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Zhenhua Li

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Open access Aug 2026

Metabolomic signatures and sex-specific associations of prenatal per- and polyfluoroalkyl substances exposure with fetal growth: A meet-in-the-middle and high-dimensional mediation analysis.

BACKGROUND Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with restricted fetal growth. However, the underlying biological mechanisms remain unclear. METHODS Based on the Ma'anshan Birth Cohort, we measured maternal serum PFAS concentrations in early pregnancy and conducted metabolomic profiling of cord serum. Associations of individual and mixed PFAS exposure with birth weight Z-score (BWZ), birth length Z-score (BLZ), and head circumference Z-score (HCZ) were evaluated using generalized linear models (GLMs) and weighted quantile sum (WQS) regression. Metabolomics data were integrated using metabolome-wide association study (MWAS), pathway enrichment analysis, meet-in-the-middle (MITM) and high-dimensional mediation analysis (HIMA) to explore relevant metabolic pathways and candidate intermediate biomarkers. RESULTS Higher early-pregnancy exposure to PFNA, PFDA, PFOS, PFOA, 6:2Cl-PFESA, and 8:2Cl-PFESA (β: -0.112 ∼  -0.092), as well as PFAS mixture (mean β = -0.056; 95% CI: -0.103, -0.009), was associated with lower BWZ. 6:2Cl-PFESA showed the highest average relative WQS weight (14.9%). A significant interaction between PFAS mixture and sex was observed (WQS*sex: β = -0.122, 95% CI: -0.227, -0.017), with negative associations in females (mean β = -0.115, 95% CI: -0.201, -0.031) but not males. MITM analysis identified phenylalanine metabolism and steroid hormone biosynthesis as key pathways jointly related to PFAS exposure and fetal growth in the overall population. Arginine metabolism and purine metabolism were identified among females. HIMA suggested several exploratory candidate intermediate metabolite features that may be involved in the associations between prenatal PFAS exposure and fetal growth. CONCLUSION Early-pregnancy PFAS exposure was associated with impaired fetal growth. Altered amino acid and lipid metabolism may underlie these associations. These findings provide preliminary mechanistic insights.

Zhenhua Li, Cheng-Yang Hu, Xia-Juan Lu et al. · 0 citations
Aug 2026

Associations of Prenatal Per- and Polyfluoroalkyl Substance Exposure with Neonatal Birth Weight z-Scores: The Potential Mediating Role of Maternal Glucose Homeostasis.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is associated with impaired fetal growth, yet evidence regarding mixture effects and the potential mediating role of maternal glucose homeostasis remains limited. We examined these associations in 642 mother-infant pairs from a prospective birth cohort in Ma'anshan, China. Multivariable linear regression (MLR) was used to assess associations of individual PFAS with neonatal birth weight z-scores (BW-z) and maternal glucose homeostasis. Weighted quantile sum regression (WQS) and Bayesian kernel machine regression (BKMR) were applied to characterize cumulative mixture effects. Sex-stratified analyses were conducted to evaluate potential effect modification. PFNA, PFDA, PFOS, L-PFHxS, 6:2 Cl-PFESA, and 8:2 Cl-PFESA were negatively associated with BW-z, with stronger negative associations observed in female infants. Mixture analyses further supported an overall negative association between PFAS mixture exposure and BW-z. Several PFAS were positively associated with 1-h and 2-h glucose levels, whereas PFNA, PFDoA, and 8:2 Cl-PFESA were negatively associated with fasting plasma glucose (FPG); in turn, higher FPG was associated with increased BW-z. Mediation analyses suggested statistically significant indirect effects through FPG in the associations of 8:2 Cl-PFESA and PFNA with BW-z, although the mediation proportions were modest at 11.5% and 9.5%, respectively. These findings suggest that prenatal PFAS exposure is associated with reduced BW-z, particularly among female infants, and that altered fasting glucose may represent one possible, but not primary, pathway linking selected PFAS to fetal growth.

Chun-Yong Wang, Zhenhua Li, Hai-Yang Weng et al. · 0 citations