubMed Central

74. Zhou, C, Gao, L, Flaws, JA. Exposure to an environmentally relevant phthalate mixture causes transgenerational effects on female reproduction in mice. Endocrinology 2017;158:1739–54. https://doi.org/10.1210/en.2017-00100.Search in Google Scholar PubMed PubMed Central

75. Warner, GR, Li, Z, Houde, ML, Atkinson, CE, Meling, DD, Chiang, C, et al.. Ovarian metabolism of an environmentally relevant phthalate mixture. Toxicol Sci 2019;169:246–59. https://doi.org/10.1093/toxsci/kfz047.Search in Google Scholar PubMed PubMed Central

76. Chuang, SC, Chen, HC, Sun, CW, Chen, YA, Wang, YH, Chiang, CJ, et al.. Phthalate exposure and prostate cancer in a population-based nested case-control study. Environ Res 2020;181:108902. https://doi.org/10.1016/j.envres.2019.108902.Search in Google Scholar PubMed

77. Ibhazehiebo, K, Koibuchi, N. Thyroid hormone receptor-mediated transcription is suppressed by low dose phthalate. Niger J Physiol Sci 2011;26:143–9.Search in Google Scholar

78. Fisher, DA. Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 1997;40:16–31. https://doi.org/10.1097/00003081-199703000-00005.Search in Google Scholar PubMed

79. Kim, BN, Cho, SC, Kim, Y, Shin, MS, Yoo, HJ, Kim, JW, et al.. Phthalates exposure and attention-deficit/hyperactivity disorder in school-age children. Biol Psychiatr 2009;66:958–63. https://doi.org/10.1016/j.biopsych.2009.07.034.Search in Google Scholar PubMed

80. Wójcikowski, J, Gołembiowska, K, Daniel, WA. Regulation of liver cytochrome P450 by activation of brain dopaminergic system: physiological and pharmacological implications. Biochem Pharmacol 2008;76:258–67. https://doi.org/10.1016/j.bcp.2008.04.016.Search in Google Scholar PubMed

81. Howarth, JA, Price, SC, Dobrota, M, Kentish, PA, Hinton, RH. Effects on male rats of di-(2-ethylhexyl) phthalate and di-n-hexylphthalate administered alone or in combination. Toxicol Lett 2001;121:35–43. https://doi.org/10.1016/s0378-4274(01)00313-7.Search in Google Scholar PubMed

82. Poon, R, Lecavalier, P, Mueller, R, Valli, V, Procter, BG, Chu, I. Subchronic oral toxicity of di-n-octyl phthalate and di (2-ethylhexyl) phthalate in the rat. Food Chem Toxicol 1997;35:225–39. https://doi.org/10.1016/s0278-6915(96)00064-6.Search in Google Scholar PubMed

83. Shen, O, Du, G, Sun, H, Wu, W, Jiang, Y, Song, L, et al.. Comparison of in vitro hormone activities of selected phthalates using reporter gene assays. Toxicol Lett 2009;191:9–14. https://doi.org/10.1016/j.toxlet.2009.07.019.Search in Google Scholar PubMed

84. Boas, M, Frederiksen, H, Feldt-Rasmussen, U, Skakkebæk, NE, Hegedüs, L, Hilsted, L, et al.. Childhood exposure to phthalates: associations with thyroid function, insulin-like growth factor I, and growth. Environ Health Perspect 2010;118:1458–64. https://doi.org/10.1289/ehp.0901331.Search in Google Scholar PubMed PubMed Central

85. Oliveira, KJ, Chiamolera, MI, Giannocco, G, Pazos-Moura, CC, Ortiga-Carvalho, TM. Thyroid function disruptors: from nature to chemicals. J Mol Endocrinol 2019;62:R1–9. https://doi.org/10.1530/jme-18-0081.Search in Google Scholar PubMed

86. Patrick, L. Thyroid disruption: mechanisms and clinical implications in human health. Alternative Med Rev 2009;14:326–46.Search in Google Scholar

87. Bility, MT, Thompson, JT, McKee, RH, David, RM, Butala, JH, Vanden Heuvel, JP, et al.. Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. Toxicol Sci 2004;82:170–82. https://doi.org/10.1093/toxsci/kfh253.Search in Google Scholar PubMed

88. Hurst, CH, Waxman, DJ. Activation of PPARα and PPARγ by environmental phthalate monoesters. Toxicol Sci 2003;74:297–308. https://doi.org/10.1093/toxsci/kfg145.Search in Google Scholar PubMed

89. Kambia, N, Renault, N, Dilly, S, Farce, A, Dine, T, Gressier, B, et al.. Molecular modelling of phthalates–PPARs interactions. J Enzym Inhib Med Chem 2008;23:611–6. https://doi.org/10.1080/14756360802205059.Search in Google Scholar PubMed

90. Kim, NY, Kim, TH, Lee, E, Patra, N, Lee, J, Shin, MO, et al.. Functional role of phospholipase D (PLD) in di (2-ethylhexyl) phthalate-induced hepatotoxicity in Sprague–Dawley rats. J Toxicol Environ Health A 2010;73:1560–9. https://doi.org/10.1080/15287394.2010.511582.Search in Google Scholar PubMed

91. Kusu, R, Oishi, A, Kakizawa, K, Kimura, T, Toda, C, Hashizume, K, et al.. Effects of phthalate ester derivatives including oxidized metabolites on coactivator recruiting by PPARα and PPARγ. Toxicol Vitro 2008;22:1534–8. https://doi.org/10.1016/j.tiv.2008.05.010.Search in Google Scholar PubMed

92. Borch, J, Metzdorff, SB, Vinggaard, AM, Brokken, L, Dalgaard, M. Mechanisms underlying the anti-andogenic effects of diethylhexyl phthalate in fetal rat testis. Toxicology 2006;223:144–55. https://doi.org/10.1016/j.tox.2006.03.015.Search in Google Scholar PubMed

93. Xu, XH, Zhang, J, Wang, YM, Ye, YP, Luo, QQ. Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down-regulation of N-methyl-d-aspartate receptors of hippocampus in male offspring mice. Horm Behav 2010;58:326–33. https://doi.org/10.1016/j.yhbeh.2010.02.012.Search in Google Scholar PubMed

94. Feige, JN, Gelman, L, Rossi, D, Zoete, V, Métivier, R, Tudor, C, et al.. The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor γ modulator that promotes adipogenesis. J Biol Chem 2007;282:19152–66. https://doi.org/10.1074/jbc.m702724200.Search in Google Scholar PubMed

95. Campioli, E, Martinez-Arguelles, DB, Papadopoulos, V. Utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring. Nutr Diabetes 2014;4:e115. https://doi.org/10.1038/nutd.2014.13.Search in Google Scholar PubMed PubMed Central

96. Duan, Y, Sun, H, Han, L, Chen, L. Association between phthalate exposure and glycosylated hemoglobin, fasting glucose, and type 2 diabetes mellitus: a case-control study in China. Sci Total Environ 2019;670:41–9. https://doi.org/10.1016/j.scitotenv.2019.03.192.Search in Google Scholar PubMed

97. Lind, PM, Zethelius, B, Lind, L. Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. Diabetes Care 2012;35:1519–24. https://doi.org/10.2337/dc11-2396.Search in Google Scholar PubMed PubMed Central

98. Reddy, JK, Azarnoff, DL, Hignite, CE. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature 1980;283:397–8. https://doi.org/10.1038/283397a0.Search in Google Scholar PubMed

99. Souter, I, Bellavia, A, Williams, PL, Korevaar, TI, Meeker, JD, Braun, JM, et al.. Urinary concentrations of phthalate metabolite mixtures in relation to serum biomarkers of thyroid function and autoimmunity among women from a fertility center. Environ Health Perspect 2020;128:067007. https://doi.org/10.1289/ehp6740.Search in Google Scholar

100. Stephen, RL, Gustafsson, MC, Jarvis, M, Tatoud, R, Marshall, BR, Knight, D, et al.. Activation of peroxisome proliferator-activated receptor δ stimulates the proliferation of human breast and prostate cancer cell lines. Canc Res 2004;64:3162–70. https://doi.org/10.1158/0008-5472.can-03-2760.Search in Google Scholar PubMed

101. Wolfrum, C, Borrmann, CM, Börchers, T, Spener, F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors α-and γ-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc Natl Acad Sci USA 2001;98:2323–8. https://doi.org/10.1073/pnas.051619898.Search in Google Scholar PubMed PubMed Central

102. Ernst, J, Jann, JC, Biemann, R, Koch, HM, Fischer, B. Effects of the environmental contaminants DEHP and TCDD on estradiol synthesis and aryl hydrocarbon receptor and peroxisome proliferator-activated receptor signalling in the human granulosa cell line KGN. Mol Hum Reprod 2014;20:919–28. https://doi.org/10.1093/molehr/gau045.Search in Google Scholar PubMed

103. Huang, LP, Lee, CC, Fan, JP, Kuo, PH, Shih, TS, Hsu, PC. Urinary metabolites of di (2-ethylhexyl) phthalate relation to sperm motility, reactive oxygen species generation, and apoptosis in polyvinyl chloride workers. Int Arch Occup Environ Health 2014;87:635–46. https://doi.org/10.1007/s00420-013-0905-6.Search in Google Scholar PubMed

104. Carpenter, DO. Polychlorinated biphenyls (PCBs): routes of exposure and effects on human health. Rev Environ Health 2006;21:1. https://doi.org/10.1515/reveh.2006.21.1.1.Search in Google Scholar PubMed

105. Dewalque, L, Pirard, C, Vandepaer, S, Charlier, C. Temporal variability of urinary concentrations of phthalate metabolites, parabens and benzophenone-3 in a Belgian adult population. Environ Res 2015;142:414–23. https://doi.org/10.1016/j.envres.2015.07.015.Search in Google Scholar PubMed

106. Nassan, FL, Coull, BA, Gaskins, AJ, Williams, MA, Skakkebaek, NE, Ford, JB, et al.. Personal care product use in men and urinary concentrations of select phthalate metabolites and parabens: results from the environment and reproductive health (EARTH) study. Environ Health Perspect 2017;125:087012. https://doi.org/10.1289/ehp1374.Search in Google Scholar

107. Zota, AR, Phillips, CA, Mitro, SD. Recent fast food consumption and bisphenol A and phthalates exposures among the US population in NHANES, 2003–2010. Environ Health Perspect 2016;124:1521–8. https://doi.org/10.1289/ehp.1510803.Search in Google Scholar

108. Chang, WY, Prins, GS. Estrogen receptor‐β: implications for the prostate gland. Prostate 1999;40:115–24. https://doi.org/10.1002/(sici)1097-0045(19990701)40:2<115::aid-pros7>3.0.co;2-3.10.1002/(SICI)1097-0045(19990701)40:2<115::AID-PROS7>3.0.CO;2-3Search in Google Scholar

109. Hirai, S, Naito, M, Kuramasu, M, Ogawa, Y, Terayama, H, Qu, N, et al.. Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice. Reprod Biol 2015;15:163–71. https://doi.org/10.1016/j.repbio.2015.06.004.Search in Google Scholar

110. Duan, J, Deng, T, Kang, J, Chen, M. DINP aggravates autoimmune thyroid disease through activation of the Akt/mTOR pathway and suppression of autophagy in Wistar rats. Environ Pollut 2019;245:316–24. https://doi.org/10.1016/j.envpol.2018.10.108.Search in Google Scholar

111. Wang, YX, Lee, CH, Tiep, S, Ruth, TY, Ham, J, Kang, H, et al.. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 2003;113:159–70. https://doi.org/10.1016/s0092-8674(03)00269-1.Search in Google Scholar

112. Buckley, JP, Engel, SM, Braun, JM, Whyatt, RM, Daniels, JL, Mendez, MA, et al.. Prenatal phthalate exposures and body mass index among 4 to 7 year old children: a pooled analysis. Epidemiology 2016;27:449. https://doi.org/10.1097/ede.0000000000000436.Search in Google Scholar

113. Harley, KG, Berger, K, Rauch, S, Kogut, K, Henn, BC, Calafat, AM, et al.. Association of prenatal urinary phthalate metabolite concentrations and childhood BMI and obesity. Pediatr Res 2017;82:405–15. https://doi.org/10.1038/pr.2017.112.Search in Google Scholar

114. Veiga-Lopez, A, Pu, Y, Gingrich, J, Padmanabhan, V. Obesogenic endocrine disrupting chemicals: identifying knowledge gaps. Trends Endrocrinol Metab 2018;29:607–25. https://doi.org/10.1016/j.tem.2018.06.003.Search in Google Scholar

115. Yeung, EH, Bell, EM, Sundaram, R, Ghassabian, A, Ma, W, Kannan, K, et al.. Examining endocrine disruptors measured in newborn dried blood spots and early childhood growth in a prospective cohort. Obesity 2019;27:145–51. https://doi.org/10.1002/oby.22332.Search in Google Scholar

116. Benjamin, S, Masai, E, Kamimura, N, Takahashi, K, Anderson, RC, Faisal, PA. Phthalates impact human health: epidemiological evidences and plausible mechanism of action. J Hazard Mater 2017;340:360–83. https://doi.org/10.1016/j.jhazmat.2017.06.036.Search in Google Scholar

117. Larsson, M, Weiss, B, Janson, S, Sundell, J, Bornehag, CG. Associations between indoor environmental factors and parental-reported autistic spectrum disorders in children 6–8 years of age. Neurotoxicology 2009;30:822–31. https://doi.org/10.1016/j.neuro.2009.01.011.Search in Google Scholar PubMed PubMed Central

118. Bornehag, CG, Lindh, C, Reichenberg, A, Wikström, S, Hallerback, MU, Evans, SF, et al.. Association of prenatal phthalate exposure with language development in early childhood. JAMA Pediatr 2018;172:1169–76. https://doi.org/10.1001/jamapediatrics.2018.3115.Search in Google Scholar PubMed PubMed Central

119. Fujimoto, T, Kubo, K, Aou, S. Prenatal exposure to bisphenol A impairs sexual differentiation of exploratory behavior and increases depression-like behavior in rats. Brain Res 2006;1068:49–55. https://doi.org/10.1016/j.brainres.2005.11.028.Search in Google Scholar PubMed

120. Hong, SB, Hong, YC, Kim, JW, Park, EJ, Shin, MS, Kim, BN, et al.. Bisphenol A in relation to behavior and learning of school‐age children. J Child Psychol Psychiatry 2013;54:890–9. https://doi.org/10.1111/jcpp.12050.Search in Google Scholar PubMed

121. Chen, T, Yang, W, Li, Y, Chen, X, Xu, S. Mono-(2-ethylhexyl) phthalate impairs neurodevelopment: inhibition of proliferation and promotion of differentiation in PC12 cells. Toxicol Lett 2011;201:34–41. https://doi.org/10.1016/j.toxlet.2010.12.002.Search in Google Scholar PubMed

122. Davey, RA, Grossmann, M. Androgen receptor structure, function and biology: from bench to bedside. Clin Biochem Rev 2016;37:3.Search in Google Scholar

123. Papakonstanti, EA, Kampa, M, Castanas, E, Stournaras, C. A rapid, nongenomic, signaling pathway regulates the actin reorganization induced by activation of membrane testosterone receptors. Mol Endocrinol 2003;17:870–81. https://doi.org/10.1210/me.2002-0253.Search in Google Scholar PubMed

124. Zhou, C, Flaws, JA. Effects of an environmentally relevant phthalate mixture on cultured mouse antral follicles. Toxicol Sci 2017;156:217–29. https://doi.org/10.1093/toxsci/kfw245.Search in Google Scholar PubMed PubMed Central


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/reveh-2020-0162).


Received: 2021-01-11
Accepted: 2021-09-09
Published Online: 2021-09-29
Published in Print: 2022-12-16

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 6.2.2023 from https://www.degruyter.com/document/doi/10.1515/reveh-2020-0162/html
Scroll Up Arrow