Organophosphate Pesticide Metabolites and Mortality in U.S. Adults: Age-Modified Dose–Response Associations from a National Cohort Study

Urinary organophosphate metabolites, DNA methylation aging, and heart disease mortality in middle-aged and older adults: an exploratory cohort study with in vitro evidence of biological plausibility

Background Chronic low-dose exposure to organophosphorus pesticides (OPPs) is widespread in the general population and has been linked to heart disease mortality, yet the biological pathways connecting such exposure to fatal outcomes remain poorly defined. We examined whether urinary OPP metabolites are associated with heart disease mortality and whether DNA methylation biomarkers might contribute to this association. Methods We studied 502 adults aged ≥50 years from the National Health and Nutrition Examination Survey (NHANES) 1999–2002 cycles with urinary OPP metabolite measurements, DNA methylation profiles, and linked mortality follow-up. Survey-weighted Cox models were used to relate baseline metabolites [per 1-standard-deviation (SD) increase] to heart disease mortality, with sensitivity analyses for exposure definition and confounding. DNA methylation biomarkers that were significant after false discovery rate (FDR) correction were examined in exploratory single-mediator models, with Benjamini–Hochberg correction applied across the five indirect-effect tests, and in a secondary survival random forest. THP-1 monocytes were exposed to chlorpyrifos as a mechanistic probe of pathways suggested by the epidemiological findings. Results Among four OPP metabolites, only diethylthiophosphate (DETP) was associated with heart disease mortality after multivariable adjustment [hazard ratio 1.33, 95% confidence interval (CI) 1.11–1.61 per 1-SD increase, FDR = 0.010], with a positive association across quartiles. After Benjamini–Hochberg correction, DETP showed FDR-significant linear associations with five DNA methylation biomarkers. In separate single-mediator models, MonoPP and ZhangAge showed nominal indirect effects at raw p < 0.05, with estimated proportions mediated of approximately 9.2 and 8.4%, respectively; however, neither remained statistically significant after Benjamini–Hochberg correction across the five mediation models. A survival random forest combining DETP with the five markers achieved a 5-fold cross-validated 20-year area under the curve (AUC) of 0.71 (95% CI 0.66–0.76). In vitro, sub-cytotoxic chlorpyrifos raised pro-inflammatory cytokines, increased DNMT1, suppressed TET2, and induced global DNA hypermethylation. Conclusion In this exploratory analysis, higher urinary DETP was associated with greater heart disease mortality in middle-aged and older adults. MonoPP and ZhangAge showed suggestive indirect effects in separate exploratory models, each accounting for an estimated 8–9% of the association, but neither effect remained significant after FDR correction. Most of the DETP-related risk, therefore, remained unexplained by the measured methylation markers. The in vitro experiments provided hypothesis-generating support—most directly for inflammatory signaling—rather than confirmation of the epidemiological pathway.

Residential pesticide exposure, mortality risk, and the potential mediating role of urinary metabolites: evidence from a nationally representative cohort

Associations of prenatal exposure to organophosphate flame retardants and organophosphorus pesticides with cardiac structure in 4-year-old children: Evidence from the Shanghai Birth Cohort.

INTRODUCTION Organophosphate flame retardants (OPFRs) and organophosphorus pesticides (OPPs) are widely used chemicals in daily environments. Yet, evidence linking prenatal exposure to them with cardiac structure development in offspring is scarce. METHODS Maternal urinary levels of OPFR and OPP metabolites were measured during the first and second trimesters. Left ventricular end-diastolic volume (LVEDV) and mass (LVM) were assessed by echocardiography in 4-year-old children. Multivariable linear regression and Bayesian kernel machine regression were used to evaluate individual and mixture effects, with sex-stratified and interaction analyses performed to assess potential modification. RESULTS Among 458 mother-child pairs from the Shanghai Birth Cohort, higher maternal urinary Di-o-cresyl-phosphate (DoCP) concentrations during both trimesters were associated with lower z-scores of LVEDV (β: -0.049, 95% CI: -0.089, -0.008; and β: -0.055, 95% CI: -0.089, -0.022, respectively) and LVM (β: -0.057, 95% CI: -0.098, -0.015; and β: -0.053, 95% CI: -0.087, -0.019, respectively) in 4-year-old offspring. Similarly, higher maternal Di-phenyl phosphate (DPHP) concentration in the second trimester negatively correlated with z-scores of LVEDV (β: -0.043, 95% CI: -0.085, -0.002) and LVM (β: -0.080, 95% CI: -0.122, -0.038). Mixture analyses revealed inverted J-shape associations between maternal mixed OPFRs/OPPs exposure and offspring LVEDV and LVM. Sex-stratified analyses suggested stronger associations among girls. CONCLUSIONS Prenatal exposure to OPFRs and OPPs was associated with smaller left ventricular structural measures in early childhood, mainly reflected by lower left ventricular volume and mass, with OPFRs emerging as main contributors and stronger associations among girls.

Organophosphate Flame Retardants Exposure Disrupts Serum Lipid Metabolism and Induces Hepatotoxicity: Evidence from the Population and Mouse Model.

Organophosphate flame retardants (OPFRs) are emerging pollutants that pose increasing health risks. The association between urinary metabolites of OPFRs (m-OPFRs) and lipid metabolism remains unclear. This study evaluated lipid metabolism disorders of OPFRs in a population-based observational study and C57BL/6 mice. Urinary m-OPFRs, serum lipid molecules, and biochemical biomarkers in serum were measured. Linear regression and quantile-based g-computation analyses assessed associations between m-OPFRs and lipid markers. Benchmark dose and 95% lower confidence limit (BMDL) for m-OPFRs were determined by Bayesian BMD analysis, and the health risk of internal exposure was further assessed by hazard quotient (HQ). Mediation analysis assessed whether lipid molecules mediated OPFRs-induced hepatotoxicity. Association analyses identified three m-OPFRs, including bis(1-chloro-2-propyl) phosphate (BCIPP), diphenyl phosphate (DPP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), which were significantly associated with the levels of docosahexaenoic acid, 18:0 choline phosphate (LysoPC (18:0)), and 18:0 phosphoethanolamine. The BMDLs of BCIPP, DPP, and BDCIPP were 1.320, 0.100, and 0.030 μg/L, respectively. BDCIPP showed the highest HQ (4.50), followed by BCIPP (2.30) and DPP (0.66), indicating that the non-cancer risk of BDCIPP should be of concern. TDCIPP exposure induced hepatotoxicity in mice. LysoPC (18:0) increased at early exposure and mediated 7.88-30.02% of hepatotoxicity (P < 0.05). In conclusion, TDCIPP may induce hepatic lipid toxicity.

Metabolomics insights into the association between organochlorine pesticides, synthetic pyrethroids exposure and thyroid cancer risk.

BACKGROUND The association between organochlorine pesticides (OCPs)/synthetic pyrethroids (SPs) and thyroid cancer (TC) remains poorly understood, with metabolic mechanisms unexplored. METHODS We conducted a 1:1 age- and sex-matched case-control study (n = 668). Serum levels of 27 target analytes (19 OCPs and 8 SPs) were quantified; subsequent analyses were restricted to 13 compounds (10 OCPs and 3 SPs) with detection frequencies ≥85%. Eight machine learning (ML) algorithms with Shapley Additive Explanations (SHAP) were used to identify key pollutants in the 334 case-control pairs. Untargeted metabolomics was performed in a subset of 50 age- and sex-matched case-control pairs. Mixture effects were assessed by Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression. Furthermore, the Latent Unknown Clustering Integrating Multi-Omics Data (LUCID) model was employed to integrate exposure and metabolic data, enabling the identification of TC patient subgroups and the exploration of underlying metabolic mechanisms. RESULTS Participants (mean age 45.2 years, 82.3% female) had serum OCPs at 0.007-0.333 ng/mL and SPs at 0.046-0.095 ng/mL. ML algorithms identified fenpropathrin, β-BHC, cyhalothrin, α-BHC, and p,p'-DDD as the top five contributors to TC. Elevated OCPs/SPs exposure was significantly associated with increased TC risk (WQS: adjusted OR = 1.45, 95%CI = 1.34-2.24, P = 0.019; LUCID: OR = 9.33). Fenpropathrin was the primary contributor (BKMR posterior inclusion probability = 1.00; WQS weight = 67.6%). A total of 45 significant differential metabolites (DMs) were identified (VIP ≥1, P < 0.05, and qualitative level 1). LUCID revealed a distinct TC cluster characterized by upregulated S-sulfo-L-cysteine/adenosine and downregulated 2-hydroxycaprylic acid. CONCLUSION OCPs/SPs mixtures, driven by fenpropathrin, disrupt amino acid/nucleotide metabolism while suppressing organic acid metabolism, representing a potential TC-associated metabolic signature.

Multi-Media Exposure, Selective Accumulation and Health Risks of Organochlorine Pesticides in Human Serum under Post-Ban Conditions

Organochlorine pesticides (OCPs), despite being banned, persist in the environment and continue to pose potential risks to human health. This exploratory study investigated the concentrations of multiple OCPs in serum samples from 10 local residents and 52 surrounding environmental samples, including soil (n = 10), air (n = 12), indoor dust (n = 10), and food (n = 20), collected in Taizhou, Zhejiang Province, in 2022. Multiple exposure pathways were quantified, and associated health risks were assessed. The results showed evidence of selective accumulation in humans, with serum ΣOCP concentrations ranging from 107.01 to 552.41 ng/g lipid weight (lw). p,p′-DDE was the predominant compound, accounting for 67.81% of total serum OCPs, while β-HCH showed relatively higher enrichment among HCH congeners. Lower proportions of p,p′-DDT and α-/γ-HCH were observed. Source contributions varied across media: food was the primary contributor to p,p′-DDE exposure, indoor dust and soil contributed more to β-HCH and certain DDT isomers, and the atmosphere showed a higher contribution of methoxychlor. Differences between integrated exposure profiles and serum composition highlighted the potential roles of metabolic transformation and lipid-associated accumulation in shaping internal OCP burdens. Risk assessment indicated that DDT metabolites and β-HCH were the major contributors to potential exposure risks. Overall, this study provides preliminary insights into the environmental–human distribution patterns of OCPs observed in Taizhou under post-ban conditions and highlights that environmental concentrations alone may not fully represent chronic internal exposure. These findings improve the understanding of potential OCP exposure pathways and emphasize the need for larger-scale studies incorporating population characteristics and refined exposure parameters for more comprehensive risk assessment