Chronic OP exposure, reflected by these indirect urinary biomarkers, is associated with increased mortality, with heightened vulnerability in younger adults, and underscore the need for stricter pesticide regulation and targeted public health interventions.
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.
The data do not support a robust county-level association between agricultural pesticide application and later PD mortality, and the apparent weak positive gradient is explained by geographic, demographic, and socioeconomic confounding.
BACKGROUND Studies have indicated that exposure to household pesticides is prevalent among the population. Nevertheless, the relationship and contributing factors linking urinary metabolites of household pesticides to circulating levels of sex steroid hormones in human serum remain insufficiently explored. OBJECTIVE To examine the correlation between household pesticides metabolites and serum sex steroid hormones levels. METHODS This study utilized data from 3,884 participants obtained through the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. NHANES measured urinary metabolites of household pesticides and serum levels of sex steroid hormones. The study utilized weighted multiple linear regression modeling combined with restricted cubic spline (RCS) analysis to investigate relationships and dose-response patterns between residential pesticide metabolites and serum sex steroid hormones across both genders. Additionally, the research examined potential modifying effects of obesity status on pesticide metabolite-sex hormone associations through interaction analysis. RESULTS Following adjustment for potential confounders, concentrations of 3,5,6-trichloro-2-pyridinol (TCPY), para-nitrophenol (PNP), and 3-phenoxybenzoic acid (3-PBA) demonstrated negative correlations with total serum testosterone (TT), estradiol concentrations(E2), and free androgen index (FAI) across all three statistical models (Ps < 0.05), while positive relationships emerged with sex hormone-binding globulin (SHBG). We found the similar results among male participants. However, the negative correlation was not found between TCPY, PNP, 3-PBA and SHBG among female participants RCS modeling revealed complex nonlinear interactions between DCBA and serum sex steroid hormone levels. Analysis stratified by body mass index showed that TCPY, PNP and 3-PBA exhibited similar negative correlations with TT, E2 and FAI in the non-obese participants. CONCLUSIONS The study reveals that the metabolites from household pesticides exhibited negative correlations with serum sex steroid hormone levels across both genders. Associations were more consistent for non-obese populations.