Organophosphate flame retardants and incident type 2 diabetes: Integrating population evidence, mechanistic insights, and effect modification by healthy lifestyle.
Aug 2026· Journal of Hazardous Materials· Vol 516, pp.
143347
· 0 citations· 38 references
Medicine
TL;DR
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.
Abstract
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.
TDCIPP exposure induced hepatotoxicity in mice, and may induce hepatic lipid toxicity in mice, indicating that the non-cancer risk of BDCIPP should be of concern.
An association between OPFRs exposure and hyperlipidemia is supported and a potential multi-target, multi-pathway regulatory mechanism is suggested, which suggests a potential multi-target, multi-pathway regulatory mechanism.
Mixture exposure showed a significant positive association with chronic obstructive pulmonary disease risk, and these substances disrupt pulmonary homeostasis through concurrent molecular activation and lipid-metabolic disturbance, evidenced by triglyceride-glucose index mediation.
Yansong Hu, Huanyu Cui, Yakun Wang et al.· BMC Pulmonary Medicine· 0 citations
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
DEHP is an important environmental risk factor for DKD and may promote the development and progression of DKD by regulating key targets and interfering with lipid metabolism.
Dapeng Yin, Yan Li, Wei Wu et al.· Diabetes/Metabolism Research...· 0 citations
Background Bisphenol A (BPA) and its structural analogs, bisphenol F (BPF) and bisphenol S (BPS), are widely used in consumer products and increasingly detected in children. Although BPA has been linked to diabetes and impaired glucose metabolism in adults, evidence for BPF and BPS, particularly in the pediatric population, remains limited and inconsistent. This study examined the associations of individual and combined bisphenol exposures with type 1 diabetes mellitus (T1DM) risk and glucose homeostasis in children. Methods We conducted a case–control study including 122 children with T1DM and 287 controls from Shenyang, China. For biomarker analysis, a subset of 110 participants (55 cases and 55 controls) was selected. Urinary bisphenol concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Associations with T1DM risk and glycemic outcomes were evaluated using multivariable logistic and linear regression models. Bayesian kernel machine regression (BKMR) and Restricted cubic spline (RCS) analyses were further used to explore potential nonlinear relationships and interaction effects. Results BPA was detected in all samples, with widespread exposure to BPF and BPS. Higher urinary BPA and BPF levels were significantly associated with increased odds of T1DM. BPS was not associated with T1DM status but was consistently linked to elevated fasting glucose (β = 0.987, 95% CI: 0.104–1.871) and HbA1c (β = 0.327, 95% CI: 0.012–0.642). BKMR characterized the joint associations of bisphenol mixtures with the study outcomes, whereas RCS analyses suggested near-linear exposure–response relationships between BPS and glycemic traits. Exploratory interaction analyses suggested heterogeneity in selected associations by sex and case–control status. Conclusion Higher urinary concentrations of BPA and BPF were associated with increased odds of T1DM in children, while BPS was linked to markers of impaired glucose regulation. These findings suggest that BPA substitutes may not be biologically inert and could be relevant to metabolic health during childhood. Further prospective and mechanistic studies are needed to better understand the biological pathways underlying these associations.
Min Yang, Xin-Ying Zhao, Yijie Wang et al.· Frontiers in Nutrition· 0 citations