Human liver perfluorooctane sulfonate associates with steatotic liver disease in a sex-dependent manner.

Perfluorooctane sulfonate (PFOS) is a persistent and widespread contaminant found in the environment and, as a consequence, in the human body, and is linked to adverse health effects, including steatotic liver disease (SLD). Human studies on the role of PFOS in SLD have been largely epidemiological, relying on plasma without measuring liver PFOS. However, using plasma PFOS levels to evaluate fatty liver disease is not comprehensive, and the effects of PFOS in human liver have not been described. We investigated the association of PFOS in plasma (P-PFOS) and liver (L-PFOS) with clinical parameters of Metabolic dysfunction-Associated SLD (MASLD) in a large human cohort with obesity and histology-confirmed MASLD. Combining liver RNA-seq and metabolomic data from liver and plasma, we correlated L- and P-PFOS with mRNA transcripts and metabolites to identify dysregulated transcriptional and metabolic pathways. In women, L-PFOS negatively correlated with MASLD prevalence and severity. Conversely, in men, P-PFOS and L-PFOS positively associated with fibrosis. L-PFOS quartile analysis showed potential threshold effects in several histological parameters in men only. In women, L-PFOS negatively correlated with metabolites from pathways implicated in MASLD progression, including diacylglycerol and sphingolipid species. At the gene expression level, L-PFOS correlated negatively with many fibrosis-related genes involved in collagen formation and extracellular matrix organization in women only. Generally, L-PFOS correlated with many disease-relevant variables in women, but with few in men. These correlations in women were opposite the clinical and molecular changes seen in MASLD progression, while the positive correlation between L-PFOS and liver fibrosis in men suggests a positive relationship with liver disease.