In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood
Nikos Stratakis # 1 , Lucy Golden-Mason # 2 , Katerina Margetaki 1 , Yinqi Zhao 1 , Damaskini Valvi 3 , Erika Garcia 1 , Léa Maitre 4 5 6 , Sandra Andrusaityte 7 , Xavier Basagana 4 5 6 , Eva Borràs 5 8 , Mariona Bustamante 4 5 6 , Maribel Casas 4 5 6 , Serena Fossati 4 5 6 , Regina Grazuleviciene 7 , Line Småstuen Haug 9 , Barbara Heude 10 , Rosemary R C McEachan 11 , Helle Margrete Meltzer 9 , Eleni Papadopoulou 9 , Theano Roumeliotaki 12 , Oliver Robinson 13 , Eduard Sabidó 5 8 , Jose Urquiza 4 5 6 , Marina Vafeiadi 12 , Nerea Varo 14 , John Wright 11 , Miriam B Vos 15 16 , Howard Hu 1 , Martine Vrijheid 4 5 6 , Kiros T Berhane 17 , David V Conti 1 , Rob McConnell 1 , Hugo R Rosen 2 , Lida Chatzi 1
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.