Background: Growing evidence links air pollution to cognitive dysfunction in older adults. The gut microbiome and circulating metabolites present an important yet unexplored pathway, given their crucial role in the gut-brain axis.
Objectives: We aimed to explore the potential roles of gut bacteria, fungi, microbial functional potentials, and circuiting metabolites in the association of residential PM2.5 and O3 exposures with cognitive dysfunction.
Methods: We analyzed gut microbiome data from 1,027 older adults using metagenome and internal transcribed spacer sequencing to profile bacterial and fungal taxa, functional pathways, and enzyme abundances. Targeted metabolomics quantified 195 circulating metabolites, such as amino acids and organic acids. Annual average ambient PM2.5 and O3 exposures were estimated using satellite-based models. Cognitive outcomes, including mild cognitive impairment and cognitive decline, were assessed using the Mini-mental State Examination and Hasegawa dementia scale. Statistical analyses included Microbiome Multivariable Association with Linear Models (with a false discovery rate threshold of 0.25) for microbial associations and multivariate regression for metabolites and cognitive outcomes.
Results: Higher PM2.5 and O3 exposures were associated with disturbances in microbial composition, altered taxonomic profiles (e.g., decreased abundances of Blautia obeum and Gordonibacter pamelaeae), and disrupted functional pathways, particularly those regulating 2-oxoglutarate. These findings were partially replicated in an independent population. Higher air pollution levels were associated with increased circulating levels of 2-oxoglutarate and L-glutamine (key metabolites in neurodegenerative progression), which were further linked to higher odds of concurrent mild cognitive impairment (OR: 1.39-1.56) and an increased 2-year risk of cognitive decline (OR: 1.26-1.37). These associations were partially mediated by air pollution-related changes in microbial anaerobic energy metabolism pathways, especially involving 2-oxoglutarate metabolism and the enzyme aspartate transaminase.
Conclusions: Our findings highlight the role of the gut microbiome and microbial metabolites in mediating the detrimental impact of air pollution on cognitive health in older adults, providing new insights into the underlying etiology for future hypothesis generation. https://doi.org/10.1289/EHP16515.
Background: Fat-soluble toxicants such as chlorpyrifos (CPF) can accumulate in adipose tissue and the liver. During weight loss, these compounds may be released into circulation, but the metabolic consequences of this mobilization remain poorly understood.
Objectives: This study aimed to investigate the mobilization of CPF during weight loss and its effects on liver health and adipose tissue metabolism in mice.
Methods: C57BL/6J mice were fed high-fat or low-fat diets and exposed to 2 mg/kg BW/day CPF by oral gavage. Weight loss was induced by β3-adrenergic stimulation (CL316243) or treadmill exercise for 4 or 10 weeks. CPF was quantified in serum and tissues using HPLC. Tissue histology, expression of genes related to CPF metabolism, liver injury markers, and metabolic protein levels were assessed.
Results: CPF-exposed LFD mice showed more severe liver fibrosis and adipose inflammation than HFD counterparts. While obese mice had lower adipose CPF concentrations, they showed higher hepatic accumulation. CPF-exposed weight loss mice had higher levels of CPF in adipose tissue, liver, and brain and higher expression of CPF metabolism-related genes, including Paraoxinase-1 and cytochrome P450 genes, and greater glucose intolerance, compared to their counterparts without CPF administration. Molecular analyses revealed suppressed AMPK signaling and P62 accumulation indicating mitophagy disruption in CPF-exposed mice after weight loss. These effects occurred even at human-relevant low doses (0.45 mg/kg BW/day) and persisted across sexes.
Discussion: Weight loss mobilizes CPF and its metabolites from fat stores, leading to tissue accumulation and damage. Even low-dose exposure contributes to hepatic and metabolic disruption in mice, highlighting a potential risk of toxicant mobilization during fat reduction.. https://doi.org/10.1289/EHP16079.
Background: Exposomics is a conceptual framework positioned at the intersection of environmental health sciences and precision medicine. It seeks to comprehensively understand how environmental exposures and the body's response to these exposures impact human health across the life course. Introduced in 2005, the exposome concept represents a paradigm shift from single-pollutant studies to an integrated approach considering a broad range of exposures.
Objectives: This commentary explores the ongoing efforts to operationalize the exposome, with a focus on NIH initiatives aimed at building capacity in exposomics research and integrating lifecourse exposure data into health research.
Methods: This commentary draws on a structured review of current NIH funding opportunities, initiatives, and strategic documents related to exposomics. Key NIH-supported projects and collaborations were identified through analysis of publicly available agency reports, grant announcements, and program descriptions. Additional insights were gathered from relevant literature and international research activities to contextualize the NIH's role in promoting exposomics and integrating life-course exposure data into health research.
Discussion: Operationalizing the exposome is essential for advancing the field of environmental health and precision medicine. NIH-supported initiatives, alongside international collaborations, aim to standardize methodologies, develop tools, and promote interdisciplinary research. Addressing the complexities of exposomics requires integrating diverse datasets and fostering global coordination, paving the way for innovative strategies to improve human health outcomes. https://doi.org/10.1289/EHP15561.
Background: Diarrheal diseases remain a leading cause of mortality and morbidity among under-five children in South Asia. In rural Bangladesh, deep tubewells that tap into low-arsenic deep aquifers have been installed to provide microbially safe and arsenic-free drinking-water at source. However, unlike more widely used shallow tubewells, deep tubwells are sparsely distributed, and households often travel farther for drinking-water consumption from such wells. Hence, benefits from deep tubewells may be abated by higher levels of microbial contamination during water handling and storage that could increase the risk of diarrheal diseases.
Objectives: We examined the association between deep tubewell use and diarrheal disease risk in under-five children and investigated the role of social and environmental factors on modifying the association.
Methods: We implemented community diarrheal disease surveillance across households with under-five children using deep and shallow tubewells in Matlab, Bangladesh from March 2018 to October 2019. We used Generalized Estimating Equations (GEE) to measure the association between deep tubewell use compared to shallow tubewell use on diarrheal disease prevalence.
Results: Children in households using deep tubewells had diarrheal disease prevalence 0.83 times that of children in households using shallow tubewells (95% Confidence interval (CI): 0.71-0.96). Protective effects of deep tubewell use on diarrhea risk were observed among children in households that drank from wells within their household compound (Risk ratio (RR) =0.70, 95% CI: 0.54-0.91), were in flood-prone areas (RR=0.83, 95% CI: 0.75-0.92), and used unimproved latrines (RR=0.62, 95% CI: 0.43-0.89). Deep tubewell use was more protective against diarrhea than shallow tubewell use during the dry season (RR = 0.71, 95% CI: 0.52-0.97).
Conclusions: Despite concerns, using deep tubewells may not translate to higher diarrhea risk among under-five children, and may reduce diarrhea further especially in social and environmental contexts associated with higher groundwater microbial contamination. https://doi.org/10.1289/EHP15725.
Background: Per- and polyfluoroalkyl substances (PFAS) are a research priority for the U.S. Environmental Protection Agency (EPA). Because PFAS include thousands of structurally diverse chemicals, there is a pressing need for identifying what data are available to assess the human health hazard of these compounds.
Objectives: We used systematic evidence map (SEM) methods to summarize the available epidemiological and mammalian bioassay evidence for ∿14,735 chemicals identified as PFAS by EPA's Center for Computational Toxicology and Exposure (CCTE). This work is a continuation of our previous 2022 and 2024 SEMs that inventoried evidence on a separate set of ∿500 PFAS. The Comprehensive PFAS Dashboard includes evidence identified from our past SEMs and completed EPA assessments.
Methods: We conducted literature searches from peer-reviewed and gray literature sources to identify, screen, and inventory mammalian bioassay and epidemiological literature. A combination of manual review and machine learning software were utilized. A diverse array of potentially relevant supplemental content was also tracked, including mechanistic data, exposure-only studies, and studies informing chemical toxicokinetics and clearance. For each study meeting predefined population, exposure, comparator, and outcome (PECO) criteria, experimental design details and health endpoints evaluated were summarized in interactive web-based literature inventory visuals. Epidemiology studies and animal bioassay studies with ≥21-day exposure duration or reproductive/developmental study design proceeded to undergo a study evaluation for risk of bias and sensitivity, as well as detailed extraction of health endpoint data. Underlying data are publicly available and can be downloaded.
Results: Scientific database searches retrieved 152,205 references. After full-text screening, there were 347 mammalian bioassay and 44 epidemiological studies that met PECO criteria. The mammalian bioassay and epidemiological evidence assessed 99 and 30 individual PFAS, respectively (n = 18 PFAS with both). The epidemiological evidence assessed 15 health systems and the mammalian bioassay evidence assessed 16 health systems.
Discussion: Results from our 2022 and 2024 SEMs and completed EPA assessments are compiled into Comprehensive PFAS Dashboard. This dashboard is a resource for better understanding the currently available PFAS human health hazard data. It can be used as a tool for researchers and regulators interested in PFAS data gaps and research needs. Across all the data sources compiled into the Comprehensive PFAS Dashboard, only 1.4% (214/14,735) of PFAS had any mammalian bioassay or epidemiological data available. The vast majority of PFAS lack publicly available information about the potential human health effects of exposure to these chemicals.. https://doi.org/10.1289/EHP16952.
Background: Organophosphate ester flame retardants and plasticizers (OPEs) have myriad uses in industry and consumer products. Increasing human exposure to OPEs has raised concerns about their potential effects on child neurodevelopment during pregnancy.
Objective: We investigated whether OPE urinary concentrations during pregnancy were associated with child autism-related outcomes.
Methods: We included 4159 mother-child pairs from 15 cohorts in the NIH Environmental influences on Child Health Outcomes (ECHO) Consortium, with children born from 2006-2020 (median age [interquartile range]: 6 [4,10] years). Nine OPE biomarkers were measured in urine samples collected mid- to late pregnancy. Dilution-adjusted biomarkers were modeled continuously, categorically (high [> median], moderate [≤ median], non-detect), or as detect/non-detect depending on their detection frequency. We assessed child autism-related traits via a) parent report on the Social Responsiveness Scale (SRS) and b) clinical autism diagnosis. We examined associations of OPEs with child outcomes, including modification by child sex, using generalized estimating equations to account for clustering by ECHO cohort.
Results: Compared with non-detectable concentrations, high exposure to bis(butoxyethyl) phosphate (BBOEP) was associated with higher autistic trait scores (adj-β 0.97, 95% confidence interval [CI]: 0.42, 1.52) and greater odds of autism diagnosis (adjusted odds ratio [adj-OR]: 1.27, 95% CI: 1.07, 1.50). Bis(1-chloro-2-propyl) phosphate (BCPP) showed associations with autistic trait scores (BCPP adj-β for high exposure vs. non-detect: 0.34, 95% CI: -0.46, 1.13; BCPP adj-β for moderate exposure vs. non-detect: 0.72, 95% CI: 0.24, 1.20). High exposure to bis(2-chloroethyl) phosphate (BCETP) was associated with lower odds of autism diagnosis (adj-OR: 0.76, 95% CI: 0.60, 0.95). Other OPEs showed no associations in adjusted models. Associations between BBOEP and higher autistic trait scores were stronger in males than females.
Discussion: Prenatal exposure to OPEs, specifically BCPP and BBOEP, may be associated with higher risk of autism diagnosis and related traits in childhood. https://doi.org/10.1289/EHP16177.
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