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.
Aug 2026· Environment International· Vol 215, pp.
110461
· 0 citations· 99 references
Medicine
TL;DR
Early-pregnancy PFAS exposure was associated with impaired fetal growth and altered amino acid and lipid metabolism may underlie these associations, and metabolomics data suggested several exploratory candidate intermediate metabolite features that may be involved in the associations.
Abstract
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.
It is suggested 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.
Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is associated with small-for-gestational age (SGA), an adverse pregnancy outcome indicative of intrauterine growth restriction (IUGR). Evidence from previous environmental epidemiologic work suggests that lipids contribute to this association through oxidative stress and inflammation. Therefore, we conducted an exploratory study by analyzing the maternal lipidome with the meet-in-the-middle approach to identify potential intermediates. In the Atlanta African American Maternal–Child Cohort, pregnant participants provided serum samples between 6 and 17 weeks gestation, which underwent targeted PFAS analysis (N: total = 513, SGA = 61) and untargeted lipidomics analysis (N: total = 330, SGA = 36). A lipidome-wide association study (LWAS) was conducted for PFNA, PFOA, PFOS, and PFHxS with multivariable regression and their mixture with quantile g-computation. A separate LWAS was performed for SGA with multivariable regression. Lipid pathway analysis was performed in LIPEA (Lipid Pathway Enrichment Analysis). Lipidomic signatures that overlapped between any PFAS LWAS and the SGA LWAS were considered intermediates. A simultaneous, 1-quartile increase in serum concentrations of PFNA, PFOA, PFOS, and PFHxS at early pregnancy was associated with a 43% increase in delivery of an SGA newborn (Odds Ratio = 1.43; 95% Confidence Interval = 1.02, 2.00). The overall mixture effect was driven by PFNA (weight = 0.42). There were 321 features associated with the PFAS mixture and 25 features associated with SGA in the maternal lipidome (all p < 0.05, but none remained significant after false discovery rate correction). After confirmation and annotation, three intermediate metabolites were identified, including phosphatidylinositol 18:1–20:4, phosphatidylcholine 32:0, and monoacylglycerol 18:0. The pathways for glycerophospholipid metabolism, retrograde endocannabinoid signaling, insulin resistance, and long-term depression were also enriched in the LWAS for PFNA, PFOA, PFOS, PFHxS, the PFAS mixture, and SGA. Global analysis of the maternal lipidome during early pregnancy revealed diverse bioactive lipid involvement in the PFAS-SGA association. Additional research is warranted to understand if antioxidants and anti-inflammatory nutrients would attenuate exposure effects on adverse maternal–child health outcomes.
K. Taibl, Anne L. Dunlop, Paula-Dene C. Nesbeth et al.· Environmental Health Perspec...· 0 citations
The observed effect modification by CYP19A1 rs2414098 suggests that hormonal pathways may contribute to the sex-specific associations, although this hypothesis requires confirmation in studies with direct hormone measurements and experimental validation.
Xu Cheng, Junya Gao, Lu Liu et al.· Environmental Health Perspec...· 0 citations
BACKGROUND
Prenatal exposure to metal mixtures may influence newborn birth size, but the underlying metabolic mechanisms remain unclear. This study aimed to evaluate the associations of 19 individual maternal metals and metal mixtures during pregnancy with birth size indicators, specifically birth weight z score (BWZ) and birth length z score (BLZ), and to identify potential metabolic pathways and mediating metabolites based on cord blood metabolomics.
METHODS
A total of 1059 mother-infant pairs were included in the full cohort. We applied ExWAS, ENET/DSA, WQS, qgcomp, and BKMR to assess both single-metal and joint exposure effects. Exploratory MWAS, pathway enrichment, and mediation analyses were conducted using cord blood metabolomics data.
RESULTS
In single-metal analyses, Zn, Se, and Mn showed positive associations with BWZ and BLZ, whereas Cu was positively associated with BWZ only; As, Pb, and Cd generally showed inverse associations. In mixture analyses, the negative-direction WQS index was associated with lower BLZ (β = -0.039, P = 0.042). Exploratory metabolomics analyses highlighted lipid-related metabolites, organic acid derivatives, and nucleotide-related metabolites, with enrichment in caffeine metabolism and steroid hormone biosynthesis pathways. Mediation analyses suggested potential indirect effect signals, including As-BWZ via 10-hydroxystearic acid (19.6%), Cu-BWZ via 2-ethyl-2-hydroxybutyric acid (30.8%), and Se-BLZ via 2-ethyl-2-hydroxybutyric acid (21.1%).
CONCLUSION
In this industrial city cohort, our findings provide evidence linking prenatal metal exposure to newborn birth size and suggest that cord blood metabolic profiles may offer exploratory mechanistic clues for understanding metal-related fetal growth patterns.
Hai-Yang Weng, Zhen-Hua Li, Chun-Yong Wang et al.· Ecotoxicology and Environmen...· 0 citations
PFAS exposure was associated with T2D, with TyG-related indices and metabolites potentially involved in this association, and palmitic acid, stearic acid, and glutamine might be involved in the pathways in the association between PFAS exposure and T2D risk.
Jun Zhu, Yu Xia, N. Dai et al.· International Journal of Hyg...· 0 citations
Prenatal exposure to environmental chemicals has been implicated in impaired fetal and early childhood growth. However, most previous studies have focused on single exposure domains, limiting understanding of the combined effects of co-occurring chemical mixtures. We investigated the joint effects of a prenatal multi-domain chemical mixture comprising endocrine-disrupting chemicals (EDCs), heavy metals, and ambient air pollutants on infant growth from birth to 36 months using data from the Korean Children's Environmental Health Study (Ko-CHENS), a nationwide prospective birth cohort of 5,056 mother-child pairs. We applied weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) to estimate mixture effects and identify key contributing exposures, WQS and BKMR were fitted separately at each of five assessment ages, and a latent class mixed model (LCMM) was used to characterize prenatal exposure trajectory subgroups, whose association with repeated growth measures was then evaluated in a linear mixed model. Ten mixture-outcome tests (two outcomes x five ages) were pre-specified as primary and were corrected for multiplicity using the Benjamini-Hochberg false discovery rate (FDR) procedure. WQS regression identified a significant inverse association between the prenatal chemical mixture and infant length-for-age z-scores at birth and 6 months, with late-pregnancy BPF and BPS consistently emerging as the top-weighted contributors; both associations remained below a 5% FDR threshold. Overall mixture effects estimated by BKMR were null at every assessment age, although BKMR suggested nonlinear and exposure-specific dose-response relationships involving bisphenol analogues and ambient air pollutants across multiple assessment time points. No significant associations were observed between LCMM-derived exposure trajectory class and longitudinal growth outcomes through 36 months. Domain-specific patterns were observed across both analyses: bisphenol analogues showed more consistent associations with length outcomes, whereas ambient air pollutants were more frequently identified as key contributors in weight-related models. These exploratory findings suggest that prenatal exposure to bisphenol analogues and ambient air pollutants may be associated with early childhood growth and warrants further investigation. They support the use of mixture-based approaches in environmental health research but should not be interpreted as evidence of causal effects.
Sungryul Shim, Taemi Kim, Sungchul Seo et al.· Environmental Pollution· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
