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BPA exposure is associated with non-monotonic alteration in ESR1 promoter methylation in peripheral blood of men and shorter relative telomere length in peripheral blood of women

Journal of Exposure Science & Environmental Epidemiology volume 29, pages 118–128 (2019)Cite this article

Abstract

The aim of this study was to evaluate the potential association of urinary Bisphenol A (BPA) levels with estrogen receptor alpha (ESR1) promoter % methylation and relative telomere length in a sample of 482 participants. Urinary BPA concentration was measured using organic phase extraction followed by high performance liquid chromatography mass spectroscopy. Peripheral blood ESR1 promoter % methylation and relative telomere length were measured using direct bisulfite sequencing and real-time polymerase chain reaction, respectively. The mean ± SD urinary BPA concentration adjusted for urinary creatinine was 2.90 ± 4.81 (μg/g creatinine) with a median of 1.86 μg/g creatinine (min–max: <LOD −69.85). There was a potentially non-monotonic relationship between adjusted urinary BPA concentrations and ESR1 promoter % methylation in men. As a matter of fact, for the lowest tertile of ESR1 promoter % methylation, the OR and 95% CI of the middle and highest tertiles of urinary adjusted BPA were 2.54 (1.01–6.39) and 1.64 (0.55–4.86) when compared to the lowest BPA tertile, respectively. After adjustment for potential confounders, similar results remained in men and appeared in the whole cohort. As for relative telomere length, there was a significant trend whereby higher adjusted urinary BPA concentrations were significantly associated with shorter relative telomere length in females. For instance, for the shortest relative telomere length tertile, the OR and 95% CI of the middle and highest tertiles of urinary adjusted BPA were 2.91 (1.38–6.16) and 3.19 (1.57–6.49) when compared to the lowest BPA tertile, respectively. This trend remained significant after adjustment for potential confounders.

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References

  1. Chen D, Kannan K, Tan H, Zheng Z, Feng YL, Wu Y, et al. Bisphenol analogues other than bpa: environmental occurrence, human exposure, and toxicity-a review. Environ Sci Technol. 2016;50:5438–53.

    Article  CAS  Google Scholar 

  2. Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, et al. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA. 2008;300:1303–10.

    Article  CAS  Google Scholar 

  3. Melzer D, Rice NE, Lewis C, Henley WE, Galloway TS. Association of urinary bisphenol a concentration with heart disease: evidence from NHANES 2003/06. PLoS ONE. 2010;5:e8673.

    Article  Google Scholar 

  4. Seachrist DD, Bonk KW, Ho SM, Prins GS, Soto AM, Keri RA. A review of the carcinogenic potential of bisphenol A. Reprod Toxicol. 2016;59:167–82.

    Article  CAS  Google Scholar 

  5. Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, et al. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007;24:199–224.

    Article  CAS  Google Scholar 

  6. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ Health Perspect. 2008;116:39–44.

    Article  CAS  Google Scholar 

  7. Bushnik T, Haines D, Levallois P, Levesque J, Van Oostdam J, Viau C. Lead and bisphenol A concentrations in the Canadian population. Health Rep. 2010;21:7–18.

    PubMed  Google Scholar 

  8. Yang M, Kim SY, Lee SM, Chang SS, Kawamoto T, Jang JY, et al. Biological monitoring of bisphenol a in a Korean population. Arch Environ Contam Toxicol. 2003;44:546–51.

    Article  CAS  Google Scholar 

  9. Arakawa C, Fujimaki K, Yoshinaga J, Imai H, Serizawa S, Shiraishi H. Daily urinary excretion of bisphenol A. Environ Health Prev Med. 2004;9:22–6.

    Article  CAS  Google Scholar 

  10. Matsumoto A, Kunugita N, Kitagawa K, Isse T, Oyama T, Foureman GL, et al. Bisphenol A levels in human urine. Environ Health Perspect. 2003;111:101–4.

    Article  CAS  Google Scholar 

  11. Ouchi K, Watanabe S. Measurement of bisphenol A in human urine using liquid chromatography with multi-channel coulometric electrochemical detection. J Chromatogr B Anal Technol Biomed Life Sci. 2002;780:365–70.

    Article  CAS  Google Scholar 

  12. Covaci A, Den Hond E, Geens T, Govarts E, Koppen G, Frederiksen H, et al. Urinary BPA measurements in children and mothers from six European member states: overall results and determinants of exposure. Environ Res. 2015;141:77–85.

    Article  CAS  Google Scholar 

  13. Mouneimne Y, Nasralla M, Zgheib NK, Nasreddine L, Nakhoul N, Ismail H, Abiad M, Koleilat L, Tamim H. Bisphenol A urinary levels, its correlates and association with cardiometabolic risks in Lebanese urban adults. Environ Monit Assess. 2017;189:517.

    Article  Google Scholar 

  14. Zhang Z, Alomirah H, Cho HS, Li YF, Liao C, Minh TB, et al. Urinary bisphenol A concentrations and their implications for human exposure in several Asian countries. Environ Sci Technol. 2011;45:7044–50.

    Article  CAS  Google Scholar 

  15. Ye X, Kuklenyik Z, Needham LL, Calafat AM. Quantification of urinary conjugates of bisphenol A, 2,5-dichlorophenol, and 2-hydroxy-4-methoxybenzophenone in humans by online solid phase extraction-high performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. 2005;383:638–44.

    Article  CAS  Google Scholar 

  16. Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Ekong J, Needham LL. Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population. Environ Health Perspect. 2005;113:391–5.

    Article  CAS  Google Scholar 

  17. Lapensee EW, Tuttle TR, Fox SR, Ben-Jonathan N. Bisphenol A at low nanomolar doses confers chemoresistance in estrogen receptor-alpha-positive and -negative breast cancer cells. Environ Health Perspect. 2009;117:175–80.

    Article  CAS  Google Scholar 

  18. Gao H, Yang BJ, Li N, Feng LM, Shi XY, Zhao WH, et al. Bisphenol A and hormone-associated cancers: current progress and perspectives. Medicine. 2015;94:e211.

    Article  CAS  Google Scholar 

  19. Dairkee SH, Luciani-Torres MG, Moore DH, Goodson WH 3rd. Bisphenol-A-induced inactivation of the p53 axis underlying deregulation of proliferation kinetics, and cell death in non-malignant human breast epithelial cells. Carcinogenesis. 2013;34:703–12.

    Article  CAS  Google Scholar 

  20. Kim JH, Rozek LS, Soliman AS, Sartor MA, Hablas A, Seifeldin IA, et al. Bisphenol A-associated epigenomic changes in prepubescent girls: a cross-sectional study in Gharbiah, Egypt. Environ Health. 2013;12:33.

    Article  CAS  Google Scholar 

  21. Miao M, Zhou X, Li Y, Zhang O, Zhou Z, Li T, et al. LINE-1 hypomethylation in spermatozoa is associated with Bisphenol A exposure. Andrology. 2014;2:138–44.

    Article  CAS  Google Scholar 

  22. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–5.

    Article  CAS  Google Scholar 

  23. Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, et al. The RNA component of human telomerase. Science. 1995;269:1236–41.

    Article  CAS  Google Scholar 

  24. Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science. 1997;276:561–7.

    Article  CAS  Google Scholar 

  25. Takahashi A, Higashino F, Aoyagi M, Kyo S, Nakata T, Noda M, et al. Bisphenol A from dental polycarbonate crown upregulates the expression of hTERT. J Biomed Mater Res B Appl Biomater. 2004;71:214–21.

    Article  Google Scholar 

  26. Hiyama E, Hiyama K, Yokoyama T, Shay JW. Immunohistochemical detection of telomerase (hTERT) protein in human cancer tissues and a subset of cells in normal tissues. Neoplasia. 2001;3:17–26.

    Article  CAS  Google Scholar 

  27. Carey LA, Hedican CA, Henderson GS, Umbricht CB, Dome JS, Varon D, et al. Careful histological confirmation and microdissection reveal telomerase activity in otherwise telomerase-negative breast cancers. Clin Cancer Res. 1998;4:435–40.

    CAS  PubMed  Google Scholar 

  28. Pellatt AJ, Wolff RK, Torres-Mejia G, John EM, Herrick JS, Lundgreen A, et al. Telomere length, telomere-related genes, and breast cancer risk: the breast cancer health disparities study. Genes Chromosomes Cancer. 2013;52:595–609.

    CAS  PubMed  Google Scholar 

  29. Zhang C, Chen X, Li L, Zhou Y, Wang C, Hou S. The Association between Telomere Length and Cancer Prognosis: Evidence from a Meta-Analysis. PLoS ONE. 2015;10:e0133174.

    Article  Google Scholar 

  30. Zgheib NK, Sleiman F, Nasreddine L, Nasrallah M, Nakhoul N, Isma’eel H, et al. Short telomere length is associated with aging, central obesity, poor sleep and hypertension in Lebanese individuals aging and disease 2017. http://www.aginganddisease.org/EN/10.14336/AD.2017.030610

  31. Akika R, Awada Z, Mogharbil N, Zgheib NK. Region of interest methylation analysis: a comparison of MSP with MS-HRM and direct BSP. Mol Biol Rep. 2017;44:295–305.

    Article  CAS  Google Scholar 

  32. Cui Y, Gao YT, Cai Q, Qu S, Cai H, Li HL, et al. Associations of leukocyte telomere length with body anthropometric indices and weight change in Chinese women. Obesity (Silver Spring). 2013;21:2582–8.

    Article  Google Scholar 

  33. Martens UM, Brass V, Sedlacek L, Pantic M, Exner C, Guo Y, et al. Telomere maintenance in human B lymphocytes. Br J Haematol. 2002;119:810–8.

    Article  CAS  Google Scholar 

  34. Kim S, Parks CG, DeRoo LA, Chen H, Taylor JA, Cawthon RM, et al. Obesity and weight gain in adulthood and telomere length. Cancer Epidemiol Biomark Prev. 2009;18:816–20.

    Article  CAS  Google Scholar 

  35. Post WS, Goldschmidt-Clermont PJ, Wilhide CC, Heldman AW, Sussman MS, Ouyang P, et al. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc Res. 1999;43:985–91.

    Article  CAS  Google Scholar 

  36. Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994;7:536–40.

    Article  CAS  Google Scholar 

  37. Kwabi-Addo B, Chung W, Shen L, Ittmann M, Wheeler T, Jelinek J, et al. Age-related DNA methylation changes in normal human prostate tissues. Clin Cancer Res. 2007;13:3796–802.

    Article  CAS  Google Scholar 

  38. Chao HH, Zhang XF, Chen B, Pan B, Zhang LJ, Li L, et al. Bisphenol A exposure modifies methylation of imprinted genes in mouse oocytes via the estrogen receptor signaling pathway. Histochem Cell Biol. 2012;137:249–59.

    Article  CAS  Google Scholar 

  39. Jang YJ, Park HR, Kim TH, Yang WJ, Lee JJ, Choi SY, et al. High dose bisphenol A impairs hippocampal neurogenesis in female mice across generations. Toxicology. 2012;296:73–82.

    Article  CAS  Google Scholar 

  40. Zhang HQ, Zhang XF, Zhang LJ, Chao HH, Pan B, Feng YM, et al. Fetal exposure to bisphenol A affects the primordial follicle formation by inhibiting the meiotic progression of oocytes. Mol Biol Rep. 2012;39:5651–7.

    Article  CAS  Google Scholar 

  41. Doshi T, Mehta SS, Dighe V, Balasinor N, Vanage G. Hypermethylation of estrogen receptor promoter region in adult testis of rats exposed neonatally to bisphenol A. Toxicology. 2011;289:74–82.

    Article  CAS  Google Scholar 

  42. Doshi T, D’Souza C, Dighe V, Vanage G. Effect of neonatal exposure on male rats to bisphenol A on the expression of DNA methylation machinery in the postimplantation embryo. J Biochem Mol Toxicol. 2012;26:337–43.

    Article  CAS  Google Scholar 

  43. Anderson OS, Nahar MS, Faulk C, Jones TR, Liao C, Kannan K, et al. Epigenetic responses following maternal dietary exposure to physiologically relevant levels of bisphenol A. Environ Mol Mutagen. 2012;53:334–42.

    Article  CAS  Google Scholar 

  44. Wolstenholme JT, Taylor JA, Shetty SR, Edwards M, Connelly JJ, Rissman EF. Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice. PLoS ONE. 2011;6:e25448.

    Article  CAS  Google Scholar 

  45. Monje L, Varayoud J, Luque EH, Ramos JG. Neonatal exposure to bisphenol A modifies the abundance of estrogen receptor alpha transcripts with alternative 5’-untranslated regions in the female rat preoptic area. J Endocrinol. 2007;194:201–12.

    Article  CAS  Google Scholar 

  46. Hiyama M, Choi EK, Wakitani S, Tachibana T, Khan H, Kusakabe KT, et al. Bisphenol-A (BPA) affects reproductive formation across generations in mice. J Vet Med Sci. 2011;73:1211–5.

    Article  CAS  Google Scholar 

  47. Abdel-Maksoud FM, Leasor KR, Butzen K, Braden TD, Akingbemi BT. Prenatal exposures of male rats to the environmental chemicals Bisphenol A and di(2-ethylhexyl) phthalate impact the sexual differentiation process. Endocrinology. 2015;156:4672–83.

    Article  CAS  Google Scholar 

  48. Melzer D, Harries L, Cipelli R, Henley W, Money C, McCormack P, et al. Bisphenol A exposure is associated with in vivo estrogenic gene expression in adults. Environ Health Perspect. 2011;119:1788–93.

    Article  CAS  Google Scholar 

  49. Cao J, Rebuli ME, Rogers J, Todd KL, Leyrer SM, Ferguson SA, et al. Prenatal bisphenol A exposure alters sex-specific estrogen receptor expression in the neonatal rat hypothalamus and amygdala. Toxicol Sci. 2013;133:157–73.

    Article  CAS  Google Scholar 

  50. Myers P, Hessler W Does ‘the dose make the poison?’ Extensive results challenge a core assumption in toxicology. Environ Health News. 2007 http://www.ourstolenfuture.org/NewScience/lowdose/2007/2007-0525nmdrc.html

  51. Lagarde F, Beausoleil, Belcher SM, Belzunces LP, Emond C, Guerbet M, et al. Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment. Environ Health 2015;14:13.

  52. Sarkar P, Shiizaki K, Yonemoto J, Sone H. Activation of telomerase in BeWo cells by estrogen and 2,3,7,8-tetrachlorodibenzo-p-dioxin in co-operation with c-Myc. Int J Oncol. 2006;28:43–51.

    CAS  PubMed  Google Scholar 

  53. Bayne S, Jones ME, Li H, Pinto AR, Simpson ER, Liu JP. Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice. Cell Res. 2008;18:1141–50.

    Article  CAS  Google Scholar 

  54. Roy D, Colerangle JB, Singh KP. Is exposure to environmental or industrial endocrine disrupting estrogen-like chemicals able to cause genomic instability? Front Biosci. 1998;3:d913–21.

    Article  CAS  Google Scholar 

  55. Zhang X, Mar V, Zhou W, Harrington L, Robinson MO. Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev. 1999;13:2388–99.

    Article  CAS  Google Scholar 

  56. Al-Attas OS, Al-Daghri NM, Alokail MS, Alkharfy KM, Alfadda AA, McTernan P, et al. Circulating leukocyte telomere length is highly heritable among families of Arab descent. BMC Med Genet. 2012;13:38.

    Article  CAS  Google Scholar 

  57. Lee M, Martin H, Firpo MA, Demerath EW. Inverse association between adiposity and telomere length: the Fels longitudinal study. Am J Hum Biol. 2011;23:100–6.

    Article  CAS  Google Scholar 

  58. Fitzpatrick AL, Kronmal RA, Gardner JP, Psaty BM, Jenny NS, Tracy RP, et al. Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol. 2007;165:14–21.

    Article  Google Scholar 

  59. Brouilette S, Singh RK, Thompson JR, Goodall AH, Samani NJ. White cell telomere length and risk of premature myocardial infarction. Arterioscler Thromb Vasc Biol. 2003;23:842–6.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the American University of Beirut Faculty of Medicine seed grant to Dr. Hani Tamim and Research grant to Dr. Nathalie K. Zgheib as well as a Lebanese National Council for Scientific Research (LNCSR) PhD scholarship award to Miss Zainab Awada.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

    Z. Awada, F. Sleiman & N. K. Zgheib

  2. Clinical Research Institute, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon

    A. Mailhac & H. Tamim

  3. Kamal A. Shair Central Research Science Laboratory, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon

    Y. Mouneimne

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Awada, Z., Sleiman, F., Mailhac, A. et al. BPA exposure is associated with non-monotonic alteration in ESR1 promoter methylation in peripheral blood of men and shorter relative telomere length in peripheral blood of women. J Expo Sci Environ Epidemiol 29, 118–128 (2019). https://doi.org/10.1038/s41370-018-0030-4

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