Association between serum perfluoroalkyl substances and COPD risk: population evidence and in vitro validation.

Organophosphate flame retardants and incident type 2 diabetes: Integrating population evidence, mechanistic insights, and effect modification by healthy lifestyle.

Higher exposure to organophosphate flame retardants (OPFRs) may contribute to type 2 diabetes mellitus (T2DM), but prospective evidence, lifestyle modification, and biological plausibility remain insufficiently characterized. We conducted a nested case-control study within the Henan Rural Cohort to evaluate associations between OPFRs exposure and incident T2DM. Cox models, WQS, QGC, BKMR, and an adaptive elastic-net-based environmental risk score were used to assess single and mixed OPFRs exposure. Baseline and trajectory-based healthy lifestyle scores were applied to evaluate joint effects, and signed Wald χ² decomposition quantified contributions of OPFRs and lifestyle domains. Mechanistic evidence was integrated from in vitro experiments and toxicogenomic analyses, including RNA-sequencing, network toxicology, molecular docking, and GEO re-analysis, to evaluate EGFR-related signaling and build an integrative adverse outcome pathway. Higher urinary OPFRs, particularly TPHP, were associated with increased T2DM risk, and OPFRs mixtures showed a linear dose-response relationship with T2DM risk. High OPFRs exposure combined with unhealthy or deteriorating lifestyle trajectories conferred the greatest risk, with OPFRs plus lifestyle explaining 55.36% of total model χ². In HepG2 cells, TPHP impaired glucose consumption and downregulated EGFR, whereas EGFR overexpression alleviated the TPHP-associated abnormal glucose consumption. EGFR overexpression was confirmed at both mRNA and protein levels. The p-AKT/total AKT results provided supportive evidence of AKT-related signaling changes, whereas total GLUT2 protein abundance was not significantly altered. Molecular docking supported potential TPHP-EGFR binding affinity of -8.5 kcal/mol, and GEO analyses provided external supportive evidence that EGFR expression tended to be higher in healthier lifestyle-related conditions. These findings suggest that mixed OPFRs exposure, dominated by TPHP, was associated with higher incident T2DM risk, partly attenuated by healthier lifestyle trajectories, supporting combined exposure-reduction and lifestyle-based prevention strategies.

Di(2‐Ethylhexyl) Phthalate Exposure and Risk of Diabetic Kidney Disease: Epidemiological Association and Mechanistic Insights

ABSTRACT Objective This study aims to explore the association between exposure to di‐(2‐ethylhexyl) phthalate (DEHP) and diabetic kidney disease (DKD), and to elucidate its potential molecular mechanisms. The study findings provide scientific evidence for the prevention and control of environmental risk factors related to DKD. Methods We utilised the United States National Health and Nutrition Examination Survey (NHANES) database to evaluate the correlations of DEHP exposure with DKD risk and renal function indices. Candidate targets were screened using network toxicology, and functional enrichment analysis was conducted. The binding ability of DEHP to the candidate mechanistic targets was verified through molecular docking. The toxicity and target effects of DEHP and its metabolites were verified using HK‐2 cells. Results The NHANES analysis demonstrated a positive correlation between DEHP exposure and the risk of DKD, with a significant dose‐response relationship observed. Network toxicology identified ALB, ESR1, and MMP9 as candidate mechanistic targets in DEHP‐induced DKD. In vitro experiments confirmed that DEHP and its metabolite MEHP reduced HK‐2 cell viability, induced lipid deposition, and altered the expression of candidate mechanistic targets. Conclusion DEHP is an important environmental risk factor for DKD. It may promote the development and progression of DKD by regulating key targets and interfering with lipid metabolism.

Association between perfluoroalkyl and polyfluoroalkyl substances and risk of obstructive sleep apnea.

OBJECTIVE Epidemiological and toxicological studies have associated perfluoroalkyl and polyfluoroalkyl substances (PFAS) with adverse effects on multiple organ systems. However, the potential link between PFAS exposure and obstructive sleep apnea (OSA) remains limited. METHODS 2,960 participants were selected from two cycles of National Health and Nutrition Examination Survey. OSA was evaluated by the multivariable apnea prediction index, and serum concentrations of nine PFAS were detected. Weighted logistic regression, RCS, and WQS regression were used to assess individual, nonlinear, and mixture associations. RESULTS  PFDeA and PFUA showed significant inverse dose-response relationships, with quartile-based analyses showing protective effects for PFDeA, PFHxS, Me-PFOSA-AcOH, PFUA, and n-PFOS. RCS analyses revealed L-shaped nonlinear relationships for PFDeA and PFUA. Sex-stratified analyses identified a female-specific inverse association for Sm-PFOS (P for interaction = 0.025). WQS regression indicated significant protective mixture effects (OR = 0.69, P = 0.007), predominantly driven by PFUA, followed by n-PFOA and PFHxS. CONCLUSION The relationships between PFAS exposure and OSA risk are characterized by compound-specific, concentration-dependent, and sex-dimorphic patterns.

Perfluoroalkyl/Polyfluoroalkyl Substances, Hemostatic/Inflammatory Biomarkers, and Incident Hypertension

Background Perfluoroalkyl/polyfluoroalkyl substances (PFAS) are emerging clinical and public health concerns, but their role in cardiovascular disease risk remains unclear. Inflammation and thrombosis may link PFAS and cardiovascular disease. Objective We investigated the association between serum PFAS concentrations and inflammatory and hemostatic markers in midlife women, and whether these markers mediated the association between PFAS and incident hypertension. Methods We analyzed 1,387 participants from the Study of Women’s Health Across the Nation from 1999 to 2000 to 2015 to 2016. Linear mixed-effects models estimated the association of 7 PFAS with high-sensitivity C-reactive protein (hs-CRP), fibrinogen, factor VII activity, plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator antigen. Quantile-g-computation evaluated mixture effects. Causal mediation analyses tested whether these markers mediated the PFAS-hypertension association. Results Individual PFAS were positively associated with hs-CRP and PAI-1. For hs-CRP, per doubling of PFAS ranged from 3.59% (95% CI: 0.01%-7.30%) for branched perfluorooctane sulfonic acid isomers to 5.32% (95% CI: 1.67%-9.10%) for 2-(N-methyl-perfluorooctane sulfonamido) acetic acid. For PAI-1, per doubling of PFAS ranged from 2.41% (95% CI: −0.86% to 5.78%) for the linear perfluorooctane sulfonic acid isomer to 3.04% (95% CI: 0.24%-5.93%) for 2-(N-methyl-perfluorooctane sulfonamido) acetic acid. However, none of these associations remained statistically significant after false discovery rate correction. PFAS mixture effects were 6.15% (95% CI: −0.83% to 13.58%) for hs-CRP and 6.05% (95% CI: 0.29%-12.14%) for PAI-1. No associations were found with other markers, and biomarkers did not mediate the PFAS-hypertension association. Conclusions These findings suggest, but do not establish, that PFAS may be linked to inflammation and impaired fibrinolysis in midlife women.

Per- and Polyfluoroalkyl Substances Exposure in New Jersey Prostate Cancer Survivors: A Pilot Biomonitoring Study

PM2.5 chemical constituents and chronic obstructive pulmonary disease mortality risk: The Pearl River Cohort study.

Chronic obstructive pulmonary disease (COPD) imposes a major burden on global health, yet evidence on the prolonged health effects of individual PM2.5 constituents remains limited. Previous research has primarily employed traditional models, which may struggle to capture the complex correlations among the PM2.5 components and be less effective in confounding adjustment. We conducted a prospective cohort study involving 182,009 participants from the Pearl River Cohort (2013-2015) followed through 2020, applying inverse probability-weighted marginal structural Cox models and quantile g-computation (QGC) to assess the associations of individual PM2.5 components and their mixtures with COPD mortality, followed by stratified analyses for effect modification. Over 1.18 million person-years of follow-up, 422 COPD deaths were documented. Long-term exposure to ammonium (NH4+), black carbon (BC), nitrate (NO3-), organic matter (OM) and chloride (Cl-) was associated with higher COPD mortality, with HRs (95% CI) of 2.75 (1.86-4.05), 2.41 (1.64-3.55), 1.86 (1.45-2.39), 1.85 (1.33-2.57) and 1.45 (1.15-1.82), respectively. Mixture analysis showed that each one-quartile increase in the PM2.5 component mixture was associated with a 39% (29%-50%) higher risk of COPD mortality, primarily driven by OM, Cl-, and NO3- (weights = 0.34, 0.34, 0.32). Stratified analyses indicated greater associations among older adults, suggesting increased susceptibility in this group. Our findings underscore the potential contribution of individual PM2.5 constituents and their mixtures in COPD mortality, while suggesting actionable source-control priorities and coordinated precursor-reduction strategies, as well as population-specific prevention approaches.