Sex-Specific Associations
Between Per- and Polyfluoroalkyl
Substances and the Risk of Type 2 Diabetes: The Role of Genetic Susceptibility
and Lipid Metabolism
Aug 2026· Environmental Health Perspectives· 0 citations· 49 references
TL;DR
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.
Abstract
To elucidate the sex-specific associations of per- and polyfluoroalkyl substances (PFASs) on type 2 diabetes (T2D) risk and to explore whether genetic susceptibility and baseline lipid profiles may help explain these associations. A nested case-control study including 985 matched case-control pairs from the Dongfeng-Tongji Cohort was conducted. Serum PFAS concentrations, T2D-related pathway polygenic risk scores (PRSs), blood lipid profiles, and plasma lipidomes were integrated. Conditional logistic regression, weighted quantile sum (WQS) regression, mediation analysis, and gene-environment interaction analysis were used to explore the associations and mechanisms. Sex-specific associations were observed between PFAS exposure and incident T2D, with PFOA and PFNA being associated with higher T2D risk in females. Liver-lipid pathway PRS strengthened these sex-specific associations. PFAS exposure was associated with triglyceride-related lipid profiles in females. Exploratory analyses suggested that the lipid score statistically accounted for part of the selected PFAS-T2D associations. CYP19A1-rs2414098 modified the association in females, with 50% mediation by the lipid score in the CC genotype (higher estrone). Baseline lipid profiles may partly account for the observed sex-specific associations between PFAS exposure and incident T2D. 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.
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
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.
Zhen-Hua Li, Cheng-Yang Hu, Xia-Juan Lu et al.· Environment International· 0 citations
It is suggested that mixed PFAS exposure, particularly to PFOA and PFHpA, may induce impaired renal function, with increased blood lipids playing an important mediating role.
Dandan Xu, Z. Mo, Jie Xiang et al.· Environmental Pollution· 0 citations
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.
It is demonstrated that adherence to a healthy lifestyle was associated with substantially weaker associations between 6:2 Cl-PFESA and PFDA exposures and hyperlipidemia, highlighting lifestyle modification may serve as a potential public health strategy to reduce environmental metabolic hazards.
Peiwen Li, Lianlong Yu, Xiao Zhang et al.· International Journal of Hyg...· 0 citations
Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals detected in populations, including children, through exposure from food, drinking water, and consumer products. Although growing evidence links PFAS exposure to altered pediatric lipid profiles, few longitudinal studies have determined whether developmental timing during early childhood is more strongly associated with lipid alterations than exposure magnitude.
Serum PFAS concentrations and lipid levels, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), were measured in 212 children from the Environment and Development of Children cohort at ages 2, 4, 6, and 8 years. Generalized additive mixed models (GAMMs) characterized longitudinal dose–response relationships, tested whether associations varied by exposure age, and whether baseline concentrations at age 2 years were associated with lipid trajectories from ages 2 to 8 years. Age-specific linear regression models (lagged and concurrent) and quantile-based g-computation (q-gcomp) were used to estimate age-specific associations and joint effects of the PFAS mixture on lipid levels at age 8 years.
In age-pooled GAMMs at ages 2, 4, 6, and 8 years, exposure-response relationships varied in both shape and direction across PFAS compounds for all lipid outcomes, including linear, non-linear and inverse patterns. Baseline PFAS concentrations at age 2 years were not associated with the rate of age-related change in any lipid outcome from ages 2 to 8 years. By contrast, in age-specific regression models evaluating lipid levels at age 8 years, higher HDL-C was associated with PFAS exposure at ages 6 and 8 years, and most associations remained significant after false discovery rate correction. In q-gcomp analyses, the PFAS mixture was positively associated with HDL-C at age 8 years for exposures measured at ages 6 and 8 years.
In age-specific analysis, childhood PFAS exposure was associated with higher HDL-C concentrations, and the strength of this association varied by exposure age rather than corresponding directly to exposure magnitude. These findings suggest that developmental timing should be considered when evaluating the effects of childhood PFAS exposure on blood lipids, and require confirmation in larger longitudinal cohort studies.
Ji-Eun Lee, Dong-Wook Lee, Youn-Hee Lim et al.· Lipids in Health and Disease· 0 citations
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