在各种人类生物样本中已鉴定出一系列广泛的双酚 S (BPS) 衍生物作为 BPS 的替代品，包括在人脐带血浆和母乳中检测到的 4-羟苯基 4-异丙氧基苯砜 (BPSIP)。然而，对于产前 BPS 衍生物暴露对后代的健康结果知之甚少。我们的研究旨在调查暴露于 BPSIP 的母鼠后代中性别对肝脏胆固醇代谢的反应。怀孕的 ICR 小鼠暴露于 5μg/kg 体重(BW)/天的 BPSIP、BPS 或 E2，从妊娠第一天到幼犬断奶，通过饮用水摄入。采用液相色谱-串联质谱法测定幼仔血浆和肝脏中 BPSIP、BPS 或 E2 的浓度。记录代谢表型，并检查组织病理学是否有肝损伤。采用转录组分析来表征不同性别差异表达基因的分布和表达模式。通过实时定量 PCR、免疫组织化学和免疫印迹验证了代谢调节。使用动物模型和肝脏类器官研究了雌激素受体 (ER) 在介导性别依赖性效应中的作用。暴露于 BPSIP 的母鼠的幼崽表现出较高的血清胆固醇水平，并且与母鼠相比，母鼠的肝脏胆固醇水平较高，而雄性则较低。控件。雄性肝脏中的BPSIP浓度为1.22±0.25ng/g，雌性肝脏中的BPSIP浓度为0.69±0.27ng/g。组织病理学分析显示雄性和雌性后代都有脂肪变性和脂质沉积。转录组和基因表达分析发现，暴露于 BPSIP 的母鼠幼崽与对照组幼鼠之间在胆固醇生物合成、吸收、处置和流出方面存在性别特异性差异。体内染色质免疫沉淀分析显示，与对照组相比，暴露于 BPSIP 的女性中 ERα 蛋白与 Hmgcr、Pcsk9 和 Abcg5 等关键基因的结合减弱，而男性中则增强。在体外，肝脏类器官实验表明，只有在联合使用 ERα 激动剂和 ERβ 激动剂时，才能将 BPSIP 诱导的关键基因（例如 Hmgcr、Ldlr 和 Cyp7a1）差异表达恢复到与对照相当的水平。这项研究的结果表明，围产期接触 BPSIP 会在小鼠模型中以性别特异性方式破坏胆固醇代谢，其中 ERα 在体内和体外都发挥着至关重要的作用。因此，系统评价 BPS 衍生物对于保护孕期孕产妇健康并防止代谢紊乱的代际传播至关重要。 https://doi.org/10.1289/EHP14643。

A broad suite of bisphenol S (BPS) derivatives as alternatives for BPS have been identified in various human biological samples, including 4-hydroxyphenyl 4-isopropoxyphenylsulfone (BPSIP) detected in human umbilical cord plasma and breast milk. However, very little is known about the health outcomes of prenatal BPS derivative exposure to offspring.Our study aimed to investigate the response of hepatic cholesterol metabolism by sex in offspring of dams exposed to BPSIP.Pregnant ICR mice were exposed to 5μg/kg body weight (BW)/day of BPSIP, BPS, or E2 through drinking water from gestational day one until the pups were weaned. The concentration of BPSIP, BPS, or E2 in the plasma and liver of pups was determined by liquid chromatography-tandem mass spectrometry. Metabolic phenotypes were recorded, and histopathology was examined for liver impairment. Transcriptome analysis was employed to characterize the distribution and expression patterns of differentially expressed genes across sexes. The metabolic regulation was validated by quantitative real-time PCR, immunohistochemistry, and immunoblotting. The role of estrogen receptors (ERs) in mediating sex-dependent effects was investigated using animal models and liver organoids.Pups of dams exposed to BPSIP showed a higher serum cholesterol level, and liver cholesterol levels were higher in females and lower in males than in the controls. BPSIP concentration in the male liver was 1.22±0.25 ng/g and 0.69±0.27 ng/g in the female liver. Histopathology analysis showed steatosis and lipid deposition in both male and female offspring. Transcriptome and gene expression analyses identified sex-specific differences in cholesterol biosynthesis, absorption, disposal, and efflux between pups of dams exposed to BPSIP and those in controls. In vivo, chromatin immunoprecipitation analysis revealed that the binding of ERα protein to key genes such as Hmgcr, Pcsk9, and Abcg5 was attenuated in BPSIP-exposed females compared to controls, while it was enhanced in males. In vitro, the liver organoid experiments demonstrated that restoration of differential expression induced by BPSIP in key genes, such as Hmgcr, Ldlr, and Cyp7a1, to levels comparable to the controls was only achieved when treated with a combination of ERα agonist and ERβ agonist.Findings from this study suggest that perinatal exposure to BPSIP disrupted cholesterol metabolism in a sex-specific manner in a mouse model, in which ERα played a crucial role both in vivo and in vitro. Therefore, it is crucial to systematically evaluate BPS derivatives to protect maternal health during pregnancy and prevent the transmission of metabolic disorders across generations. https://doi.org/10.1289/EHP14643.