Gestational exposure to per- and polyfluoroalkyl substances drives maternal liver dysfunction through lipid...

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous persistent pollutants in pregnant women, yet mechanisms of PFAS-triggered gestational liver injury remain poorly understood. This work quantified 18 serum PFAS in 221 pregnant participants and explored PFAS-liver function associations via epidemiological analyses, network toxicology and supportive experiments in HepG2 cells. Ten PFAS exhibited detection rates over 80%, with Perfluorooctane sulfonate (PFOS, 6.14 μg L^-1), perfluorohexane sulfonate (PFHxS, 5.54 μg L^-1) and perfluorooctanoic acid (PFOA, 4.79 μg L^-1) as dominant congeners. Population correlations showed that perfluorononanoic acid (PFNA) was positively associated with glutamate dehydrogenase (GLDH) levels (β = 0.57), suggesting potential hepatocellular injury. Perfluorotridecanoic acid (PFTrDA) and PFHxS were negatively associated with gamma-glutamyl transferase (GGT) levels (β = -1.88 and -0.13, respectively), while PFHxS was also negatively associated with prealbumin (PAB; β = -0.07) and albumin (ALB; β = -0.02), suggesting potential alterations in bile-related metabolism and hepatic protein synthesis. Network toxicology identified candidate targets associated with PFNA and PFHxS and highlighted biological processes related to lipid metabolism and inflammatory responses, with hub targets including albumin (ALB), tumor necrosis factor (TNF), interleukin-6 (IL-6), and other inflammation- and metabolism-related proteins. Cellular assays indicated that both congeners were associated with hepatic lipid accumulation and inflammatory responses, accompanied by changes in nuclear factor-κB (NF-κB) and EGFR/STAT3 signaling and increased expression of the proinflammatory cytokines TNF, IL-6 and interleukin-1β (IL-1β). The observed changes in GLDH, GGT, ALB, and PAB may reflect alterations in hepatocellular function, lipid and bile-related metabolism, and hepatic protein synthesis. PFNA showed stronger inflammation-related responses, whereas PFHxS showed more pronounced effects on lipid accumulation. Overall, the findings suggest that lipid metabolic dysregulation and inflammatory responses may be involved in PFAS-associated alterations in maternal liver function. This study provides population-based and supportive mechanistic evidence for evaluating the potential hepatic effects of PFAS exposure during pregnancy.