Perfluoroalkyl substances and non-alcoholic fatty liver disease in children: Leveraging magnetic resonance imaging to unravel potential mechanisms and exposure mixture effects

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PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease globally. In the U.S., almost 30% of adults, and over 10% of children are estimated to have NAFLD facing increased risk for long-term complications, such as liver failure, hepatocellular carcinoma, extrahepatic comorbidities, and need for liver transplantation in later life. NAFLD is more prevalent in Asian countries, however Asians are underrepresented in previous NAFLD studies in the U.S. and elsewhere. Per- and polyfluoroalkyl substances (PFAS) are high-priority pollutants that bioaccumulate and persist in the environment and human tissues, such as the liver. Existing evidence from experimental models shows hepatotoxic effects caused by PFAS exposure, such as altered lipid metabolism, hepatic steatosis, and more advanced stages of NAFLD. There findings are in line with recent prospective epidemiology studies that have reported associations between prenatal PFAS exposures and multiple adverse metabolic outcomes. However, no previous study has utilized novel magnetic resolution imaging technologies that permit the quantification of fat and lipid content in the target liver tissue, and therefore can establish a causal link between PFAS and NAFLD. Moreover, human evidence is lacking to elucidate the potential interplay between PFAS exposures and well-established metabolic and genetic risk factors in NAFLD etiology. We hypothesize that prenatal exposure to PFAS promotes liver steatosis and injury in children (Aim 1) via alterations in lipid and amino acid metabolism (Aim 2), and that these effects are stronger in children who have higher genetic and/or metabolic susceptibility to NAFLD (Aim 3). To test these hypotheses, we will leverage the unique, existing, population-based mother-child cohort ‘Growing Up in Singapore Towards Healthy Outcomes (GUSTO)’ in Singapore with comprehensive assessments of pre- and perinatal PFAS exposures in maternal and cord serum, non-invasive proton magnetic resonance spectroscopy (MRS) measures of liver fat content and targeted metabolomics in 530 children aged 6-7.5 years, as well as extensive genome-wide, metabolic phenotype, lifestyle and relevant covariate data from longitudinal follow-up examinations. This is the first and most comprehensive study on PFAS exposures and pediatric NAFLD using state-of-the-art liver MRS imaging, metabolomics, environmental exposure mixture, and polygenic risk score approaches to determine the interplay of environmental, genetic, and metabolic risk factors in NAFLD. Findings will contribute to establish a causal link between PFAS exposures and pediatric NAFLD and inform early-life prevention and interventions strategies sorely needed to address the current NAFLD epidemic.