Research on the influence of repeated exposure to antimicrobial chemicals, such as triclosan, on the microbiome is lacking. The goal of this study was to elucidate the associations of time-varying urinary triclosan concentrations with the adolescent gut microbiome. We used data from a prospective cohort based in Cincinnati, OH (enrolled 2003-2006, n = 146), to assess the time-varying associations of urinary triclosan concentrations with adolescent (age ∼ 12 years) gut microbiome diversity and composition. Individuals ≥ 18-years-old were recruited during the second trimester of pregnancy, and urinary triclosan concentrations were measured in pregnant women up to 2 times in pregnancy and up to 7 times in the child from ages 1 through 12 years. At age ∼ 12 years, fecal microbiome diversity and composition was characterized with metagenomic sequencing. We estimated differences in the relative abundance of prevalent (≥50%) bacterial species and gene pathways using linear regression and generalized estimating equations to assess windows of heightened susceptibility adjusted for sociodemographic characteristics. Additionally, we examined sex-specific associations by including an interaction term. The adolescent median Shannon diversity was 3.5 (IQR: 3.3, 3.5). Higher gestational triclosan concentrations with lower gut microbiome diversity [β = -0.13 per 10-fold increase (95%CI: -0.24, -0.02)]. Triclosan concentrations were also positively associated with higher abundance of antibiotic resistance genes and differential abundance of some bacterial species, with the strongest associations observed in early life and at age 12 years. We also found differences depending on sex, with more significant associations observed among males. Our findings provide insight into windows of triclosan exposure that are relevant to gut microbiome composition and the impacts of antimicrobial agents.

Growing evidence suggests that exposure to metals, such as molybdenum, contributes to significant health risks. However, very little is known about its potential male reproductive toxicity due to paternal exposure across generations. The aim of the present study was to investigate the male reproductive toxicity of paternal exposure to sodium molybdate (Na2MoO4) across generations and reveal the underlying mechanism. Adult F0 male C57 mice were administered sodium molybdate at doses of 0.01 and 0.1 mg/kg/day. The assessment included testicular toxicity evaluation and metabolomic profiling, followed by mechanistic studies in vivo and in vitro from F0 to F2. A large sample of case-control study including 958 subjects verified the findings. Reduced sperm counts and damages to seminiferous tubules across generations were observed in Mo-treated groups. Metabolomics analysis revealed a transgenerational elevation of 17α-hydroxyprogesterone (17α-OHP) in the testes of Mo-treated groups. Apoptosis and ferroptosis were enhanced in GC-2 cells in vitro after 17α-OHP treatment and were validated in vivo. Molecular competition experiments revealed that 17α-OHP competes for the NADPH binding site in FSP1, hindering FSP1's catalytic function, as supported by metabolomics analysis. Enzyme activity analysis found a reduction in FSP1 activity after 17α-OHP treatment, promoting ferroptosis and apoptosis in GC-2 cells in vitro. AHCY was identified as a potential target and was reduced after Mo exposure both in vivo and in vitro, accompanied by testicular DNA hypomethylation and elevated expression of key enzymes for 17α-OHP synthesis across generations, including Hsd3b and Cyp17a1. Human studies revealed that Mo exposure was associated with an increased risk of male infertility via 17α-OHP. This study innovatively elucidated the mechanisms by which paternal Mo exposure induced transgenerational male reproductive toxicity through metabolic and epigenetic alterations using human, mouse, and in vitro models.

Evidence on associations between green space, air pollution mixture, and heterogeneous biological aging patterns remains limited. We investigated the opposing effects of green space and air pollution mixture on biological aging patterns using an accelerated longitudinal design based on repeated-measures data from 11,760 adults (aged 20-65 years) in a high-pollution Chinese city. Biological age acceleration (BAA) was derived via the Klemera-Doubal method. Group-based trajectory modeling identified three stable BAA profiles, labeled as "slow", "moderate", and "accelerated" aging, which were primarily distinguished by overall BAA magnitude rather than divergent slopes over age. Multinomial generalized linear mixed models and weighted quantile sum regression were applied to assess environmental associations. Higher green space (500 m normalized difference vegetation index (NDVI)) was associated with lower odds of membership in the "accelerated aging" trajectory (OR: 0.84; 95% CI: 0.75, 0.95). Even under limited exposure contrast in this high-pollution setting, higher exposures to PM2.5, PM10, SO2, and O3 were associated with higher odds of membership in the accelerated aging trajectory. The air pollution mixture showed a consistent positive association (OR: 1.16; 95% CI: 1.08, 1.24), driven primarily by O3 and PM10. Mediation analysis revealed that 25.0% of the protective association of green space was mediated by reduced pollution exposure. These findings highlight green space as a vital resilience resource, supporting synergistic urban greening and pollution control strategies to promote healthy aging.

With the intensification of climate change, temperature variability (TV), a critical climatic dimension, is projected to increase. As a climate-sensitive disease, ischemic stroke may be affected by temperature variability; however, the evidence on the ischemic stroke burdens of short-term temperature variability in a changing climate remains unknown, especially accounting for long-term exposure adaptation. Based on a nationally representative, multicenter data set of over 1.6 million individual-level, hourly data on ischemic stroke onset from 2015 to 2022, we adopted a case-crossover study design to evaluate the association between short-term exposure to TV and ischemic stroke onset using conditional logistic regression. Furthermore, we took the long-term TV adaptation into account to derive the modified nonlinear exposure-response function and evaluated the ischemic stroke burden under different climate change scenarios. Short-term exposure to TV was positively associated with the risk of ischemic stroke onset, and long-term TV significantly modified the effects with populations living in regions of persistently high TV being more vulnerable. The ischemic stroke cases attributable to TV have more than doubled from 2000 to 2020. Under the high-emission scenario (SSP5-8.5), the attributable fraction of ischemic stroke is projected to increase substantially (19-58%) by the end of the century, particularly in vulnerable regions such as Southwest and South China. These findings demonstrate that individuals have limited adaptive capacity to temperature variability. Incorporating temperature variability into climate-health risk assessments, public health preparedness, and mitigation strategies will be essential to safeguard populations in an increasingly unstable climate system.

Breast cancer (BC) among women in all age groups continues to increase. Changes in reproductive risk factors cannot explain these trends, and rising rates among women under 40 cannot be explained by cancer screening, suggesting other factors are involved. We recently identified 920 chemicals whose biological activity suggests they can increase BC risk, the breast cancer-relevant chemical (BC-Chem) list, because they induce mammary tumors in rodents or activate estrogen or progesterone signaling in vitro. To develop exposure reduction strategies and inform BC research, we used US government databases to identify production volumes, uses, environmental releases, and predicted exposure levels in the US population. We found that exposure to potential breast carcinogens is ubiquitous. Billions of pounds of BC-Chems were emitted to air in 2020; tens of millions of pounds were released to the environment through industrial activities in 2024; and 143 were produced at 1 million pounds or more in 2019. Further, we found 500 BC-Chems likely present in consumer products, 462 in food, 162 in drinking water, 485 in pesticide formulations, 142 in pharmaceuticals, and 106 in construction materials. High-end predictions for median daily intakes in the US population exceeded 0.1 mg/kg body weight for 84 BC-Chems. Exposure could be reduced by health protective policies such as regulating drinking water contaminants and avoiding use in common products. These findings provide quantitative evidence to guide systematic prioritization of chemicals and mixtures for studying health effects, monitoring exposures, assessing risks, and preventing harm through exposure reduction.

Exposure assessment in kidney disease epidemiology remains challenging because kidney function impairment may alter urinary chemical excretion, limiting the utility of urinary biomonitoring and highlighting the need for alternative tools. We combined targeted and nontargeted analyses of silicone wristbands worn by 43 male agricultural workers to characterize their personal chemical exposome and evaluate preliminary associations of these exposures, urinary biomarkers, and kidney health. Kidney function was assessed via estimated glomerular filtration rate (eGFR, mL/min/1.73m[2]). Pesticides were quantified in wristbands (worn 8-11 days) and spot urine samples using targeted analysis. A custom GC-HRMS nontargeted workflow was applied to examine potential chemical exposure differences from wristband measurements. Associations between pesticide exposure and kidney function were evaluated using minimally adjusted linear regression for continuous eGFR (β) and log-binomial regression for binary eGFR < 90 (prevalence ratio [PR]). Overall, our findings suggest that higher wristband pesticide concentrations may be associated with lower kidney function among participants. In adjusted models, a 10-fold increase in wristband chlorpyrifos concentration yielded a higher prevalence of eGFR < 90 (PR = 1.53; 95% CI: 0.99, 2.36). Oxyfluorfen detection was similarly associated with a higher prevalence of eGFR < 90 (PR = 2.38; 95% CI: 1.01, 5.61). Conversely, most urinary biomarkers showed no association, though specific gravity-corrected AMPA concentrations were inversely associated with eGFR < 90 (PR = 0.31; 95% CI: 0.11, 0.87). Exploratory nontargeted analysis identified 193 tentative features that were higher on wristbands from participants with eGFR < 90 and only one feature that was higher on wristbands from participants with eGFR ≥ 90. Silicone wristbands show promise for enhancing characterization of the personal chemical exposome and warrant further investigation as a complementary tool to urinary biomonitoring for reducing exposure misclassification in kidney disease epidemiology. These exploratory findings, based on a small sample, are hypothesis-generating and require validation through larger, longitudinal studies.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is associated with small-for-gestational age (SGA), an adverse pregnancy outcome indicative of intrauterine growth restriction (IUGR). Evidence from previous environmental epidemiologic work suggests that lipids contribute to this association through oxidative stress and inflammation. Therefore, we conducted an exploratory study by analyzing the maternal lipidome with the meet-in-the-middle approach to identify potential intermediates. In the Atlanta African American Maternal-Child Cohort, pregnant participants provided serum samples between 6 and 17 weeks gestation, which underwent targeted PFAS analysis (N: total = 513, SGA = 61) and untargeted lipidomics analysis (N: total = 330, SGA = 36). A lipidome-wide association study (LWAS) was conducted for PFNA, PFOA, PFOS, and PFHxS with multivariable regression and their mixture with quantile g-computation. A separate LWAS was performed for SGA with multivariable regression. Lipid pathway analysis was performed in LIPEA (Lipid Pathway Enrichment Analysis). Lipidomic signatures that overlapped between any PFAS LWAS and the SGA LWAS were considered intermediates. A simultaneous, 1-quartile increase in serum concentrations of PFNA, PFOA, PFOS, and PFHxS at early pregnancy was associated with a 43% increase in delivery of an SGA newborn (Odds Ratio = 1.43; 95% Confidence Interval = 1.02, 2.00). The overall mixture effect was driven by PFNA (weight = 0.42). There were 321 features associated with the PFAS mixture and 25 features associated with SGA in the maternal lipidome (all p < 0.05, but none remained significant after false discovery rate correction). After confirmation and annotation, three intermediate metabolites were identified, including phosphatidylinositol 18:1-20:4, phosphatidylcholine 32:0, and monoacylglycerol 18:0. The pathways for glycerophospholipid metabolism, retrograde endocannabinoid signaling, insulin resistance, and long-term depression were also enriched in the LWAS for PFNA, PFOA, PFOS, PFHxS, the PFAS mixture, and SGA. Global analysis of the maternal lipidome during early pregnancy revealed diverse bioactive lipid involvement in the PFAS-SGA association. Additional research is warranted to understand if antioxidants and anti-inflammatory nutrients would attenuate exposure effects on adverse maternal-child health outcomes.

Background: Diarrhea in children is a climate-sensitive disease that causes a large disease burden worldwide, while the impact of El Niño-Southern Oscillation (ENSO) remains unclear. Objectives: This study aimed to evaluate the diarrhea risk among children associated with ENSO in low- and middle-income countries. Methods: Individual data on 1,340,334 children under five years of age were collected from 53 low- and middle-income countries from the Demographic and Health Surveys Program during 2005-2019, including information on diarrhea, demographic characteristics, cluster location, water, sanitation, and hygiene (WASH). ENSO indexes (E and C index) were calculated with sea surface temperature through Empirical Orthogonal Function analysis. Teleconnection (τ[E] and τ[C]) of the locations where the cluster sites were located was calculated based on population-weighted temperature and total precipitation. For each location, ENSO exposure (El Niño and La Niña strength) were calculated by month-specific ENSO indexes and its teleconnection, respectively. A binomial generalized linear mixed-effects model was used to explore the association between ENSO exposure and diarrhea risk in children. Results: Odds ratios of diarrhea in children were 1.032 (95%CI: 1.025, 1.040) and 0.977 (95%CI: 0.971, 0.984) for each standard deviation increase in El Niño and La Niña strength, respectively. The effect size of El Niño was greater for children in rural areas [OR: 1.042 (95%CI: 1.033, 1.052)] and low-income households [OR: 1.047 (95%CI: 1.035, 1.060)]. The association between El Niño and diarrhea risk was stronger among those with unimproved toilet facilities and source of drinking water compared to those with improved conditions, while associations were similar by other WASH conditions, and La Niña showed similar results in the subgroup analyses. Discussion: This multicountry study indicates an association between ENSO and the diarrhea risk in children under five years globally. Our findings will benefit international prevention and control policy development for diarrhea in children to immediately reduce ENSO-related impacts.

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.

Hospital readmissions are a major concern among people living with Alzheimer's disease and related dementias (ADRD), contributing to substantial burden on patients, caregivers, and health care systems. We evaluated whether short-term exposure to fine particulate matter (PM2.5) was associated with 30-day all-cause readmission among older adults with ADRD and whether residential green and blue space modified this association. We conducted a nationwide time-stratified case-crossover study using Medicare fee-for-service inpatient claims from 2000 to 2016 in the contiguous United States. We identified 30-day all-cause readmissions following the first index admission with ADRD. Daily modeled PM2.5 concentrations were linked to residential ZIP Codes, and exposure windows up to lag 2 days were examined. Measures of green and blue space were derived from Landsat and Google Street View data. Conditional logistic regression was used to estimate associations between PM2.5 and readmission with interaction terms used to evaluate effect modification by levels of green and blue space. Among 6,098,836 beneficiaries with an index admission with ADRD, 759,128 (12.4%) experienced a 30-day all-cause readmission. An interquartile range (IQR; 7.2 μg/m[3]) increase in PM2.5 averaged over lag 0 to 2 days was associated with a higher risk of readmission (odds ratio: 1.010; 95% confidence interval: 1.006, 1.015). Associations were higher for beneficiaries with longer intervals to readmission (>7 days). Effect modification by green or blue space was not conclusive. These findings suggest that short-term PM2.5 exposure may increase the risk of 30-day all-cause hospital readmission among Medicare beneficiaries with ADRD. Reducing ambient PM2.5 exposure may help prevent avoidable readmissions and lessen burden on patients, caregivers, and health care systems.

Personal care products (PCPs) are widespread environmental exposures, yet their combined and system-wide effects on serum lipid profiles in the aging population remain poorly understood. This study aimed to comprehensively assess the association between exposure to multiple PCPs and serum lipid profiles in healthy older adults and to explore underlying molecular pathways and biological mechanisms. We conducted a prospective panel study with five monthly follow-up surveys between September 2018 and January 2019 among 76 healthy older adults (60-69 years) in Jinan, China. This study measured urinary concentrations of PCPs, serum lipid markers, and multiomics profiles (transcriptomics, lipidomics, and metabolomics). We employed linear mixed-effects models to analyze exposure-outcome associations and integrated multiomics data with causal inference testing and Ingenuity Pathway Analysis to identify mediating biomolecules and biological mechanisms. Additional analyses examined the relationships of PCP exposures with inflammatory cytokines, oxidative stress biomarkers, and electrocardiographic (ECG) parameters to provide functional support for the identified pathways and their associated phenotypic consequences. Four PCPs [Benzophenone-2 (BP-2), Benzophenone-3 (BP-3), 4-Hydroxy benzophenone (4-OHBP), and Ethyl p-Hydroxybenzoate (EtP)] were significantly associated with altered serum lipid profiles. Multiomics analyses suggested their convergence on a PPAR-centered immunometabolic network, with S100 signaling identified as a novel activation pathway. Specifically, BP-2 was associated with patterns consistent with IL-4/IL-13-mediated alternative macrophage activation, while PPAR appeared to be involved in inflammatory polarization and metabolic reprogramming. Cytokine analysis revealed associations between BP-2 and key inflammatory mediators (e.g., IL-1β), oxidative stress assessment linked BP-2 exposure to elevated markers of oxidative damage (e.g., 8-PGF2α), and ECG analysis associated BP-2 exposure with altered cardiac electrophysiology (e.g., QRS duration). These multifaceted findings suggest associations between PCP exposures and serum lipid profiles, and highlight the potential contribution to cardiovascular risk. Our findings provide integrated, multilayered evidence suggesting associations between exposure to PCPs and alterations in serum lipid profiles in older adults, bridging exposure profiles, biomolecular perturbations, and subclinical functional changes. These results serve as a hypothesis-generating theoretical foundation that, pending confirmation in larger studies or experimental validation, advances the understanding of environmental metabolic disruption in aging populations.