Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Hepatology. 2021 Sep;74(3):1546-1559. doi: 10.1002/hep.31809. Epub 2021 Aug 30.
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant-associated fatty liver disease.
We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother-child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5-8.7) from the European Human Early-Life Exposome cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 μg/L; IQR, 1.1-3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation-related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating IL-1β, IL-6, IL-8, and TNF-α. Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up-regulation of genes encoding these four cytokines and increased concentrations of IL-8 and TNF-α in the supernatants.
These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.
非酒精性脂肪性肝病（NAFLD）是儿童最常见的肝病病因。汞（Hg）作为一种普遍存在的有毒金属，被认为是导致与毒物相关的脂肪性肝病的环境因素之一。
我们通过结合多中心母婴队列的流行病学研究结果和体外单核细胞实验，研究了产前暴露于汞对儿童肝脏损伤的影响，单核细胞已知在肝脏免疫稳态和 NAFLD 中发挥关键作用。我们使用了来自欧洲人类早期生活外显子组队列的 872 名母亲及其儿童的数据（中位数年龄为 8.1 岁；四分位距[IQR]为 6.5-8.7）。我们测量了母亲怀孕期间血液中的汞浓度（中位数为 2.0μg/L；IQR 为 1.1-3.6）。我们还评估了儿童的丙氨酸氨基转移酶（ALT）水平，这是一种常用于筛查儿童非酒精性脂肪性肝病的常用工具，以及与炎症相关的细胞因子在血浆中的浓度。我们发现，产前 Hg 暴露与儿童的表型有关，其特征是 ALT 升高（女性≥22.1 U/L，男性≥25.8 U/L）和循环中白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）和肿瘤坏死因子-α（TNF-α）浓度增加。同样，体外暴露于生理相关剂量 Hg 的炎性单核细胞表现出编码这四种细胞因子的基因显著上调，并且上清液中 IL-8 和 TNF-α的浓度增加。
这些发现表明，发育过程中暴露于 Hg 可能导致生命早期炎症和增加非酒精性脂肪性肝病的风险。
