Bisphenol-A, an endocrine disruptive chemical widely used to manufacture polycarbonate plastics and epoxy resins, acts via multiple mechanisms that perturb cellular and molecular functions. BPA has the potential to induce hepatotoxicity via generation of ROS and oxidative stress. However, the mechanism of BPA induced oxidative stress and autophagy is still ambiguous at molecular and cellular levels. This study aims to elucidate the impact of BPA exposure (50 and 100 μM) in primary rat hepatocytes. AMP kinase, an intracellular energy sensor and key regulator in cellular signaling were found to be activated during BPA exposure. The increased AMP/ATP ratio and subsequent phosphorylation by its upstream mediator Liver Kinase B1 (LKB1) activates AMPK. BPA down-regulated AMPK downstream molecule i.e. mammalian target of rapamycin (mTOR) by inhibiting its phosphorylation, eventually enhances expression of autophagic markers LC3B, Beclin-1 while lowers p62. Results also revealed that BPA induces mitophagy by promoting accumulation of PINK1 and translocation of Parkin to damaged mitochondria culminating in decreased mitochondrial mass. Ultra-structural changes also confirmed mitochondrial disintegration, enhanced autophagic induction as evident from autophagosome formation. Findings confirm that BPA caused oxidative stress which eventually triggered LKB1/AMPK mediated autophagy and maintains cellular energy balance by mitophagic removal of unhealthy mitochondria in primary rat hepatocytes.
Keywords: AMPK; Autophagy; LKB1; Mitophagy; Oxidative stress; mTOR.
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