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
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.
World Health Organization. State of the science of endocrine-disrupting chemicals. Geneva: International Programme on Chemical Safety; 2012.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Newbold RR, Padilla-Banks E, Jefferson WN. Environmental estrogens and obesity. Mol Cell Endocrinol. 2009;304:84–9.
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.
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.
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.
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.
Masuda M, Kubota T, Karnada S, Aso T. Nitric oxide inhibits steroidogenesis in cultured porcine granulosa cells. Mol Hum Reprod. 1997;3:285–92.
Integrated risk information system (IRIS). Bisphenol A (CASRN 80-05-7), vol 2003.US-EPA.
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.
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.
Lowry OH, Rosebrough MJ, Farr AL, Randall RJ. Protein measurement with the Folin Phenol reagent. J Biol Chem. 1951;193:265–75.
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.
Yagi K. Lipid peroxides and human diseases. Chem Phys Lipids. 1987;45:337–51.
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8.
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.
Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys. 1984;21:130–2.
Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972;47:389–94.
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.
Beutler E, Kelley BM. The effect of sodium nitrate on RBC glutathione. Experientia. 1963;29:96–7.
Zlatkis A, Zak B, Boyle GJ. A new method for the direct determination of serum cholesterol. J Lab Clin Med. 1953;41:486–92.
Foster LB, Dunn RT. Stable reagents for determination of serum triglycerides by a colorimetric Hantzsch condensation method. Clin Chem. 1973;19:338–40.
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.
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.
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.
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.
Gao Q, Horvath TL. Cross-talk between estrogen and leptin signaling in the hypothalamus. Am J Physiol Endocrinol Metab. 2008;294:E817–26.
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.
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.
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.
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.
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.
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.
Del Punta K, Charreau EH, Pignataro OP. Nitric oxide inhibits Leydig cell steroidogenesis. Endocrinology. 1996;137:5337–43.
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.
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.
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.
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.
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.
Szabó C, Ischiropoulos H, Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007;6:662–80.
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.
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.
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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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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DOI: https://doi.org/10.1007/s12291-017-0696-8