Sex-specific association of prenatal exposure to halogenated persistent organic pollutants (Hal-POPs) with neonatal sex hormone levels and birth size: a birth cohort study using meconium as a biomonitoring matrix

Halogenated persistent organic pollutants (Hal-POPs) are endocrine disruptors that posing risks to fetal development via transplacental transfer. This study utilized neonatal meconium, a non-invasive matrix reflecting cumulative exposure during the second- and third-trimester, to assess prenatal levels of per- and polyfluoroalkyl substances (PFASs), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides (OCPs) in 271 mother-infant pairs from Guangzhou, China. The associations between Hal-POP exposure, neonatal sex hormones, and birth size Z-scores [weight (BWZ), length (BLZ), head circumference (HCZ)], as well as the potential hormonal mediation were explored. Results showed ubiquitous Hal-POP detection, with 4:2 fluorotelomer sulfonic acid (4:2 FTSA; median: 0.53 nmol/g), BDE-47 (0.11 nmol/g), and p, p'-DDE (0.04 nmol/g) being the dominant chemicals within their respective classes. 4:2 FTSA levels were higher in male neonates (p < 0.05). Generalized linear models (GLMs) revealed sex-specific endocrine association of 4:2 FTSA, elevating androgens [testosterone (T) and dihydrotestosterone (DHT)] and reducing estrogens [estrone (E1) and estriol (E3)] and progesterone (P4) in males, whereas only decreasing E1 modestly in females. Bayesian Kernel Machine Regression (BKMR) identified PFASs (Group-PIP ≥ 0.98) as the primary contributors to elevated androgen (T and DHT) and reduced E3, with 4:2 FTSA as the key driver (Cond-PIP ≥ 0.95). Mediation analyses revealed that both E1 and E3 mediated 22.2 % of the negative association between 4:2 FTSA and BLZ. Sex-stratified analyses showed E3 mediated 22.8 % of this relationship in males, while exerted a suppression effect on the 4:2 FTSA-HCZ associations in females. Molecular docking revealed that 4:2 FTSA exhibits high-affinity binding to key steroidogenic enzymes (including CYP19A1, 17β-HSD1, AKR1C2, and AKR1C3), suggesting direct disruption on steroid hormone synthesis. This study highlights the endocrine-disrupting potential of emerging PFAS alternatives and their sex-specific effects on fetal growth, providing critical evidence for targeted strategies to reduce prenatal Hal-POP exposure and associated developmental risks.