Prenatal exposure to perfluoroalkyl sulfonic and carboxylic acids and neurodevelopmental delay in children up to 5 years old: Effect modification by progesterone and estradiol

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants associated with neurodevelopmental toxicity. However, the combined effects of PFAS subclasses and the modifying role of endogenous hormones remain poorly understood. Using data from the Maoming birth cohort (n = 543), we longitudinally assessed associations between prenatal exposure to perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs) and developmental delay in children aged 3–60 months, employing generalized linear mixed models for individual PFAS and grouped weighted quantile sum regression for effects of PFAS mixtures. We further examined the effect modification by cord blood estradiol and progesterone, classified via latent profile analysis, and conducted molecular docking to explore potential receptor interactions. Both individual compounds [e.g., perfluorooctanoic acid and perfluorooctane sulfonic acid (PFOS)] and PFCA mixtures were associated with increased odds of developmental delay, particularly in total-ASQ, communication, and motor domains. These associations were significantly modified by latent profiles of cord blood hormones. For example, in the low-hormone profile, perfluorodecanoic acid was associated with fine motor delay (Odds ratio [OR] = 2.04; 95% CI: 1.18, 3.49), whereas linear-PFOS was associated with gross motor delay (OR = 4.76; 95% CI: 1.96, 11.54) in the high-hormone profile. Molecular docking indicated that most PFCAs have a preferential binding affinity for the ligand-binding domains of estradiol and progesterone receptors, supporting the biological plausibility of the observed hormonal effect modification. Our findings demonstrate that the association between prenatal PFAS exposure and neurodevelopment is subclass-specific and critically shaped by the in utero hormonal environment.