Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) associated with non-alcoholic fatty liver disease (NAFLD). The effects of gestational BPA exposure on hepatic lipid accumulation in offspring are not fully understood. Here, we investigate the sex-dependent effects of gestational BPA exposure on hepatic lipid and glucose metabolism in the offspring of mice to reveal the mechanisms underlying gestational BPA exposure-associated NAFLD. Pregnant mice were administered gavage with or without 1 μg kg⁻¹ day⁻¹ BPA at embryonic day 7.5 (E7.5)–E16.5. Hepatic glucose and lipid metabolism were evaluated in these models. Both male and female offspring mice exhibited hepatic fatty liver after BPA treatment. Lipid accumulation and dysfunction of glucose metabolism were observed in male offspring. We revealed abnormal expression of lipid regulators in the liver and that inhibition of peroxisome proliferator-activated receptor γ (PPARγ) repressed hepatic lipid accumulation induced by gestational BPA exposure. We also found a sex-dependent decrease of hepatocyte nuclear factor 1b (HNF1b) expression in male offspring. The transcriptional repression of PPARγ by HNF1b was confirmed in L02 cells. Downregulation of HNF1b, upregulation of PPARγ, and subsequent upregulation of hepatic lipid accumulation were essential for NAFLD development in male offspring gestationally exposed to BPA as well as BPA-exposed adult male mice. Dysregulation of the HNF1b/PPARγ pathway may be involved in gestational BPA exposure-induced NAFLD in male offspring. These data provide new insights into the mechanism of gestational BPA exposure-associated sex-dependent glucose and lipid metabolic dysfunction.

Schematic of the mechanism of gestational BPA exposure-induced glucose and lipid metabolic dysfunction.

双酚 A (BPA) 是一种与非酒精性脂肪肝 (NAFLD) 相关的内分泌干扰化学物质 (EDC)。妊娠期 BPA 暴露对后代肝脏脂质积累的影响尚不完全清楚。在这里，我们研究了妊娠期 BPA 暴露对小鼠后代肝脏脂质和葡萄糖代谢的性别依赖性影响，以揭示妊娠期 BPA 暴露相关 NAFLD 的潜在机制。在胚胎第7.5天（E7.5）–E16.5时，对怀孕小鼠进行管饲，添加或不添加1 μg kg ^-1 day ^-1 BPA。在这些模型中评估了肝脏葡萄糖和脂质代谢。 BPA 治疗后，雄性和雌性子代小鼠均出现肝脂肪肝。在雄性后代中观察到脂质积累和葡萄糖代谢功能障碍。我们发现肝脏中脂质调节因子的异常表达，并且抑制过氧化物酶体增殖物激活受体 γ (PPARγ) 可抑制妊娠期 BPA 暴露引起的肝脏脂质积累。我们还发现男性后代中肝细胞核因子 1b (HNF1b) 表达存在性别依赖性下降。 HNF1b 对 PPARγ 的转录抑制在 L02 细胞中得到证实。 HNF1b 的下调、PPARγ 的上调以及随后肝脏脂质积累的上调对于妊娠期暴露于 BPA 的雄性后代以及暴露于 BPA 的成年雄性小鼠的 NAFLD 发展至关重要。 HNF1b/PPARγ 通路的失调可能与妊娠期 BPA 暴露诱发的男性后代 NAFLD 有关。这些数据为妊娠期 BPA 暴露相关的性别依赖性葡萄糖和脂质代谢功能障碍的机制提供了新的见解。

妊娠期 BPA 暴露引起葡萄糖和脂质代谢功能障碍的机制示意图。