Bisphenol A impairs reproductive fitness in zebrafish ovary: Potential involvement of oxidative/nitrosative stress, inflammatory and apoptotic mediators

Abstract

Bisphenol A (BPA) is a highly pervasive chemical in consumer products with its ascribed endocrinedisrupting properties. Several studies have shown the cytotoxic, genotoxic, and carcinogenic property of BPA over a multitude of tissues. Although BPA exposure has earlier been implicated in female infertility, the underlying molecular mechanisms explaining the toxicity of BPA in the ovary remains less understood. In the present study, a plausible correlation between redox balance or inflammatory signaling and reproductive fitness upon BPA exposure has been examined in zebrafish (Danio rerio) ovary. Congruent with significant alteration of major antioxidant enzymes (SOD1, SOD2, catalase, GPx1a, GSTa1) at the transcript level, 30 d BPA exposure at environmentally relevant concentrations (1, 10 and 100 mg L 1 ) promotes ovarian ROS/RNS synthesis, lipid peroxidation but attenuates catalase activity indicating elevated stress response. BPA promotes a sharp increase in ovarian p38 MAPK, NF-kB phosphorylation (activation), inducible nitric oxide synthase (Nos2a), and pro-inflammatory cytokines (TNF-a and IL-1b) expression, the reliable markers for inflammatory response. Congruent to an increased number of atretic follicles, BPA-exposed zebrafish ovary reveals elevated Bax/Bcl2 ratio, activation of caspase-8, -3 and DNA breakdown suggesting heightened cell death. Importantly, significant alteration in nuclear estrogen receptor (ER) transcripts (esr1, esr2a, and esr2b) and proteins (ERa, ERb), gonadotropin receptors, and markers associated with steroidogenesis and growth factor gene expression in BPAexposed ovary correlates well with impaired ovarian functions and maturational response. Collectively, elevated oxidative/nitrosative stress-mediated inflammatory response and altered ER expression can influence ovarian health and reproductive fitness in organisms exposed to BPA environment.