Environmental chemical exposures have been implicated as risk factors for the development of non-alcoholic fatty liver (NAFLD). Bisphenol S (BPS), widely used in multitudinous consumer products, could disrupt lipid metabolism in the liver. This study aimed at examining the hypothesis that long-term exposure to BPS promotes the development of liver fibrosis and inflammation by means of the application of a semi-static exposure experiment that exposed zebrafish to 1, 10, and 100 μg/L BPS from 3 h post fertilization to 120 day post fertilization. Results showed that the 120-d BPS exposure elevated plasma aspartate aminotransferase and alanine aminotransferase activities, increased triacylglycerol (TAG) and total cholesterol levels in male liver, and even induced hepatic apoptosis and fibrosis. Hepatic lipid accumulation observed in the 30-d BPS-exposed zebrafish was recovered after a 90-d depuration phase, thereby indicating that long-term BPS exposure promotes the progression of simple steatosis to non-alcoholic steatohepatitis. Furthermore, BPS exposure for 120-d promoted the synthesis of TAG and lipotoxic free fatty acids by elevating the transcription of srebp1, acc, fasn, and elovl6, induced endoplasmic reticulum (ER) stress with increasing expression levels of unfolded protein response (UPR) genes (perk, hsp5, atf4a, and ddit3), and then stimulated the expression of two key autophagy genes (atg3 and lc3) and inflammatory genes (il1b and tnfα). It is indicated that BPS can induce the development of steatohepatitis via the activation of the PERK-ATF4a pathway of the UPR. Data gathered suggest that environmental pollutants-induced ER stress with the activation of UPR can potentially trigger the NAFLD development in males. Overall, our study provided new sights into understanding of the adverse health effects of metabolism disrupting chemicals.

中文翻译：

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长期双酚S暴露会通过调节脂质代谢并诱导雄性斑马鱼中未折叠的蛋白质反应激活来诱导内质网应激反应，从而加剧非酒精性脂肪肝。

环境化学暴露已被认为是发展非酒精性脂肪肝（NAFLD）的危险因素。双酚S（BPS）被广泛用于多种消费品中，可能会破坏肝脏中的脂质代谢。这项研究旨在检验以下假设：长期暴露于BPS会通过半静态暴露实验将斑马鱼从3、1、10和100μg/ L BPS中暴露出来，从而促进肝纤维化和炎症的发展。受精后h至受精后120天。结果显示，暴露120天的BPS升高了男性肝脏中的血浆天冬氨酸转氨酶和丙氨酸转氨酶活性，增加了三酰甘油（TAG）和总胆固醇水平，甚至诱发了肝细胞凋亡和纤维化。在暴露90天的净化阶段后，在暴露30天BPS的斑马鱼中观察到的肝脂质蓄积得以恢复，因此表明长期暴露于BPS会促进单纯性脂肪变性发展为非酒精性脂肪性肝炎。此外，BPS暴露120天可通过增加srebp1，acc，fasn和elov16的转录，诱导内质网（ER）应激，并增加未折叠蛋白应答（UPR）的表达水平，从而促进TAG和脂毒性游离脂肪酸的合成。基因（perk，hsp5，atf4a和ddit3），然后刺激两个关键的自噬基因（atg3和lc3）和炎症基因（il1b和tnfα）的表达。表明BPS可以通过UPR的PERK-ATF4a途径的活化来诱导脂肪性肝炎的发展。收集的数据表明，环境污染物诱导的内质网应激和UPR的激活可能会触发男性NAFLD的发展。总体而言，我们的研究为了解新陈代谢破坏化学物质对健康的不利影响提供了新的见解。