Effects of gestational exposure to individual and mixed PFASs on maternal liver function: evidence from the Wuxi Birth Cohort, animal studies, and toxicogenomic analyses

Per- and polyfluoroalkyl substances (PFASs) are persistent environmental contaminants with potential hepatotoxicity. Their impact during pregnancy remains poorly characterized. We investigated 601 pregnant women from the Wuxi Birth Cohort, measuring serum concentrations of 23 PFASs and 11 liver function markers. Associations between individual PFASs and liver function markers were evaluated with generalized linear model (GLM) and generalized additive model (GAM), while mixture effects were assessed using weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR). Independent validation was performed using National Health and Nutrition Examination Survey (NHANES) data. To explore underlying mechanisms, pregnant rats were exposed to perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) followed by liver function assays and RNA sequencing. In the present study, twelve PFASs had detection rates above 90%, with perfluoropentanoic acid (PFPeA) being the predominant compound. Serum perfluorooctanoic acid (PFOA), PFNA, PFDA, and perfluoroundecanoic acid (PFUdA) were significantly associated with alanine aminotransferase (ALT) [β (95% CI): 0.100 (0.023, 0.178), 0.080 (0.033, 0.126), 0.068 (0.025, 0.111), 0.061 (0.021, 0.101), respectively], and were also associated with higher levels of aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP). Both WQS and BKMR models indicated positive associations between PFAS mixtures and liver function markers, particularly ALT, AST, and ALP. Similar patterns were observed in NHANES data. In animal experiments, gestational exposure to PFDA (0.3 mg/kg/day) and PFNA (0.2 mg/kg/day) at human-relevant levels altered maternal liver function markers in pregnant rats, while transcriptomic analyses revealed disruptions in key hepatic metabolic pathways, including unsaturated fatty acid biosynthesis, peroxisome, and PPAR/AMPK signaling. This study provides epidemiological and experimental evidence supporting an association between PFAS exposure and altered maternal liver function during pregnancy, suggesting potential implications for maternal health.