In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood
Nikos Stratakis, Lucy Golden‐Mason, Katerina Margetaki, Yinqi Zhao, Damaskini Valvi, Erika Garcia, Léa Maître, Sandra Andrušaitytė, Xavier Basagaña, Eva Borràs, Mariona Bustamante, Maribel Casas, Serena Fossati, Regina Gražulevičienė, Line Småstuen Haug, Barbara Heude, Rosemary McEachan, Helle Margrete Meltzer, Eleni Papadopoulou, Theano Roumeliotaki, Oliver Robinson, Eduard Sabidó, José Urquiza, Marina Vafeiadi, Nerea Varo, John Wright, Miriam B. Vos, Howard Hu, Martine Vrijheid, Kiros Berhane, David V. Conti, Rob McConnell, Hugo R. Rosen, Lida Chatzi
Abstract
BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.