Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort

By Jesse A. Goodrich, Douglas Walker, Xiangping Lin, Hongxu Wang, Tiffany Lim, Rob McConnell, David V. Conti, Lida Chatzi, and Veronica Wendy Setiawan
JHEP Reports
August 8, 2022
DOI: https://doi.org/10.1016/j.jhepr.2022.100550

Background

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 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 (90^th percentile from NHANES; >55 μg/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.

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