Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 31, Vishvigyan Bhawan, Mahatma Gandhi Marg, Lucknow, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 31, Vishvigyan Bhawan, Mahatma Gandhi Marg, Lucknow, 226001, India; Department of Biochemistry, University of Lucknow, Lucknow, 226007, India.
Food Chem Toxicol. 2020 Jul;141:111314. doi: 10.1016/j.fct.2020.111314. Epub 2020 Apr 17.
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.
双酚 A，一种广泛用于制造聚碳酸酯塑料和环氧树脂的内分泌干扰化学物质，通过多种机制干扰细胞和分子功能。BPA 有通过产生 ROS 和氧化应激诱导肝毒性的潜力。然而，BPA 诱导氧化应激和自噬的机制在分子和细胞水平上仍然不清楚。本研究旨在阐明 BPA 暴露（50 和 100 μM）对原代大鼠肝细胞的影响。细胞内能量传感器和细胞信号转导中的关键调节剂 AMP 激酶在 BPA 暴露期间被发现被激活。AMP/ATP 比值的增加及其上游介质肝激酶 B1 (LKB1) 的磷酸化导致 AMPK 激活。BPA 通过抑制其磷酸化而下调 AMPK 下游分子即雷帕霉素靶蛋白（mTOR）的表达，最终增强自噬标志物 LC3B、Beclin-1 的表达，同时降低 p62 的表达。结果还表明，BPA 通过促进 PINK1 的积累和 Parkin 向受损线粒体的易位来诱导线粒体自噬，导致线粒体质量减少。超微结构变化也证实了线粒体的解体，增强了自噬的诱导，自噬体的形成就是明显的证据。研究结果证实，BPA 引起氧化应激，最终触发 LKB1/AMPK 介导的自噬，并通过清除不健康的线粒体来维持细胞能量平衡。
