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Monotonic Dose Effect of Bisphenol-A, an Estrogenic Endocrine Disruptor, on Estrogen Synthesis in Female Sprague-Dawley Rats

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Abstract

Bisphenol-A (BPA) is a ubiquitous environmental chemical that produces adverse effect on reproduction system due to its potent estrogenic endocrine disruptive activity. The present study was aimed to investigate the monotonic dose effect of BPA on estrogen synthesis in female Sprague-Dawley rats. For this purpose, we administered three different doses of BPA (10, 50, 100 µg/kg bw/day) into rats and analyzed various biochemical, hormonal, molecular and histological parameters. 10 µg BPA treated rats showed significantly decreased levels of phase I detoxification agents (CYP450, Cyt-b5). Overexpression of eNOS with decreased expression of StAR and steroidogenic enzymes (CYP11A1, aromatase) indicate decreased production of estrogen. Increased levels of serum gonadotropins (FSH, LH) and decreased levels of estradiol suggest mimetic action of BPA and its feedback inhibition. Increased body weight, lipid profile status of 10 µg BPA treated rats and histological analysis of ovary and mammary tissue support the study. Overall, our results suggest that BPA exerts its estrogen mimetic effects in a monotonic manner.

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Abbreviations

BPA:

Bisphenol-A

TC:

Total cholesterol

TG:

Triglycerides

HDL-C:

High density lipoprotein-cholesterol

TBARS:

Thiobarbituric acid substances

GSH:

Reduced glutathione

StAR:

Steroidogenic acute regulatory protein

eNOS:

Endothelial nitric oxide synthase

CYP11A1:

Cytochrome P450 monooxygenase

References

  1. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: an endocrine society scientific statement. Endocr Rev. 2009;30:293–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. World Health Organization. State of the science of endocrine-disrupting chemicals. Geneva: International Programme on Chemical Safety; 2012.

    Google Scholar 

  3. Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, et al. Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology. 2012;153:4097–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM. Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev. 2009;30:75–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Souter I, Smith KW, Dimitriadis I, Ehrlich S, Williams PL, Calafat AM, et al. The association of bisphenol-A urinary concentrations with antral follicle counts and other measures of ovarian reserve in women undergoing infertility treatments. Reprod Toxicol. 2013;42:224–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wetherill YB, Akingbemi BT, Kanno J, McLachlan JA, Nadal A, Sonnenschein C, et al. In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol. 2007;24:178–98.

    Article  CAS  PubMed  Google Scholar 

  7. Hugo ER, Brandebourg TD, Woo JG, Loftus J, Alexander JW, Ben-Jonathan N. Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes. Environ Health Perspect. 2008;116:1642–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Berger RG, Foster WG, deCatanzaro D. Bisphenol-A exposure during the period of blastocyst implantation alters uterine morphology and perturbs measures of estrogen and progesterone receptor expression in mice. Reprod Toxicol. 2010;30:393–400.

    Article  CAS  PubMed  Google Scholar 

  9. Fernández M, Bianchi M, Lux-Lantos V, Libertun C. Neonatal exposure to bisphenol a alters reproductive parameters and gonadotropin releasing hormone signaling in female rats. Environ Health Perspect. 2009;117:757–62.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Abrahám IM, Han SK, Todman MG, Korach KS, Herbison AE. Estrogen receptor beta mediates rapid estrogen actions on gonadotropin-releasing hormone neurons in vivo. J Neurosci. 2003;23:5771–7.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fernandez M, Bourguignon N, Lantos LV. Neonatal exposure to bisphenol A and reproductive and endocrine alteration resembling the polysystic ovarian syndrome in adult rats. Environ Health Perspect. 2010;118:1217–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hunt PA, Susiarjo M, Rubio C, Hassold TJ. The bisphenol A experience: a primer for the analysis of environmental effects on mammalian reproduction. Biol Reprod. 2009;81:807–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Newbold RR, Padilla-Banks E, Jefferson WN. Environmental estrogens and obesity. Mol Cell Endocrinol. 2009;304:84–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rubin BS, Murray MK, Damassa DA, King JC, Soto AM. Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environ Health Perspect. 2001;109:675–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cabaton NJ, Wadia PR, Rubin BS, Zalko D, Schaeberle CM, Askenase MH, et al. Perinatal exposure to environmentally relevant levels of bisphenol A decreases fertility and fecundity in CD-1 mice. Environ Health Perspect. 2011;119:547–52.

    Article  CAS  PubMed  Google Scholar 

  16. Wang W, Craig ZR, Basavarajappa MS, Hafner KS, Flaws JA. Mono-(2-ethylhexyl) phthalate induces oxidative stress and inhibits growth of mouse ovarian antral follicles. Biol Reprod. 2012;87:152.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Drazen DL, Klein SL, Burnett AL, Wallach EE, Crone JK, Huang PL, et al. Reproductive function in female mice lacking the gene for endothelial nitric oxide synthase. Nitric Oxide. 1999;3:366–74.

    Article  CAS  PubMed  Google Scholar 

  18. Masuda M, Kubota T, Karnada S, Aso T. Nitric oxide inhibits steroidogenesis in cultured porcine granulosa cells. Mol Hum Reprod. 1997;3:285–92.

    Article  CAS  PubMed  Google Scholar 

  19. Integrated risk information system (IRIS). Bisphenol A (CASRN 80-05-7), vol 2003.US-EPA.

  20. EFSA. Opinion of the EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) on the risk to public health related to the presence of bisphenol A (BPA) in foodstuffs. EFSA J. 2015;13:3978.

    Article  Google Scholar 

  21. Hanioka N, Jinno H, Nishimura T, Anto M. Changes in cytochrome P450 enzymes by 1, 1- dichloroethylene in rat liver and kidney. Arch Toxicol. 1997;72:9–16.

    Article  CAS  PubMed  Google Scholar 

  22. Lowry OH, Rosebrough MJ, Farr AL, Randall RJ. Protein measurement with the Folin Phenol reagent. J Biol Chem. 1951;193:265–75.

    CAS  PubMed  Google Scholar 

  23. Omura T, Sato R. The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem. 1964;239:2370–8.

    CAS  PubMed  Google Scholar 

  24. Yagi K. Lipid peroxides and human diseases. Chem Phys Lipids. 1987;45:337–51.

    Article  CAS  PubMed  Google Scholar 

  25. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8.

    Article  CAS  PubMed  Google Scholar 

  26. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957;226:497–509.

    CAS  PubMed  Google Scholar 

  27. Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys. 1984;21:130–2.

    CAS  PubMed  Google Scholar 

  28. Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972;47:389–94.

    Article  CAS  PubMed  Google Scholar 

  29. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973;179:588–90.

    Article  CAS  PubMed  Google Scholar 

  30. Beutler E, Kelley BM. The effect of sodium nitrate on RBC glutathione. Experientia. 1963;29:96–7.

    Article  Google Scholar 

  31. Zlatkis A, Zak B, Boyle GJ. A new method for the direct determination of serum cholesterol. J Lab Clin Med. 1953;41:486–92.

    CAS  PubMed  Google Scholar 

  32. Foster LB, Dunn RT. Stable reagents for determination of serum triglycerides by a colorimetric Hantzsch condensation method. Clin Chem. 1973;19:338–40.

    CAS  PubMed  Google Scholar 

  33. Burstein M, Scholnick HR, Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res. 1970;11:583–95.

    CAS  PubMed  Google Scholar 

  34. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.

    CAS  PubMed  Google Scholar 

  35. Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology. 2006;147:S56–69.

    Article  CAS  PubMed  Google Scholar 

  36. Zsarnovszky A, Le HH, Wang HS, Belcher SM. Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A. Endocrinology. 2005;146:5388–96.

    Article  CAS  PubMed  Google Scholar 

  37. Gao Q, Horvath TL. Cross-talk between estrogen and leptin signaling in the hypothalamus. Am J Physiol Endocrinol Metab. 2008;294:E817–26.

    Article  CAS  PubMed  Google Scholar 

  38. Somm E, Schwitzgebel VM, Toulotte A, Cederroth CR, Combescure C, Nef S, et al. Perinatal exposure to bisphenol a alters early adipogenesis in the rat. Environ Health Perspect. 2009;117:1549–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Marmugi A, Lasserre F, Beuzelin D, Ducheix S, Huc L, Polizzi A, et al. Adverse effects of long-term exposure to bisphenol A during adulthood leading to hyperglycaemia and hypercholesterolemia in mice. Toxicology. 2014;325:133–43.

    Article  CAS  PubMed  Google Scholar 

  40. Welshons WV, Engler KS, Taylor JA, Grady LH, Curran EM. Lithium-stimulated proliferation and alteration of phosphoinositide metabolites in MCF-7 human breast cancer cells. J Cell Physiol. 1995;165:134–44.

    Article  CAS  PubMed  Google Scholar 

  41. Welshons WV, Thayer KA, Judy BM, Taylor JA, Curran EM, vom Saal FS. Large effects from small exposures.I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. Environ Health Perspect. 2003;111:994–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Srivastava VK, Dissen GA, Ojeda SR, Hiney JK, Pine MD, Dees WL. Effects of alcohol on intraovarian nitric oxide synthase and steroidogenic acute regulatory protein in the prepubertal female rhesus monkey. J Stud Alcohol Drugs. 2007;68:182–91.

    Article  PubMed  Google Scholar 

  43. Ducsay CA, Myers DA. eNOS activation and NO function: differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia. J Endocrinol. 2011;210:259–69.

    Article  CAS  PubMed  Google Scholar 

  44. Del Punta K, Charreau EH, Pignataro OP. Nitric oxide inhibits Leydig cell steroidogenesis. Endocrinology. 1996;137:5337–43.

    Article  PubMed  Google Scholar 

  45. Peretz J, Gupta KRK, Singh J, Hernández-Ochoa I, Flaws JA. Bisphenol A impairs follicle growth, inhibits steroidogenesis, and down regulates rate-limiting enzymes in the estradiol biosynthesis pathway. Toxicol Sci. 2011;119:209–17.

    Article  CAS  PubMed  Google Scholar 

  46. Drewett JG, Adams-Hays RL, Ho BY, Hegge DJ. Nitric oxide potently inhibits the rate-limiting enzymatic step in steroidogenesis. Mol Cell Endocrinol. 2002;194:39–50.

    Article  CAS  PubMed  Google Scholar 

  47. Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, et al. Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect. 2014;122:775–86.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lee SG, Kim JY, Chung JY, Kim YJ, Park JE, Oh S, et al. Bisphenol A exposure during adulthood causes augmentation of follicular atresia and luteal regression by decreasing 17β-estradiol synthesis via downregulation of aromatase in rat ovary. Environ Health Perspect. 2013;121:663–9.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ooe H, Taira T, Iguchi-Ariga SM, Ariga H. Induction of reactive oxygen species by bisphenol A and abrogation of bisphenol A-induced cell injury by DJ-1. Toxicol Sci. 2005;88:114–26.

    Article  CAS  PubMed  Google Scholar 

  50. Szabó C, Ischiropoulos H, Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007;6:662–80.

    Article  PubMed  Google Scholar 

  51. Atkinson A, Roy D. The In vitro conversion of environmental estrogenic chemical bisphenol A to DNA binding metabolite(s). Biochem Biophys Res Commun. 1995;210:424–33.

    Article  CAS  PubMed  Google Scholar 

  52. Hanioka N, Jinno H, Nishimura T, Ando M. Suppression of male-specific cytochrome P450 isoforms by bisphenol A in rat liver. Arch Toxicol. 1998;72:387–94.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors grateful to Prof. J. Thanka, Head, Department of Pathology, Sri Ramachandra Medical College and RI, Sri Ramachandra University, Porur, Chennai for their help in histopathological studies. We gratefully acknowledge the financial assistance from University Grants Commission (UGC), New Delhi, India in the form of Major Research Project.

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Correspondence to Pachaiappan Pugalendhi.

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Thilagavathi, S., Pugalendhi, P., Rajakumar, T. et al. Monotonic Dose Effect of Bisphenol-A, an Estrogenic Endocrine Disruptor, on Estrogen Synthesis in Female Sprague-Dawley Rats. Ind J Clin Biochem 33, 387–396 (2018). https://doi.org/10.1007/s12291-017-0696-8

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