PFAS internal exposure levels across two generations and endocrine-metabolic biomarker associations in women from the French E3N-Generations cohort.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals suspected to act as endocrine-active compounds, disrupting lipid metabolism and hormonal homeostasis, while possible multigenerational effects are an emerging concern. Although legacy PFAS such as perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been restricted in France since 2009, the impact of these measures on long-term exposure remains unclear. OBJECTIVES: We aimed to (1) compare serum PFAS concentrations across two generations of adult French women and identify determinants of exposure; (2) evaluate associations between PFAS (individually and as mixtures) and early hormonal and metabolic biomarkers; and (3) explore potential intergenerational associations between maternal PFAS exposure and adult daughters' biomarkers. METHODS: We analyzed serum PFAS concentrations among two generations of women from the E3N-Generations cohort (1995-1999 and 2024). Biomarkers included thyroid-stimulating hormone (TSH), testosterone, sex hormone-binding globulin (SHBG), triglycerides, and total, HDL, and LDL cholesterol. Multivariable models assessed determinants of exposure and PFAS-biomarker associations, with exploratory analyses of maternal-daughter pairs. RESULTS: Total PFAS concentrations decreased substantially over time, particularly for PFOS and PFOA, although these compounds remained the predominant PFAS detected in both generations. Sociodemographic, anthropometric, and reproductive factors were associated with PFAS serum concentrations, with generation-specific patterns. The results showed a positive cumulative association between PFAS and testosterone and a negative association with TSH and HDL cholesterol, while associations with other lipid biomarkers were heterogeneous. No consistent associations were observed between maternal PFAS concentrations and adult daughters' biomarkers. CONCLUSIONS: Despite regulatory-driven declines, PFAS exposure remains widespread and associated with endocrine and metabolic biomarkers in adult women. These findings are consistent with the need for strengthened, class-based PFAS regulation and dedicated studies to rigorously evaluate potential multigenerational associations.