State Key Laboratory of Reproductive Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing 211166, China.
Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China.
Toxicol In Vitro. 2020 Oct;68:104959. doi: 10.1016/j.tiv.2020.104959. Epub 2020 Aug 5.
Bisphenol A (BPA) has a variety of adverse effects on human health; therefore, BPA analogs are increasingly used as replacements. Notably, recent studies have revealed that BPA exposure induced hepatic lipid accumulation, but few studies are available regarding the similar effects of other bisphenol analogues (BPs). Thus, in the present study, a high-content screening (HCS) assay was performed to simultaneously evaluate the hepatic lipid accumulation of 13 BPs in vitro. The BPs induced lipid deposition in HepG2 cells ranking as below: 4,4'-thiodiphenol (TDP) < bisphenol S (BPS) < 4,4'-dihydroxybenzophenone (DHBP) < tetrabromobisphenol A (TBBPA) < tetrachlorobisphenol A (TCBPA) < bisphenol E (BPE) < bisphenol F (BPF) < bisphenol B (BPB) < bisphenol AF (BPAF) < bisphenol A (BPA) < bisphenol C (BPC) < tetramethylbisphenol A (TMBPA) < bisphenol AP (BPAP). Meanwhile, Oil Red O staining and triacylglycerol detection further validated the lipid accumulation elicited by the latter 8 BPs, which exhibited the more significant effects on lipid deposition. Mechanistically, significantly increased expressions of genes involved in fatty acid synthesis and nuclear receptors and decreased levels of genes associated with fatty acid β-oxidation were observed under BPs treatment. Therefore, the present work is the first to systematically provide direct evidence for BPs-induced hepatic lipid accumulation in vitro via HCS, which can be helpful for safety assessments of BPs.
双酚 A (BPA) 对人类健康有多种不良影响；因此，双酚 A 类似物被越来越多地用作替代品。值得注意的是，最近的研究表明，BPA 暴露会导致肝内脂质积累，但关于其他双酚类似物 (BPs) 的类似作用的研究较少。因此，本研究采用高通量筛选 (HCS) assay 同时评估了 13 种 BPs 在体外诱导肝内脂质积累的作用。BPs 在 HepG2 细胞中诱导脂质沉积的能力排序如下：4,4'-硫代二苯酚 (TDP) < 双酚 S (BPS) < 4,4'-二羟基二苯酮 (DHBP) < 四溴双酚 A (TBBPA) < 四氯双酚 A (TCBPA) < 双酚 E (BPE) < 双酚 F (BPF) < 双酚 B (BPB) < 双酚 AF (BPAF) < 双酚 A (BPA) < 双酚 C (BPC) < 四甲基双酚 A (TMBPA) < 双酚 AP (BPAP)。同时，油红 O 染色和三酰甘油检测进一步验证了后 8 种 BPs 引起的脂质积累，它们对脂质沉积的影响更为显著。从机制上看，在 BPs 处理下，与脂肪酸合成和核受体相关的基因表达显著增加，而与脂肪酸β-氧化相关的基因水平显著降低。因此，本研究首次通过 HCS 系统地提供了 BPs 诱导体外肝内脂质积累的直接证据，这有助于对 BPs 进行安全性评估。
