23 June 2022
Goodrich JA, Walker D, Lin X, Wang H, Lim T, McConnell R, Conti DV, Chatzi L, Setiawan VW,
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 is 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/controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolize 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; >55μg/L) were associated with 4.5 fold increased risk of HCC (OR=4.5, 95% CI: 1.2-16.0). Pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also 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 7α-Hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC.
Conclusion: This proof-of-concept analysis shows that exposure to high PFOS levels was associated with increased risk of non-viral HCC, and the likely mechanisms were via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are needed to confirm these findings.
Key Words: Chemical exposure, exposome, perfluorinated alkyl substance, hepatocellular carcinoma, 53 metabolome, bile acid, metabolic pathway.
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