Exposure To Perfluoroalkyl Substances And Risk Of Hepatocellular Carcinoma In The Multiethnic Cohort

Abstract

BACKGROUND AND AIM: Exposure to per- and polyfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data are lacking. We examined associations of PFAS exposure, altered metabolic pathways, and risk of non-viral HCC. METHODS: In this nested case-control study, prediagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort Study (MEC). Cases and controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach. RESULTS: High perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES>55 μg/L) were associated with more than 4 fold increased risk of HCC (OR=4.5; 95% CI: 1.2-16.0). The pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were in turn associated with HCC risk. We identified four metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short chain fatty acid), α-Ketoisovaleric acid (a branched-chain α-keto acid), and 7alpha-Hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC. CONCLUSTIONS: Exposure to high levels of PFOS was associated with increased risk of HCC, and the likely mechanisms were via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are warranted to confirm these findings. Key Words: Chemical exposure, exposome, perfluorinated alkyl substance, hepatocellular carcinoma, metabolome, bile acid, metabolic pathway