Abstract：
Thyroid dysfunction has become a serious public health problem, which is considered a trigger of nonalcoholic fatty liver disease (NAFLD). Pesticide exposure could contribute to thyroid dysfunction and NAFLD, but the relationship between these factors remains unclear. In this study, the effects of subchronic famoxadone exposure on thyroid and liver at no observed adverse effect level (NOEL) related concentrations were investigated using in vivo, in vitro, and in silico models. Famoxadone caused hepatic steatosis, lipid metabolism disorder, and liver oxidative stress and induced NAFLD in male mice. The suppression of hepatic fatty acid β-oxidation was the key factor of NAFLD, which was highly associated with hypothalamic-pituitary-thyroid (HPT) axis hormones disorder. Famoxadone disrupted thyroid hormone biosynthesis by causing thyroid follicle aberrations and abnormal HPT axis-related gene expression. In vitro studies confirmed that famoxadone inhibited the transport of thyroxine (T4) into hepatocytes and the conversion of T4 to triiodothyronine (T3). In silico studies verified that famoxadone interfered with the binding of thyroid hormones to proteins mediating thyroid hormone transport, conversion, and activation. This study comprehensively reported the association between NAFLD and thyroid dysfunction caused by famoxadone, providing new perspectives for the health risk evaluation of pesticides with a similar structure in mammals.
摘要：
甲状腺功能异常已成为严重的公共卫生问题,这被认为是非酒精性脂肪性肝病（NAFLD）的触发因素。农药暴露可能导致甲状腺功能障碍和NAFLD，但这些因素之间的关系仍不清楚。在这项研究中,亚慢性法莫沙酮暴露对甲状腺和肝脏的影响在没有观察到的不良反应水平（NOEL）相关浓度进行了体内研究，在体外，和硅模型。法莫沙酮引起的肝脂肪变性，脂质代谢紊乱，和肝脏氧化应激和诱导雄性小鼠NAFLD。肝脏脂肪酸β-氧化抑制是NAFLD发病的关键因素,与下丘脑-垂体-甲状腺（HPT）轴激素紊乱高度相关。Famoxadone通过引起甲状腺滤泡畸变和异常的HPT轴相关基因表达来破坏甲状腺激素的生物合成。体外研究证实，法莫沙酮抑制甲状腺素（T4）向肝细胞的转运以及T4向三碘甲状腺原氨酸（T3）的转化。在计算机研究中证实，法莫沙酮干扰甲状腺激素与介导甲状腺激素转运的蛋白质的结合，转换，和激活。这项研究全面报道了NAFLD与法莫沙酮引起的甲状腺功能障碍之间的关系。为哺乳动物中具有相似结构的农药的健康风险评价提供了新的视角。
