Healthy lifestyle modifies the association between per- and polyfluoroalkyl substances and hyperlipidemia: A propensity score-matched case-control study.
Aug 2026· International Journal of Hygiene and Environmental Health· Vol 277, pp.
114880
· 0 citations· 35 references
Medicine
TL;DR
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.
Abstract
The impact of per- and polyfluoroalkyl substances (PFAS) on hyperlipidemia and the potential modifying role of overall lifestyle remain underexplored. We examined six serum PFAS and a composite lifestyle score among 192 propensity score-matched case-control pairs. Individual and joint associations were evaluated using conditional logistic regression, quantile g-computation, and Bayesian kernel machine regression. A composite healthy lifestyle score was constructed based on smoking, alcohol drinking, physical activity, body shape, and diet. Per interquartile range (IQR) increase in ln-transformed concentrations, perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), and perfluoroundecanoic acid (PFUnDA) were associated with 89%, 110%, 67%, 49%, and 42% higher odds of hyperlipidemia, respectively. Mixture analyses revealed a joint positive association (OR = 1.57; 95% CI: 1.22, 2.02), driven predominantly by PFNA, the emerging alternative 6:2 Cl-PFESA, and PFHxS. Among participants with an unhealthy lifestyle (defined as a composite score ≤2 based on the population median), higher levels of PFOA, PFHxS, and PFNA were associated with significantly elevated odds of hyperlipidemia. However, for 6:2 Cl-PFESA, perfluorodecanoic acid (PFDA), and PFUnDA, these associations were generally weaker in participants adhering to a relatively healthy lifestyle, as supported by significant multiplicative interactions. Negative additive interactions were also observed for 6:2 Cl-PFESA and PFNA. Our findings demonstrate 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.
Per- and polyfluoroalkyl substances (PFAS), including emerging alternatives, have been implicated in type 2 diabetes (T2D), but epidemiological evidence remains inconsistent and the underlying mechanisms are unclear. We aimed to investigate the associations of individual and mixed PFAS exposure with T2D risk and to explore the roles of triglyceride-glucose (TyG)-related indices and metabolomic alterations. A total of 1647 participants (749 participants with T2D and 898 controls) were included. Multivariable logistic regression and weighted quantile sum (WQS) regression were used to evaluate the associations of single PFAS and mixed PFAS with T2D risk, respectively. Mediation analyses were conducted for TyG-related indices, and untargeted metabolomics and sequential mediation analyses were further performed in a nested case-control subset. Most individual PFAS were positively associated with T2D risk. Mixed-exposure analyses consistently showed that PFAS mixture was associated with increased T2D risk, with 6:2 FTS, PFNS, and PFPeS identified as the main contributors. Mediation analyses indicated that TyG-related indices (TyG, TyG-BMI, TyG-WC, and TyG-WHtR) were significantly associated with both PFAS mixture and T2D. Metabolomic analyses identified 35 shared metabolites associated with both PFAS mixture and T2D, mainly enriched in lipid-related pathways. Sequential mediation analyses further suggested that palmitic acid, stearic acid, and glutamine, together with TyG, might be involved in the pathways in the association between PFAS exposure and T2D risk. PFAS exposure was associated with T2D, with TyG-related indices and metabolites potentially involved in this association.
J. Zhu, Yu Xia, N. Dai et al.· International Journal of Hyg...· 0 citations
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.
Xu Cheng, Junya Gao, Lu Liu et al.· Environmental Health Perspec...· 0 citations
Limiting to directly measured exposures, incorporating the full NHANES design in the primary regression, and triangulating across complementary mixture frameworks provide a more rigorous platform than prior single-pollutant or design-naive approaches.
Rifa Tasnia, E. Obeng-Gyasi· Journal of Xenobiotics· 0 citations
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.
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
Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), are persistent environmental pollutants with potential immunotoxic effects. Emerging epidemiological evidence suggests a link between PFAS exposure and autoimmune diseases, including rheumatoid arthritis (RA). However, the causal nature of this relationship remains unclear. Genetic instruments for circulating PFOA and PFOS levels were obtained from genome-wide association studies of European populations, while RA outcome data were sourced from the FinnGen consortium and United Kingdom Biobank. Associations were evaluated using multiple Mendelian randomization (MR) methods to assess the robustness of the findings. The inverse variance weighted method served as the primary approach. Additional methods, including MR-Egger, weighted median, simple mode, weighted mode, maximum likelihood estimation, and robust adjusted profile score, were applied to address potential pleiotropy and weak instrument bias. Sensitivity analyses, including Cochran Q-test for heterogeneity, MR-pleiotropy residual sum and outlier (MR-PRESSO) for pleiotropy detection, and leave-one-out analysis, were performed to validate the robustness of the findings. MR analysis identified a significant association between genetically predicted PFOA levels and increased RA risk (odds ratio = 1.87, 95% confidence interval [1.13–3.11], P = .015). Similarly, genetically predicted PFOS levels were positively associated with seropositive RA risk (odds ratio = 1.14, 95% confidence interval [1.00–1.29], P = .049). Sensitivity analyses confirmed the robustness of these findings, and reverse MR analysis did not indicate bidirectional causality. Our findings provide genetic evidence suggesting a potential association between PFAS exposure and RA risk. Given the widespread environmental persistence of PFAS, further investigation into potential health impacts and strategies to reduce exposure may be warranted. Further mechanistic studies are warranted to elucidate the biological pathways underlying the potential relationship between PFAS exposure and RA.