Epigenetic effects of in utero bisphenol A administration: Diabetogenic and atherogenic changes in mice offspring

Document Type : Original Article


Department of Anatomy, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan


Objective(s): Bisphenol A (BPA) that is a monomer of plastic products may possibly interfere with epigenetics and be involved in onset and progression of several diseases. This study was aimed to detect the epigenetic effects of in utero BPA exposure in mice offspring.
Materials and Methods: All experiments were performed according to the national guidelines for laboratory animals and after ethical approval. Thirty adult BALB/c female mice were divided into 3 equal groups, G1 (controls), G2 (ethanol 0.10 ml/100ml of PBS so that final concentration would be 0.01%) vehicle control and G3 (BPA 10 mg/kg). Chemicals were given twice a week throughout the pregnancy. Once delivered at term, female offspring were observed for body weight, behavior and movements. Blood glucose, serum insulin, cholesterol and high-density lipoprotein cholesterol (HDLc) were measured at 5 and 15 months postnatal. Animals were sacrificed at 15 months and pancreas, kidney, adipose tissue and uterine tissue were taken and stained with either Hematoxylin and eosin (H & E) or immunostaining and examined under light microscope.
Results: Offspring of group G3 revealed abnormal changes of body weight, behavior and movements. Blood glucose, serum insulin, cholesterol and HDLc were high in group G3 offspring compared to controls. H & E staining showed changes in the parenchyma of pancreas, kidneys and uterus, which were confirmed by staining with anti- islet-1, kidney-specific (Ksp) cadherin, and anti- MLH antibody.
Conclusion: In utero exposure of BPA exerts diabetogenic and atherogenic effects with less parenchymal tissue in endocrine pancreas, kidney and uterus.


Main Subjects

1. Wang T, Xie C, Yu P, Fang F, Zhu J, Cheng J, et al. Involvement of insulin signaling disturbances in bisphenol a-induced alzheimer’s disease-like neurotoxicity. Sci Rep 2017; 7:1-12.
2. Pivnenko K, Pedersen GA, Eriksson E, Astrup TF. Bisphenol A and its structural analogues in household waste paper. Waste Manag 2015; 44:39-47.
3. vom Saal FS, Nagel SC, Coe BL, Angle BM, Taylor JA. The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity. Mol Cell Endocrinol 2012; 354:74-84.
4. Ahmed RA, Elghamrawy TA, Salama EE. Effect of prenatal exposure to bisphenol a on the vagina of albino rats: immunohistochemical and ultrastructural study. Folia Morphol 2014; 73:399-408.
5. Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci 2007; 104:13056-13061.
6. Gauderat G, Picard-Hagen N, Toutain PL, Servien R, Viguie C, Puell S. Prediction of human prenatal exposure to bisphenol A and bisphenol A glucuronide from an ovine semi-physiological toxicokinetic model. Sci Rep 2017; 7:1-13.
7. Le HH, Carlson EM, Chua JP, Belcher SM. Bisphenol-A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol Lett 2008; 176:149-156.
8. Ribeiro E, Ladeira C, Viegas S. Occupational exposure to bisphenol-A (BPA): a reality that still needs to be unveiled. Toxics 2017; 5:1-16.
9. Danzo BJ. The effects of environmental hormones on reproduction. Cell Mol Life Sci 1998; 54:1249-1264.
10. Miller SD, Karpus WJ, Davidson TS. Experimental autoimmune encephalomyelitis in the mouse. Curr Protoc Immunol 2010; 88:1-26.
11. Robert PB, Cyril B, Yves DK. A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von frey filaments. Mol Pain 2014; 10:10-26.
12. Kim S, Christopher L, John B. Bancroft’s Theory and Practice of Histological Techniques. United Kingdom: Elsevier; 2012.p.584.
13. Alonso-Magdalena P, Vieira E, Soriano S, Menes L, Burks D, Quesada I, et al. Bisphenol-A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environ Health Perspect 2010; 118:1243-1250.
14. Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A. The estrogenic effect of bisphenol-A disrupts pancreatic beta-cell function In vivo and induces insulin resistance. Environ Health Perspect 2006; 114:106-112.
15. Alonso-Magdalena P, Quesada I, Nadal A. Prenatal exposure to BPA and offspring outcomes: the diabesogenic behavior of BPA dose-response. Dose Response 2015: 12:1-8.
16. Angle BM, Do RP, Ponzi D, Stahlhut RW, Drury BE, Nagel SC, et al. Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol-A (BPA): evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation. Reprod Toxicol 2013; 42:256-268.
17. Garcia-Arevalo M, Alonso-Magdalena P, Rebelo Dos Santos J, Quesada I, Carneiro EM, Nadal A. Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice. PLoS One 2014; 9: 100214-100227.
18. Wei J, Lin Y, Li Y, Ying C, Chen J, Song L. Perinatal exposure to Bisphenol-A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet. Endocrinol 2011; 152:3049-3061. 19. Ding S, Fan Y, Zhao N, Yang H, Ye X, He D. High-fat diet aggravates glucose homeostasis disorder caused by chronic exposure to bisphenol-A. J Endocrinol 2014; 221:167-179.
20. Ke ZH, Pan JX, Jin LY, Xu HY, Yu TT, Ullah K, et al. Bisphenol-A exposure may induce hepatic lipid accumulation via reprogramming the DNA methylation patterns of genes involved in lipid metabolism. Sci Rep 2016; 6:313-331.
21. Ma Y, Xia W, Wang DQ, Wan YJ, Xu B, Chen X, et al. Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood. Diabetologia 2013; 56:2059-2067.
22. Whitehead R, Guan H, Arany E, Cernea M, Yang K. Prenatal exposure to bisphenol-A alters mouse fetal pancreatic morphology and islet composition. Horm Mol Biol Clin Investig 2016; 25:171-179.
23. Li Q, Davila J, Kannan A, Flaws JA, Bagchi MK, Bagchi IC. Chronic exposure to bisphenol-A affects uterine function during early pregnancy in mice. Endocrinol 2016; 157:1764-1774.
24. Olea-Herrero N, Arenas MI, Munoz-Moreno C, Moreno-Gomez-Toledano R, Gonzalez-Santander M, Arribas I, et al. Bisphenol-A induces podocytopathy with proteinuria in mice. J Cell Physiol 2014; 229:2057-2066.
25. Guerrero-Bosagna C, Trevor R, Covert M, Haque M, Settles M. Epigenetic transgenerational inheritance of vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers. Reprod Toxicol 2012; 34:694-707.
26. Rissman EF, Adli M. Transgenerational epigenetic inheritance: focus on endocrine disrupting compounds. Endocrinol 2014; 155:2770-2780.
27. Peretz J, Vrooman L, William AR, Hunt PA, Ehrlich S. Bisphenol-A and reproductive health. update of experimental and human evidence, 2007- 2013. Environ Health Perspect 2014; 122:775-786.
28. Doherty FL, Bromer JG, Zhou Y, Aldad TS, Taylor HS. In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland. An epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer 2010; 1:146-155.