Research Project 2: PFAS and Liver Health in Latino Youth: A Longitudinal Multi-Omics Study

University Of Southern California, Los Angeles CA

Investigators

Abstract

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous, persistent chemicals that can accumulate in the human body for long periods of time and are major water contaminants around Superfund sites. PFAS partition to the liver and robust evidence generated by animal toxicological studies shows that PFAS are hepatotoxic, even at low levels of exposure. However, human studies are scarce and the mechanisms of PFAS effects on human liver disease are not well understood. Previous human studies underscore limitations such as small sample sizes, cross-sectional study designs, lack of gold standard imaging measures of liver disease, lack of evaluation of PFAS mixtures, and lack of focus on susceptible populations who are disproportionally affected by metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease in the U.S. To date, there is no current Superfund Center that specifically addresses the health effects of PFAS in relation to their effects on liver disease. Project 2 aims to address the Superfund Research Program Mandates 1 & 2 and assess the PFAS effects on hepatic fat accumulation in susceptible populations by using innovative statistical methods for exposure mixtures and pharmacokinetic modeling, repeated magnetic resonance imaging (MRI) measurements of liver fat, and integration of high-dimensional omics in a longitudinal study design. Our preliminary results support our hypothesis that high exposure to PFAS is associated with increased hepatic fat accumulation in adolescents, potentially via dysregulated metabolic and inflammation pathways. Relying on two already established cohorts in Southern California who live near multiple Superfund sites, this project will efficiently utilize wide range of exposures and gold standard outcome data covering a 20-year span and two different life periods (adolescence and young adulthood). We propose to use high-throughput metabolomics and proteomics, providing broad coverage of inflammation and metabolism-regulating omics profiles to comprehensively characterize dysregulations in biological pathways associated with PFAS hepatotoxicity. Our specific aims are: (1) To examine prospective associations of exposures to individual PFAS and PFAS mixtures with longitudinal changes in hepatic fat fraction (HFF) in youth; (2) To identify omics signatures that will serve as biomarkers of PFAS exposure identified in Project 1; (3) To identify risk profiles for increased HFF in youth using innovative statistical methods that integrate data on PFAS exposures, multi-omics measures, and social determinants of health; and (4) To apply a causal inference framework and estimate potential health effects for real-life PFAS exposure interventions [informed by Project 4, and the Community Engagement Core (CEC)]. Collectively, this study will increase our understanding of the impact of PFAS exposures on liver health in youth, who face increasingly high burdens of MASLD. Findings could be used in clinical practice for risk stratification in youth and tailored personalized precision prevention approaches for high-risk populations near Superfund sites, and other contaminated areas in the US.