Yue Huifeng, Hu Yangcheng, Wu Xiaoyun, Tian Yuchai, Liang Xiaomin, Zhang Jiyue, Li Bin, Zhu Huizhen, Ji Xiaotong
Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan, Shanxi 030006, China; Shandong Key Laboratory of Environmental Processes and Health, School of Environmental Science and Engineering, Shandong University, Qingdao, Shandong 266237, China.
Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan, Shanxi 030006, China.
Ecotoxicol Environ Saf. 2025 Sep 1;302:118702. doi: 10.1016/j.ecoenv.2025.118702. Epub 2025 Jul 23.
Accumulating evidence identifies bisphenol A (BPA) as an endocrine disruptor with demonstrated hepatotoxicity, driving the adoption of structural analogs like bisphenol B (BPB). Pregnancy constitutes a critical developmental window for endocrine disruptor-mediated hepatotoxicity in offspring. However, systematic toxicity evidence about BPB exposure-induced transgenerational hepatotoxicity in offspring remains scarce, and the regulatory mechanisms need to be further explored. To elucidate the gene markers and signaling pathways involved in the developmental origins of liver dysfunction induced by direct/maternal BPB exposure. In this study, we systematically analyzed the mechanism of hepatotoxicity and transgenerational effects of BPB by animal models (BPB, direct exposure and maternal exposure, 300 μg/kg bw (body weight)/day). Biochemical indicators and histopathological changes were examined, and bioinformatics analysis was used to explain the relationship between BPB exposure and the liver injuries. The results showed that direct BPB exposure induced subclinical hepatotoxicity with significant cholesterol reduction, circadian rhythm disruption, and Tmem87b/Fkbp1a-mediated chemoresistance. Maternal BPB exposure caused offspring hepatomegaly, transaminase elevation, drove oxidative stress and lipid metabolism imbalance through the Ppard-Slc23a2 dysregulation. Bioinformatics validation in human hepatocellular carcinoma (HCC) confirmed prognostic significance of Tmem87b/Fkbp1a/Ppard/Slc23a2. The study confirmed that BPB induces hepatotoxicity through circadian disruption and oxidative stress pathways, establishing these genes as dual biomarkers for early detection and therapeutic response prediction.
越来越多的证据表明双酚A（BPA）是一种具有肝毒性的内分泌干扰物，这促使人们采用双酚B（BPB）等结构类似物。孕期是内分泌干扰物介导的子代肝毒性的关键发育窗口。然而，关于BPB暴露诱导子代跨代肝毒性的系统毒性证据仍然匮乏，其调控机制有待进一步探索。为了阐明直接/母体BPB暴露诱导肝功能障碍发育起源所涉及的基因标志物和信号通路。在本研究中，我们通过动物模型（BPB，直接暴露和母体暴露，300μg/kg体重/天）系统分析了BPB的肝毒性机制和跨代效应。检测了生化指标和组织病理学变化，并采用生物信息学分析来解释BPB暴露与肝损伤之间的关系。结果表明，直接BPB暴露诱导亚临床肝毒性，伴有显著的胆固醇降低、昼夜节律紊乱以及Tmem87b/Fkbp1a介导的化疗耐药性。母体BPB暴露导致子代肝肿大、转氨酶升高，通过Ppard-Slc23a2失调引发氧化应激和脂质代谢失衡。在人肝细胞癌（HCC）中的生物信息学验证证实了Tmem87b/Fkbp1a/Ppard/Slc23a2的预后意义。该研究证实BPB通过昼夜节律紊乱和氧化应激途径诱导肝毒性，将这些基因确立为早期检测和治疗反应预测的双重生物标志物。
