Developmental origins of child liver injury: Effects of prenatal environmental exposures

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ABSTRACT Emerging experimental evidence indicates that exposure to environmental pollutants causes liver injury and contributes to “toxicant-associated fatty liver disease”, specially if exposure occurs during critical stages of development. Animal studies show hetatotoxic effects even at low levels of exposure to many endocrine disrupting chemicals (EDCs), including persistent organic pollutants, plasticizers and certain metals. Moreover, chronic exposures to ambient fine particulate matter have been shown to induce liver steatosis, inflammation and fibrosis in mice, accompanied by elevated blood liver enzymes. Human studies have largely been cross- sectional, and no previous population study has examined associations of in utero exposure to air pollution and EDCs with subsequent pediatric liver injury. We propose a novel analytyical approach for investigating effects of in utero environmental exposures on child liver injury, leveraging the extraordinary existing resources of the “Human Early Life Exposome (HELIX)” project, which provides completely harmonized biomonitoring data on environmental exposures, geospatial data and omics biomarkers in 1200 pregnant mothers and their children followed longitudinally up to the age of 6-10 years in 6 European countries. We hypothesize that higher ambient air pollution and targeted EDC exposures during pregnancy are associated with subsequent child liver injury and associated dysregulation of metabolic and inflammatory pathways. We propose to measure in archived serum samples established clinical biomarkers of child liver injury. We will apply novel statistical methods to conduct integrated analyses of HELIX chemical exposures, endogenous metabolites, cytokines, adipokines, and established clinical liver injury biomarkers, with the goal of identifying latent variables representing distinct groups of children at risk for liver injury. Our specific aims are: 1: To evaluate the associations of pregnancy trimester-specific fine particle and other regulated air pollution exposures with biomarkers of child liver injury. 2: To evaluate the associations of prenatal exposure to targeted EDCs with biomarkers of child liver injury. 3: To assess associations of prenatal environmental exposures with biological distinct subgroups of children at risk for liver injury, using an innovative latent variable approach that integrates exposure profiles, clinical biomarkers, engogenous metabolites, cytokine and adipokine data. The proposal brings together international experts on environmental epidemiology, pediatric hepatology, omics, and biostatistics from different research institutes in the U.S. and Europe and will be the first study to link multiple prenatal environmental exposures with childhood liver injury outcomes. The study is cost efficient, leveraging a large European investment in HELIX, and has potential to advance our understanding of early life environmental contributions to child liver injury and to identify new targets for prevention and interventions starting early in life.