Integrating Lipid Metabolomics and Epidemiology: A Mediation Analysis of Blood Lipids between Per- and Polyfluoroalkyl Substances (PFAS) and Renal Impairment.
Aug 2026· Environmental Pollution· Vol 408, pp.
128967
· 0 citations· 62 references
Medicine
TL;DR
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.
Abstract
Exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to renal impairment, but evidence on mixed PFAS exposure in the general Chinese population and the underlying mechanisms remains limited. This study therefore investigated the associations between PFAS exposure and renal function and evaluated the potential mediating role of blood lipids. Serum levels of legacy and emerging PFAS, renal function parameters, and blood lipid profiles were measured in 1,370 adult residents from Zhejiang Province, China; additionally, 452 lipid metabolites were quantified in a subset of 316 participants. Using multiple linear regression, restricted cubic splines (RCS), and mixture exposure models, we found that PFAS mixture exposure was associated with reduced renal function, with eGFR decreases ranging from 2.2% to 2.9% per quartile increase across models, and PFOA as a predominant contributor. Mediation analyses further revealed that elevated total cholesterol, low-density lipoprotein cholesterol, and disturbances in fatty acids and phospholipids mediated 6.3% to 65.9% of the association between PFAS exposure and renal function decline. Collectively, these findings suggest that mixed PFAS exposure, particularly to PFOA and PFHpA, may induce impaired renal function, with increased blood lipids playing an important mediating role.
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
The relationship between low-to-moderate arsenic exposure and lipid metabolism remains unclear, particularly for different urinary arsenic species and the potential role of urinary albumin-to-creatinine ratio (UACR).
This cross-sectional study used NHANES 2009–2020 data and an adult population from Zhaodong, China. The NHANES analysis included 2,104 participants, representing 52,612,536 adults, and the Zhaodong analysis included 310 participants. Creatinine-adjusted urinary total arsenic (UTA) and dimethylarsinic acid (DMA) were designated as the principal exposure indicators, whereas monomethylarsonic acid (MMA), arsenite (As
III
), and arsenate (As
V
) were evaluated in supplementary exploratory analyses. Triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and UACR were examined as outcomes. Multivariable regression, restricted cubic spline, subgroup, and mediation analyses were performed.
The median UTA concentrations were 3.73 μg/L in NHANES and 12.37 μg/L in the Zhaodong population. In NHANES, after multivariable adjustment, UTA and DMA were positively associated with LDL-C levels, with β values of 0.68 and 0.85, respectively, and both associations remained significant after FDR correction (
q
< 0.1). Restricted cubic spline analyses revealed a nonlinear association between DMA and LDL-C. In the Zhaodong population, the highest quartile of DMA was associated with lower odds of abnormal LDL-C compared with the lowest quartile. In NHANES, both UTA and DMA were positively associated with UACR. Mediation analyses did not support a meaningful mediating role of UACR, although small negative indirect effects were observed in the LDL-C models involving UTA and DMA. Supplementary exploratory analyses involving MMA, As
III
, and As
V
yielded several nominal associations.
Low-to-moderate urinary arsenic exposure may be associated with altered LDL-C levels and increased UACR, with species- and population-specific differences. The mediation analyses did not support a meaningful mediating role of UACR. Prospective studies are needed to confirm these findings.
Di Wu, Shirui Yan, Xinxiao Li et al.· Frontiers in Endocrinology· 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
PER: and polyfluoroalkyl substances (PFAS) have been implicated in metabolic dysregulation; however, longitudinal evidence linking PFAS to metabolic syndrome (MS) across the transition from adolescence or young adulthood into early adulthood is still lacking. We analyzed 516 participants aged 12-30 years in the Young Taiwanese Cohort (YOTA) with baseline examinations in 2006-2008 and follow-up in 2017-2019. Eleven plasma PFAS and MS components were quantified at both time points. We used joint models that simultaneously included baseline PFAS and long-term PFAS changes to evaluate associations with follow-up MS and its components. A PFAS exposure index was derived as the mean of standardized ln-PFAS. The baseline PFAS exposure index was not associated with MS or its components. Among individual baseline PFAS, linear PFOA was inversely associated with impaired fasting glucose, and both linear PFOA and PFHxS were inversely associated with elevated blood pressure. In contrast, the PFAS exposure index change was inversely associated with follow-up MS (OR 0.36, q = 0.050) and follow-up MS waist (OR 0.22, q < 0.001). Among individual PFAS changes, follow-up MS was inversely associated with changes in linear PFOA, PFHxS, and PFDoA, and MS waist was inversely associated with changes in linear PFOA, linear PFOS, PFNA, PFDA, PFUdA, and PFDoA. The associations between PFAS exposure index change with MS and MS waist were robust across sensitivity analyses, including qgcomp. Analyses of continuous metabolic traits showed concordant patterns for waist circumference and HDL-C. Exploratory backward models further suggested that adiposity change may influence measured PFAS change. In this Taiwanese cohort, higher ΔPFAS exposure index was associated with lower odds of MS and abdominal obesity, but the findings are consistent with reciprocal coupling rather than a protective effect of PFAS exposure. Studies with three or more repeated measurements are needed to clarify causal direction and underlying mechanisms.
Highlights • Elevated MMA levels are associated with increased stroke risk in US adults.• Restricted cubic spline analysis identified a nonlinear relationship between MMA and stroke, with a cutoff at ln (MMA = 5).• The MMA-stroke correlation is stronger in younger adults than in older adults (P for interaction = 0.013).• Combined detection of NLR, TG, and FPG may help identify populations at elevated stroke risk in this cross-sectional exploratory analysis.
N. Wei, Boyi Tang, Yuan Cheng· Clinics· 0 citations
Circulating lipids and lipoproteins have been implicated in lung health and disease, yet their associations with the risk of developing idiopathic pulmonary fibrosis (IPF) remain poorly characterized. We integrated a prospective cohort study of 479,738 UK Biobank participants (1,236 incident IPF cases during 10 years of follow-up) with two-sample Mendelian randomization using the largest available genome-wide association data (5,159 IPF cases and 27,459 controls). Circulating lipids and lipoproteins were quantified via nuclear magnetic resonance spectroscopy (138 biomarkers) and clinical biochemistry (6 biomarkers). Multivariable-adjusted Cox proportional hazards models estimated associations with incident IPF, and Mendelian randomization using genetic variants as instruments was performed to assess potential causal relationships. After multiple-testing correction, 83 lipid biomarkers were significantly associated with incident IPF in the prospective analysis. Apolipoprotein B (ApoB)-containing lipoproteins, including low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), showed broadly inverse associations across lipid components and particle sizes. A size-dependent pattern was observed for high-density lipoprotein (HDL) particles, with small HDL subfractions inversely associated with IPF risk, whereas very large HDL subfractions were positively associated. Inverse associations were also observed for ApoB, apolipoprotein A1 (ApoA-1), and broader lipid classes, including sphingomyelins. Triangulating evidence across approaches, Mendelian randomization analyses supported inverse associations of genetically predicted total cholesteryl esters and sphingomyelins with IPF risk This study identifies circulating lipids and lipoproteins associated with IPF risk and highlights cholesterol and sphingolipid metabolism as potential contributors to IPF susceptibility. Further mechanistic studies and validation in independent cohorts are warranted.
Jiahao Zhu, Yu-Hao Shen, Zhe-An Yan et al.· Journal of Lipid Research· 0 citations
