Bisphenol-A-induced ovarian cancer: Changes in epithelial diversity, apoptosis, antioxidant and anti-inflammatory mechanisms

This research was designed to study the carcinogenic mechanisms of BPA on ovarian epithelial cells. For four months, mice were treated with low (LD, 1 mg/kg) and high (HD, 5 mg/kg of body weight) doses of BPA on alternate days through oral gavage; the control group was given corn oil through gavaging during 4 months. The histopathological data suggest that repeated BPA administration induces a borderline epithelial neoplasm with altered epithelial morphology with branching papillae. Various epithelial cells (ECs) in ovaries were identified by flow cytometry based on anti-mouse CD74 and podoplanin (PDPL) receptors expression. Three different populations of ovarian epithelial cells were identified: epithelial cells type 1 (PDPL⁺CD74^-,EC1), epithelial cells type 2 (PDPL^-CD74⁺_, EC2), and transition epithelial cells (PDPL⁺CD74⁺, TEC). The EC1 decreased, but EC2 was increased in BPA-exposed mice. The population of TEC was comparable to that in the control group at the low dose (LD) but decreased in the high dose (HD) BPA-treated groups. A significant increase in PDPL, CD74 receptor expression and apoptosis and necrosis in BPA-treated ovarian cells was seen. The RT-qPCR results suggest that the relative expression levels of pro-apoptotic (Bax and Casp3) and anti-apoptotic Cytc were markedly decreased, but Bcl2 expression was increased. The anti-inflammatory (IFN-γ, TNF-α, TGF-β, IL-6) gene expression was reduced, but NF-kB expression was increased. Hypoxia regulator (Hif-1α and Nrf2) and tumour suppressor genes (p53 and p21) were also decreased. Thus, BPA exposure changes EC diversity, induces mortality and alters antioxidant, apoptotic and inflammatory gene expression in ovary.