As an alternative plasticizer to conventional phthalates, di(2-ethylhexyl) terephthalate (DEHTP) has attracted considerable concerns, given its widespread detection in the environment and humans. However, the potential toxicity, especially liver toxicity, posed by DEHTP remains unclear. In this study, based on the 2017–2018 National Health and Nutrition Examination Survey, two metabolites of DEHTP, i.e., mono(2-ethyl-5-hydroxyhexyl) terephthalate (MEHHTP) and mono(2-ethyl-5-carboxypentyl) terephthalate (MECPTP), were found to be present in the urine samples of nearly all representative U.S. adults. Moreover, a positive linear correlation was observed between the concentrations of the two metabolites and the risk of nonalcoholic fatty liver disease (NAFLD) in the population. Results of weighted quantile sum and Bayesian kernel machine regression indicated that MEHHTP contributed a greater weight to the risk of NAFLD in comparison with 12 conventional phthalate metabolites. In vitro experiments with hepatocyte HepG2 revealed that MEHHTP exposure could increase lipogenic gene programs, thereby promoting a dose-dependent hepatic lipid accumulation. Activation of liver X receptor α may be an important regulator of MEHHTP-induced hepatic lipid disorders. These findings provide new insights into the liver lipid metabolism toxicity potential of DEHTP exposure in the population.

中文翻译：

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对苯二甲酸二（2-乙基己基）酯及其代谢物与非酒精性脂肪肝的关联：流行病学和毒理学研究

作为传统邻苯二甲酸酯的替代增塑剂，对苯二甲酸二（2-乙基己基）酯（DEHTP）因其在环境和人类中的广泛检测而引起了相当大的关注。然而，DEHTP 造成的潜在毒性，特别是肝脏毒性仍不清楚。本研究基于2017-2018年全国健康与营养调查，研究了DEHTP的两种代谢物，即对苯二甲酸单(2-乙基-5-羟基己基)酯(MEHHTP)和对苯二甲酸单(2-乙基-5-羧基戊基)酯(MECPTP)，被发现存在于几乎所有有代表性的美国成年人的尿液样本中。此外，两种代谢物的浓度与人群中非酒精性脂肪性肝病（NAFLD）的风险之间观察到呈正线性相关。加权分位数和和贝叶斯核机回归的结果表明，与 12 种传统邻苯二甲酸酯代谢物相比，MEHHTP 对 NAFLD 风险的权重更大。肝细胞 HepG2 的体外实验表明，MEHHTP 暴露可以增加脂肪生成基因程序，从而促进剂量依赖性的肝脏脂质积累。肝脏X受体α的激活可能是MEHHTP诱导的肝脂质紊乱的重要调节因子。这些发现为了解人群中暴露于 DEHTP 的肝脏脂质代谢毒性潜力提供了新的见解。