Research Project 1: Mechanisms of PFAS hepatotoxicity: A Multi-Omics Study Using Human Liver Spheroids

University Of Southern California, Los Angeles CA

Investigators

Abstract

RESEARCH PROJECT 1 (RP1): PROJECT SUMMARY Humans are ubiquitously exposed to per- and polyfluoroalkyl substances (PFAS), a group of man-made chemicals that contaminate drinking water sources throughout the United States and are linked nonalcoholic fatty liver disease (NAFLD), a serious liver condition that can lead to cirrhosis and liver cancer. However, the critical gaps in the current knowledge limit the development of tools to identify individuals at high risk of PFAS-induced NAFLD. Therefore, RP1 of ShARP will primarily address the Superfund Research Program (SRP) Mandate 1 by identifying the biological mechanisms by which PFAS disrupt liver metabolism. Our central hypothesis is that the metabolic changes caused by PFAS exposure in the liver favor NAFLD development and progression, and those changes may not be reversible after prolonged PFAS exposure. RP1 propose a multi-omic study to investigate PFAS impact on liver metabolism with an experimental approach that will evaluate the effects of PFAS exposure on 3D liver spheroid models using a combination of single-cell transcriptomics and epigenomics, proteomic and metabolomics assays, and spheroid histology. RP1 will collaborate with RPs 2, 3, and 4, and Cores to address all SRP mandates and achieve the ShARP Center's overall goals of developing a problem-based, solution-oriented center to address the issue of PFAS water contamination in multiple Superfund Sites across the United States. RP1 will help to address Mandate 2 in collaboration with RP2 (human cohort study) by reproducing in vitro the PFAS concentrations and ratios found in the plasma of Southern California residents and generating biomarker panels to identify individuals at high risk of PFAS-induced NAFLD. RP1 will help to address Mandate 3 in cooperation with RP3 (environmental study) by evaluating the toxicity of legacy and emerging PFAS found in high concentrations in Southern California drinking water sources. RP1 will help to address Mandate 4 by designing experimental approaches with RP4 (remediation study) to determine the hazardous effects of byproducts generated by PFAS defluorination. DMAC will help RP1 integrate the transcriptomic, proteomic, metabolomic, and spheroid histological findings. CEC will help RP1 translate the scientific findings into layman's terms to inform the community about PFAS health effects. RETCC will coordinate with RP1 the trainees involved in the project implementation. RP1 will rely on the Administrative Core to provide an integrated infrastructure to support collaboration. Findings will bring new insights for developing tools to identify individuals at high risk of PFAS-induced NAFLD to provide an opportunity for early intervention. Results will contribute to educating the scientific and medical communities and the general public about the adverse health effects of PFAS, promote evidence-based decision-making in PFAS regulation, and develop an improved methodology to evaluate the impact of other environmental pollutants on human health.