“Dioxins” are persistent organic pollutants (POPs) that are continuously present in the environment at appreciable levels and have been associated with increased risk of steatotic liver disease (SLD). However, current understanding of the role of sex and effects of mixtures of dioxins in SLD development is limited. Additionally, there exists debates on the levels of dioxins required to be considered dangerous as emphasis has shifted from high level exposure events to the steady state of lower-level exposures. We therefore investigated sex-dependent effects of low-level exposures to a mixture of dioxins: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) and Polychlorinated biphenyl 126 (PCB126), in the context of SLD and associated metabolic dysfunction. Male and female C57BL/6J mice were fed a low-fat diet and weekly administered either vehicle control or TCDD (10 ng/kg), PeCDF (80 ng/kg) and PCB 126 (140 ng/kg) over a two-week period. Female mice generally demonstrated higher hepatic fat content compared to males. However, exposure to dioxins further elevated hepatic cholesterol levels in females, and this was accompanied by increased lipogenic gene expression (Acaca, Fasn) in the liver. In contrast, exposed males but not females displayed higher white adipose tissue weights. Furthermore, TCDD + PeCDF + PCB126 activated the AHR (hepatic Cyp1a1, Cyp1a2 induction); with Cyp1a1 induction observed only in exposed females. Notably, gene expression of hepatic albumin (Alb) was also reduced only in exposed females. Overall, exposure to the low dose dioxin mixture compromised hepatic homeostasis via metabolic perturbations, and hepatic dysregulation was more accelerated in female livers.

中文翻译：

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低剂量暴露于二恶英会以性别特异性方式改变肝能量代谢和脂肪性肝病的发展


“二恶英”是持久性有机污染物 （POP），持续以可观的水平存在于环境中，并且与脂肪性肝病 （SLD） 的风险增加有关。然而，目前对性的作用和二恶英混合物在 SLD 发展中的影响的理解是有限的。此外，随着重点已从高水平暴露事件转移到低水平暴露的稳定状态，关于需要被视为危险的二恶英水平存在争议。因此，我们研究了低水平暴露于二恶英混合物的性别依赖性影响：2,3,7,8-四氯二苯并对二恶英 （TCDD）、2,3,4,7,8-五氯二苯并呋喃 （PeCDF） 和多氯联苯 126 （PCB126），在 SLD 和相关代谢功能障碍的背景下。雄性和雌性 C57BL/6J 小鼠饲喂低脂饮食，并在两周内每周施用载体对照或 TCDD （10 ng/kg）、PeCDF （80 ng/kg） 和 PCB 126 （140 ng/kg）。与雄性小鼠相比，雌性小鼠通常表现出更高的肝脏脂肪含量。然而，暴露于二恶英会进一步升高女性的肝脏胆固醇水平，并伴有肝脏中脂肪生成基因表达（Acaca、Fasn）的增加。相比之下，暴露的雄性而不是雌性表现出更高的白色脂肪组织重量。此外，TCDD + PeCDF + PCB126 激活 AHR （肝脏 Cyp1a1，Cyp1a2 诱导）; 仅在暴露的雌性中观察到 Cyp1a1 诱导。值得注意的是，肝白蛋白 （Alb） 的基因表达也仅在暴露的雌性中降低。总体而言，暴露于低剂量二恶英混合物会通过代谢扰动损害肝脏稳态，而女性肝脏的肝脏失调更为加速。