At the time of this writing, most pediatricians or child psychiatrists will probably have treated a child with early acute-onset obsessive compulsive disorder (OCD) behaviors due to the pediatric autoimmune neuropsychiatric disorder associated with Group A beta-hemolytic streptococcus, abbreviated PANDAS, described more than two decades ago; or Tourette syndrome, incorporating motor and vocal tics, described more than a century ago. One typically self-limited post-infectious OCD resulting from exposure to other putative microbial disease triggers defines PANS, abbreviating pediatric autoimmune neuropsychiatric syndrome. Tourette syndrome, PANDAS and PANS share overlapping neuroimaging features of hypometabolism of the medial temporal lobe and hippocampus on brain 18Fluorodeoxyglucose positron emission tomography fused to magnetic resonance imaging (PET/MRI) consistent with involvement of common central nervous system (CNS) pathways for the shared clinical expression of OCD. The field of pediatric neuropsychiatric disorders manifesting OCD behaviors is at a crossroads commensurate with recent advances in the neurobiology of the medial temporal area, with its wide-ranging connectivity and cortical cross-talk, and CNS immune responsiveness through resident microglia. This review advances the field of pediatric neuropsychiatric disorders and in particular PANS, by providing insights through clinical vignettes and descriptive clinical and neuroimaging correlations from the author's file. Neuroscience collaborations with child psychiatry and infectious disease practitioners are needed to design clinical trials with the necessary rigor to provide meaningful insights into the rational clinical management of PANS with the aim of developing evidence-based guidelines for the clinical management of early, abrupt-onset childhood OCD to avert potentially life-long neuropsychological struggles.

Understanding the interplay between genetic predisposition and environmental and lifestyle exposures is essential for advancing precision medicine and public health. The exposome, defined as the sum of all environmental exposures an individual encounters throughout their lifetime, complements genomic data by elucidating how external and internal exposure factors influence health outcomes. This treatise highlights the emerging discipline of translational exposomics that integrates exposomics and genomics, offering a comprehensive approach to decipher the complex relationships between environmental and lifestyle exposures, genetic variability, and disease phenotypes. We highlight cutting-edge methodologies, including multi-omics technologies, exposome-wide association studies (EWAS), physiology-based biokinetic modeling, and advanced bioinformatics approaches. These tools enable precise characterization of both the external and the internal exposome, facilitating the identification of biomarkers, exposure-response relationships, and disease prediction and mechanisms. We also consider the importance of addressing socio-economic, demographic, and gender disparities in environmental health research. We emphasize how exposome data can contextualize genomic variation and enhance causal inference, especially in studies of vulnerable populations and complex diseases. By showcasing concrete examples and proposing integrative platforms for translational exposomics, this work underscores the critical need to bridge genomics and exposomics to enable precision prevention, risk stratification, and public health decision-making. This integrative approach offers a new paradigm for understanding health and disease beyond genetics alone.

Single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) contribute to inadequate metabolic profiles in individuals with type 2 diabetes mellitus (T2DM).

We sought to elucidate the relationship among SNPs in the VDR and markers for glycemic control, lipid profile, and inflammation in individuals with T2DM.

We performed a systematic search in the MEDLINE (via PubMed), EMBASE, and SCOPUS databases in July 2021 and updated the search in October 2023.

6 observational studies were selected from the databases, and 1 study was included after checking the reference list. Two authors independently completed the selection and data extraction of studies and population characteristics, the prevalence of SNPs in the VDR, genotyping methods, and laboratory findings, and performed summary statistics of the results.

The meta-analyses were performed on 5 studies including 1198 adults with T2DM. The duration of the diabetes diagnosis ranged from 5.0 to 14.7 years. A random-effects model was used to pool the results using a 2-tailed (P < .05). Effect sizes were reported as standardized mean differences (SMDs) and 95% confidence intervals (CIs). Four SNPs in the VDR were identified (Fokl, BsmI, Taql, and Apal) by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Fokl SNP was identified in 5 studies and associated with a higher percentage of glycated hemoglobin (HbA1c%) (SMD,  0.41 [95% CI, 0.15-0.67]). The Bsml in 4 studies was associated with higher triacylglycerol (SMD, 0.21 [95% CI, 0.03-0.38]). The Taql SNP was identified in 2 studies and did not show any associations, and the Apal SNP was identified in only 1 study and was not analysed in the meta-analysis.

Although the studies identified 4 SNPs in the VDR, the results of the meta-analysis allowed us to infer only the association of the SNPs Fokl and Bsml with increased %HbA1c and triacylglycerol levels, respectively, in individuals with T2DM.

PROSPERO registration number CRD42021268152.

The exposome is the measure of all the exposures of an individual in a lifetime and how those exposures relate to health. Exposomics is the emerging field of research to measure and study the totality of the exposome. Exposomics can assist with molecular medicine by furthering our understanding of how the exposome influences cellular and molecular processes such as gene expression, epigenetic modifications, metabolic pathways, and immune responses. These molecular alterations can aid as biomarkers for the diagnosis, disease prediction, early detection, and treatment and offering new avenues for personalized medicine. Advances in high throughput omics and other technologies as well as increased computational analytics is enabling comprehensive measurement and sophisticated analysis of the exposome to elucidate their cumulative and combined impacts on health, which can enable individuals, communities, and policymakers to create programs, policies, and protections that promote healthier environments and people. This review provides an overview of the potential role of exposomics in molecular medicine, covering its history, methodologies, current research and applications, and future directions.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by both genetic and environmental factors, collectively termed the exposome. Among these determinants, diet emerges as a pivotal component, with diverse nutrients, contaminants, and additives shaping immune responses, microbiota composition, and systemic inflammatory status. This literature review aimed to elucidate the interplay between dietary factors and skin dysbiosis in AD, providing insights into how these interactions may impact disease susceptibility and progression. A comprehensive search of PubMed and Scopus was conducted using relevant keywords and medical subject headings (MeSH). Studies published in English within the past 25 years were included, encompassing in vitro, in vivo, and ex vivo research, as well as reviews. Priority was given to frequently cited articles, reflecting significant contributions to current understanding. Findings suggest that dietary habits influence AD by modulating both gut and skin microbiota, immune pathways, and inflammatory processes. These insights underscore the importance of considering diet within a broader exposome framework, paving the way for targeted interventions to improve AD management. Further research is needed to clarify the mechanisms and optimize nutritional strategies, potentially informing preventive and therapeutic approaches for AD.

The characterization of the human chemical exposome through daily estimated intakes or biomonitoring has become paramount to understand the causal pathways leading to common diseases. The paradigm shift that has taken place in looking at health has moved research from the classical biomedical model based on "one exposure, one disease" to a more comprehensive approach based on multiple chemicals and low dose effects. For this purpose, untargeted and/or suspect analysis of chemicals based on liquid chromatography and high-resolution mass spectrometry (LC-HRMS) has been proposed as the most relevant strategy for sequencing the exposome. A key aspect in this respect is the development of unbiased sample preparation methods that efficiently concentrate the wide range of untargeted/suspected chemicals while minimizing interference from sample matrices. Here, we aim to critically discuss the potential of tailored supramolecular solvents (SUPRAS) for achieving all-in-one extractions in chemical exposomics, as an alternative to overcome the limitations of the current sample treatment strategies, on the basis of their intrinsic properties and the applications reported so far.

The nervous and immune systems have complementary roles in the adaptation of organisms to environmental changes. However, the mechanisms that mediate cross-talk between the nervous and immune systems, called neuroimmune interactions, are poorly understood. In this Review, we summarize advances in the understanding of neuroimmune communication, with a principal focus on the central nervous system (CNS): its response to immune signals and the immunological consequences of CNS activity. We highlight these themes primarily as they relate to neurological diseases, the control of immunity, and the regulation of complex behaviours. We also consider the importance and challenges linked to the study of the neuroimmune connectome, which is defined as the totality of neuroimmune interactions in the body, because this provides a conceptual framework to identify mechanisms of disease pathogenesis and therapeutic approaches. Finally, we discuss how the latest techniques can advance our understanding of the neuroimmune connectome, and highlight the outstanding questions in the field.

The increasing risk of cardiovascular disease (CVD) associated with worsening environmental exposure is a critical health concern garnering global research attention.

To systematically assess the scope and characteristics of research on the relationship between environmental exposure and CVD.

A thorough examination of publications on the relationship between environmental exposure and CVD from 1999 to 2022 was carried out by extensively screening the literature using the Web of Science Core Collection. The language of the selected publications was standardized to English. Afterward, different academic tools such as CiteSpace, VOSviewer, HistCite, Python, Matplotlib, and Bibliometrix were utilized to examine the research trends in this field.

The study's findings indicated a steady increase in scientific publications among the 1640 analyzed documents, peaking in 2022 with 197 publications. The United States emerged as the leading nation regarding high-quality publications and international collaboration. Harvard University was identified as the most prolific institution. "Environmental research" was the most frequently contributing journal, and Muenzel T was recognized as the top contributor. Current research hotspots are primarily concentrated on themes such as "cardiovascular disease", "exposure", "risk", "mortality", and "air pollution".

This study highlights increasing research on the link between environmental exposure and CVD, identifying key exposures and diseases while emphasizing the need for further investigation into underlying mechanisms.

Humans encounter diverse environmental factors which can have impact on their health. One such environmental factor is ultraviolet (UV) radiation, which is part of the physical component of the exposome. UV radiation is the leading cause of skin cancer and is a significant global health concern. A large body of published research has been conducted to uncover the mechanisms underlying the adverse outcomes of UV radiation exposure on living beings. These studies involve identifying the biomolecules induced upon UV radiation exposure. A few previous efforts have attempted to compile this information in the form of a database, but such earlier efforts have certain limitations. To fill this gap, we present a structured database named UVREK (UltraViolet Radiation Expression Knowledgebase), containing manually curated data on biomolecules induced by UV radiation exposure from the published literature. UVREK has compiled information on 985 genes, 470 proteins, 54 metabolites, and 77 miRNAs along with their metadata. Thereafter, an enrichment analysis performed on the human gene set of the UVREK database showed the importance of transcription-related processes in UV-related response and enrichment of pathways involved in cancer and aging. While significantly contributing toward characterizing the physical component of the exposome, we expect that the compiled data in UVREK will serve as a valuable resource for the development of better UV protection mechanisms such as UV sensors and sunscreens. Noteworthily, UVREK is the only resource to date compiling varied types of biomolecular responses to UV radiation with the corresponding metadata. UVREK is openly accessible at https://cb.imsc.res.in/uvrek/.

Childhood obesity poses a significant public health challenge, yet the molecular intricacies underlying its pathobiology remain elusive. Leveraging extensive multi-omics profiling (methylome, miRNome, transcriptome, proteins and metabolites) and a rich phenotypic characterization across two parts of Europe within the population-based Human Early Life Exposome project, we unravel the molecular landscape of childhood obesity and associated metabolic dysfunction. Our integrative analysis uncovers three clusters of children defined by specific multi-omics profiles, one of which characterized not only by higher adiposity but also by a high degree of metabolic complications. This high-risk cluster exhibits a complex interplay across many biological pathways, predominantly underscored by inflammation-related cascades. Further, by incorporating comprehensive information from the environmental risk-scape of the critical pregnancy period, we identify pre-pregnancy body mass index and environmental pollutants like perfluorooctanoate and mercury as important determinants of the high-risk cluster. Overall, our work helps to identify potential risk factors for prevention and intervention strategies early in the life course aimed at mitigating obesity and its long-term health consequences.

Daily-use products, including personal care products, household products, and dietary supplements, often contain ingredients that raise concerns regarding harmful chemical exposure. Endocrine-disrupting chemicals (EDCs) found in daily-use products are associated with numerous adverse health effects.

This pilot study explores the relationship between concentrations of EDCs in urine samples and products used 24 h prior to sample collection, and ingredients of concern in those products, in 140 adults of reproductive age in Northern Nevada.

Having higher numbers of products and ingredients of concern, especially in the personal care category, was associated with higher levels of mono-(-ethyl-5-carboxypentyl) phthalate (MECPP). Similarly, taking more supplements was associated with higher levels of methylparaben (MePB). In contrast, using household products with more ingredients of concern was associated with lower levels of monobutyl phthalate (MBP). Generally, women used more products, were exposed to more ingredients of concern and had higher urinary metabolites than men. Participants who rated themselves as being in poor/fair health were exposed to more personal care and supplement ingredients of concern than those in better health. Interestingly, those in excellent health also took supplements with more ingredients of concern.

Greater product use and more ingredients of concern are associated with urinary metabolites of known EDCs and self-ratings of poor health. Women and people who take supplements are at greater risk, and even people who consider themselves to be healthy can be highly exposed. More education among the general public is needed to make people aware of the presence of these chemicals in their everyday products so they can make efforts to avoid them.

A critical unanswered question is what is causing the increase in the prevalence of autoimmunity and autoimmune diseases around the world. Given the rapidity of change, this is likely the result of major recent alterations in our exposures to environmental risk factors for these diseases. More evidence is becoming available that the evolution of autoimmune disease, years or even decades in the making, results from multiple exposures that alter susceptible genomes and immune systems over time. Exposures during sensitive phases in key developmental or hormonal periods may set the stage for the effects of later exposures. It is likely that synergistic and additive impacts of exposure mixtures result in chronic low-level inflammation. This inflammation may eventually pass thresholds that lead to immune system activation and autoimmunity, and with further molecular and pathologic changes, the complete clinical syndrome emerges. Much work remains to be done to define the mechanisms and risk and protective factors for autoimmune conditions. However, evidence points to a variety of pollutants, xenobiotics, infections, occupational exposures, medications, smoking, psychosocial stressors, changes in diet, obesity, exercise, and sleep patterns, as well as climate change impacts of increased heat, storms, floods, wildfires, droughts, UV radiation, malnutrition, and changing infections, as possible contributors. Substantial investments in defining the role of causal factors, in whom and when their effects are most important, the necessary and sufficient gene-environment interactions, improved diagnostics and therapies, and preventive strategies are needed now to limit the many negative personal, societal, and financial impacts that will otherwise occur.

Limited data document the spectrum of exposures in the agricultural environment. We describe here the wide range of chemical and physical agents, and organizational factors, encountered in agricultural jobs held in the past in Canada and abroad.

We used data from a population-based case-control study of prostate cancer including 3,925 male participants residing in Montreal, Canada in 2005-2012. Lifetime occupational histories and detailed job descriptions were collected in-person. Industrial hygienists and an agronomist conducted semi-quantitative evaluations of exposure, including intensity and reliability, to some 300 chemical and physical agents in each job held. Analyses focused on the 156 agricultural jobs ever held in the study population. Clusters of agricultural co-exposures were derived.

Agricultural jobs had taken place in 1946-2012, 53% ending in 1970 or after. Jobs were often (43%) held in Quebec, Canada; 22% in Italy, Portugal or Greece, and 10% in Haiti. Jobs entailed exposure to an average of 10 chemical agents (±7) and most were characterized by long working hours, high physical activity levels, and did not provoke stress or anxiety. Few involved early morning shifts. Exposure to 78 agents was assigned with probable or definite certainty. The most common definite or probable carcinogens were ultraviolet radiation (92% of jobs), environmental tobacco smoke (39%), diesel engine exhaust (23%), wood dust (20%), lubricating oils and greases (20%) and lead (15%). Pesticide exposure (as a group) occurred in 31% of jobs. Fifty-four percent of jobs entailed exposure to ≥2 recognized carcinogens. Exposure clusters varied according to countries and type of agricultural activities (general, animal, crops, horticulture, vineyards, etc.).

Findings highlight the heterogeneity of exposure patterns in past agricultural environments based on their setting and activities involved. Studies on health-related effects of farming should account for numerous potential exposures, beyond their typical focus on pesticides.

Type 1 diabetes (T1D) is a devastating autoimmune disease for which advanced mass spectrometry (MS) methods are increasingly used to identify new biomarkers and better understand underlying mechanisms. For example, integration of MS analysis and machine learning has identified multimolecular biomarker panels. In mechanistic studies, MS has contributed to the discovery of neoepitopes, and pathways involved in disease development and identifying therapeutic targets. However, challenges remain in understanding the role of tissue microenvironments, spatial heterogeneity, and environmental factors in disease pathogenesis. Recent advancements in MS, such as ultra-fast ion-mobility separations, and single-cell and spatial omics, can play a central role in addressing these challenges. Here, we review recent advancements in MS-based molecular measurements and their role in understanding T1D.

Exposures to endocrine disrupting chemicals (EDCs) have been linked to chronic diseases including breast cancer, metabolic syndrome, diabetes, and infertility. Exposure during pregnancy may have a lifelong impact on the fetus. Services are needed to allow individuals to learn about their personal EDC exposures and how to reduce them. Million Marker (MM) aims to crowdsource and scale the biomonitoring of environmental chemicals and provide actionable results to empower individuals to proactively assess, track, and reduce their EDC exposures. In previous research, we developed and tested the first mobile EDC intervention service (mail-in urine testing and exposure report-back) for its efficacy in increasing EH literacy (EHL), willingness to reduce exposures (i.e., readiness to change, RtC), and system usability. After intervention, we found increased EHL, increased RtC in women (but not men), and decreased EDC exposure. However, some participants did not increase their RtC and had difficulty carrying out the intervention on their own. The reasons for these less optimal results were the difficulty in the EHL subject matter-participants still felt ill-prepared to apply their knowledge to making healthier lifestyle changes. Therefore, in this study, we will address these perceived limitations.

We will test a self-directed online interactive curriculum with live counseling sessions and individualized support modeled after the highly effective Diabetes Prevention Program (DPP). Recruiting from the Healthy Nevada Project (HNP), one of the largest population health cohorts in the world, we test the effectiveness of our EDC-specific online intervention curriculum via EHL and RtC surveys and determine changes in EDC exposure before and after intervention in a randomized controlled trial. We will also test for common clinical biomarkers via a commercially available at-home test (Siphox). We will recruit and randomize 300 women and 300 men of reproductive age (total n=600) from HNP. Our target population is men and women of reproductive age (18-44 years old).

At the conclusion of this project, we will be well-positioned to scale our services to clinics and the general public, with the eventual aims of FDA approval, insurance coverage, and incorporation into routine clinical care.

Comprehensive environmental risk characterization, encompassing physical, chemical, social, ecological, and lifestyle stressors, necessitates innovative approaches to handle the escalating complexity. This is especially true when considering individual and population-level diversity, where the myriad combinations of real-world exposures magnify the combinatoric challenges. The GeoTox framework offers a tractable solution by integrating geospatial exposure data from source-to-outcome in a series of modular, interconnected steps.

Here, we introduce the GeoTox open-source R software package for characterizing the risk of perturbing molecular targets involved in adverse human health outcomes based on exposure to spatially-referenced stressor mixtures. We demonstrate its usage in building computational workflows that incorporate individual and population-level diversity. Our results demonstrate the applicability of GeoTox for individual and population-level risk assessment, highlighting its capacity to capture the complex interplay of environmental stressors on human health.

The GeoTox package represents a significant advancement in environmental risk characterization, providing modular software to facilitate the application and further development of the GeoTox framework for quantifying the relationship between environmental exposures and health outcomes. By integrating geospatial methods with cutting-edge exposure and toxicological frameworks, GeoTox offers a robust tool for assessing individual and population-level risks from environmental stressors. GeoTox is freely available at https://niehs.github.io/GeoTox/.

Exposure science plays an essential role in the U.S. Environmental Protection Agency's (U.S. EPA) mission to protect human health and the environment. The U.S. EPA's Center for Public Health and Environmental Assessment (CPHEA) within the Office of Research and Development (ORD) provides the exposure science needed to characterize the multifaceted relationships between people and their surroundings in support of national, regional, local and individual-level actions. Furthermore, exposure science research must position its enterprise to tackle the most pressing public health challenges in an ever-changing environment. These challenges include understanding and confronting complex human disease etiologies, disparities in the social environment, and system-level changes in the physical environment. Solutions will sustainably balance and optimize the health of people, animals, and ecosystems. Our objectives for this paper are to review the role of CPHEA exposure science research in various recent decision-making contexts, to present current challenges facing U.S. EPA and the larger exposure science field, and to provide illustrative case examples where CPHEA exposure science is demonstrating the latest methodologies at the intersection of these two motivations. This blueprint provides a foundation for applying exposomic tools and approaches to holistically understand real-world exposures so optimal environmental public health protective actions can be realized within the broader context of a One Health framework. IMPACT STATEMENT: The U.S. EPA's Center for Public Health and Environmental Assessment exposure research priorities reside at the intersection of environmental decision contexts and broad public health challenges. The blueprint provides a foundation for advancing the tools and approaches to holistically understand real-world exposures so optimal environmental protection actions can be realized. A One Health lens can help shape exposure research for maximum impact to support solutions that are transdisciplinary and must engage multiple sectors.

The presence of two new disinfectant by-product (DBP) groups in the UK was recently shown using non-target analysis, halogenated-hydroxycyclopentenediones and halogenated-methanesulfonic acids. In this work, we confirmed the structure of 2,2,4-tribromo-5-hydroxycyclopent-4-ene-1,3-dione (TBHCD), and quantified it together with dibromomethanesulfonic acid at 122 ± 34 and 326 ± 157 ng L-1 on average in London's drinking water, respectively (n = 21). We found TBHCD to be photolabile and unstable in tap water and at alkaline pH. Furthermore, spectral and computational data for TBHCD and three other halogenated-hydroxycyclopentenediones indicated they could act as a source of radicals in water and in the body. Importantly, TBHCD was calculated to have a 14.5 kcal mol-1 lower C-Br bond dissociation enthalpy than the N-Br bond of N-bromosuccinimide, a common radical substitution reagent used in organic synthesis. TBHCD was mutagenic in Salmonella/microsome assays using strains TA98, TA100 and TA102. This work reveals the unique features, activity and toxicity of trihalogenated hydroxycyclopent-4-ene-1,3-diones, prompting a need to more comprehensively assess their risks.

Background: The exposome (e.g., totality of environmental exposures) and its role in Alzheimer's Disease and Alzheimer's Disease and Related Dementias (AD/ADRD) are increasingly critical areas of study. However, little is known about how interventions on the exposome, including personal behavioral modification or policy-level interventions, may impact AD/ADRD disease burden at the population level in real-world settings and the cost-effectiveness of interventions. Methods: We performed a critical review to discuss the challenges in modeling exposome interventions on population-level AD/ADRD burden and the potential of using agent-based modeling (ABM) and other advanced data science methods for causal inference to achieve this. Results: We describe how ABM can be used for empirical causal inference modeling and provide a virtual laboratory for simulating the impacts of personal and policy-level interventions. These hypothetical experiments can provide insight into the optimal timing, targeting, and duration of interventions, identifying optimal combinations of interventions, and can be augmented with economic analyses to evaluate the cost-effectiveness of interventions. We also discuss other data science methods, including structural equation modeling and Mendelian randomization. Lastly, we discuss challenges in modeling the complex exposome, including high dimensional and sparse data, the need to account for dynamic changes over time and over the life course, and the role of exposome burden scores developed using item response theory models and artificial intelligence to address these challenges. Conclusions: This critical review highlights opportunities and challenges in modeling exposome interventions on population-level AD/ADRD disease burden while considering the cost-effectiveness of different interventions, which can be used to aid data-driven policy decisions.

This study introduces HairDB, an online database serving as a comprehensive repository of hair-related chemicals for exposome research. HairDB was created via an integrative approach. It first extracted 4,184 unique hair-related chemicals through text mining of over 34 million PubMed abstracts and 5.2 million PubMed Central articles, followed by manual data checking. HairDB also applied an artificial intelligence-enabled search to discover organic aerosol biomarkers in literature. A set of 768 chemicals used in hair-related products was then curated through a combination of manual searches and data extraction from the Cosmetic Ingredient Database (CosIng) of the European Union. From manually reading review papers, 29 organic aerosol biomarkers were extracted. Furthermore, 3,679 known exposure chemicals extracted from the Toxin and Toxin Target Database (T3DB) were incorporated in HairDB to represent the possible environmental exposures detected on hair surfaces. The comprehensive set of chemicals captured in HairDB represents the current knowledge of what can be found in and on hair. HairDB was constructed as a user-friendly web interface, allowing easy exploration of hair-related chemicals and tailored for annotating mass spectrometry-based hair exposomics data. The development of HairDB marks an important step forward in using hair as a biological matrix for chemical exposure measurement, facilitating the adoption of hair for exposome research. HairDB is publicly available at https://www.hairdb.ca/.

Ubiquitously distributed environmental electrophiles covalently modify DNA and proteins, potentially leading to adverse health effects. However, the impacts of specific electrophiles on target proteins and their physiological roles remain largely unknown. In the present study, we focused on DNA methylation, which regulates gene expression and physiological responses. A total of 45 environmental electrophiles were screened for inhibitory effects on the activity of DNA methyltransferase 3B (DNMT3B), a key enzyme in DNA methylation, and four compounds were identified. We focused on 1,2-naphthoquinone (1,2-NQ), an air pollutant whose toxicity has been reported previously. Interestingly, we found that 1,2-NQ modified multiple lysine and histidine residues in DNMT3B, one of which was near the active site in DNMT3B. It was found that 1,2-NQ altered gene expression and evoked inflammatory responses in lung adenocarcinoma cell lines. Furthermore, we found that 1,2-NQ upregulated CXCL8 expression through DNA demethylation of the distal enhancer and promoted cancer cell growth. Our study reveals novel mechanisms of epigenetic regulation by environmental electrophiles through the inhibition of DNMT3B activity and suggests their physiological impact.

For comprehensive chemical exposomics in blood, analytical workflows are evolving through advances in sample preparation and instrumental methods. We hypothesized that gas chromatography-high-resolution mass spectrometry (GC-HRMS) workflows could be enhanced by minimizing lipid coextractives, thereby enabling larger injection volumes and lower matrix interference for improved target sensitivity and nontarget molecular discovery. A simple protocol was developed for small plasma volumes (100-200 μL) by using isohexane (H) to extract supernatants of acetonitrile-plasma (A-P). The HA-P method was quantitative for a wide range of hydrophobic multiclass target analytes (i.e., log Kow > 3.0), and the extracts were free of major lipids, thereby enabling robust large-volume injections (LVIs; 25 μL) in long sequences (60-70 h, 70-80 injections) to a GC-Orbitrap HRMS. Without lipid removal, LVI was counterproductive because method sensitivity suffered from the abundant matrix signal, resulting in low ion injection times to the Orbitrap. The median method quantification limit was 0.09 ng/mL (range 0.005-4.83 ng/mL), and good accuracy was shown for a certified reference serum. Applying the method to plasma from a Swedish cohort (n = 32; 100 μL), 51 of 103 target analytes were detected. Simultaneous nontarget analysis resulted in 112 structural annotations (12.8% annotation rate), and Level 1 identification was achieved for 7 of 8 substances in follow-up confirmations. The HA-P method is potentially scalable for application in cohort studies and is also compatible with many liquid-chromatography-based exposomics workflows.

Exposure to environmental pollutants or contaminants is correlated with detrimental effects on human health, such as neurodegenerative diseases. Adopting hair as a biological matrix for biomonitoring is a significant innovation, since it can reflect the long-term chemical exposome, spanning months to years. However, only a limited number of studies have developed analytical strategies for profiling the chemical exposome in this heterogeneous biological matrix. In this study, a systematic investigation of the chemical extraction procedure from human hair was conducted, using a design of experiments and a high-resolution mass spectrometry (HRMS)-based suspect screening approach. The PlackettBurman (PB) design was applied to identify the significant variables influencing the number of detected features. Then, a central composite design was implemented to optimize the levels of each identified significant variable. Under the optimal conditions-15-minute pulverization, 25 mg of hair weight, 40 min of sonication, and a sonication temperature of 35 °C-approximately 32,000 and 15,000 aligned features were detected in positive and negative ion modes, respectively. This optimized analytical procedure was applied to hair samples from patients with Alzheimer's disease (AD) and individuals with normal cognitive function. Overall, 307 chemicals were identified using the suspect screening approach, with 37 chemicals differentiating patients with AD from controls. This study not only optimized an analytical procedure for characterizing the long-term chemical exposome in human hair but also explored the associations between AD and environmental factors.

Wristband personal samplers enable human exposure assessments for a diverse range of chemical contaminants and exposure settings with a previously unattainable scale and cost-effectiveness. Paired with nontargeted analyses, wristbands can provide important exposure monitoring data to expand our understanding of the environmental exposome. Here, a custom scripted suspect screening workflow was developed in the R programming language for feature selection and chemical annotations using gas chromatography-high-resolution mass spectrometry data acquired from the analysis of wristband samples collected from five different cohorts. The workflow includes blank subtraction, internal standard normalization, prediction of chemical uses in products, and feature annotation using multiple library search metrics and metadata from PubChem, among other functionalities. The workflow was developed and validated against 104 analytes identified by targeted analytical results in previously published reports of wristbands. A true positive rate of 62 and 48% in a quality control matrix and wristband samples, respectively, was observed for our optimum set of parameters. Feature analysis identified 458 features that were significantly higher on female-worn wristbands and only 21 features that were significantly higher on male-worn wristbands across all cohorts. Tentative identifications suggest that personal care products are a primary driver of the differences observed.

Exposomics, the study of the exposome, is flourishing, but the field is not well defined. The term "exposome" refers to all environmental influences and associated biological responses throughout the lifespan. However, this definition is very similar to that of the term "environment"-the external elements and conditions that surround and affect the life and development of an organism. Consequently, the exposome seems to be nothing more than a synonym for the environment, and exposomics a synonym for environmental research. As a result, some have rebranded their "standard" environmental health research with the neologistic exposome term, whereas others ignore or seek to abandon the seemingly redundant concept of the exposome.

We argue that exposomics needs to sharpen its mission focus to counteract this apparent redundancy. Exposomics should be defined as a research program in environmental health aimed at enabling a comprehensive and discovery-driven approach to identifying environmental determinants of human health. Similar to the aim of the Human Genome Project, exposomics aims to analyze the complete complexity of exposures and their corresponding biological responses. Exposomics' primary premise is that the existence of undiscovered, potentially interconnected, nongenetic (environmental) risk factors for health necessitates a comprehensive discovery-driven analysis approach.

We argue that exposomics researchers should adopt our reconceptualization of exposomics and focus on the productiveness and integrity of their research program: its purpose and principles. We suggest that exposomics researchers should coordinate the writing of reviews that assess the program's productiveness and integrity, as well as provide a platform for exposomics researchers to define their vision for the field. https://doi.org/10.1289/EHP14509.

We present a case of acne successfully treated with a topical spray containing live bacteria. The live bacteria used in the spray contain CRISPR, and adaptive immune system in the bacteria that are used to disable viral replication. Because acne skin contains bacteria in the microbiome where a shift toward non-CRISPR bacteria occurs, these bacteria are susceptible to bacteriophage infection and lysogeny. Normalizing the bacterial microbiome to one containing more CRISPR-containing bacteria renormalizes the microbiome by killing inflammation-causing bacteriophage infecting the non-CRISPR bacteria associated with acne.

Exposures to hazardous chemicals have been linked to many detrimental health effects and it is therefore critical to have effective biomonitoring methods to better evaluate key environmental exposures that increase the risk of chronic disease and death. Traditional biomonitoring utilizing blood and urine is limited due to the specialized skills and invasiveness of collecting these fluid samples. This systematic review focuses on tear fluid, which is largely under-researched, as a promising complementary matrix to the traditional fluids used for biomonitoring. The objective is to evaluate the practicability of using human tear fluid for biomonitoring environmental exposures, highlighting potential pitfalls and opportunities.

Tear fluid biomonitoring represents a promising method for assessing exposures because it can be collected with minimal invasiveness and tears contain exposure markers from both the external and internal environments. Tear fluid uniquely interfaces with the external environment at the air-tear interface, providing a surface for airborne chemicals to diffuse into the ocular environment and interact with biomolecules. Tear fluid also contains molecules from the internal environment that have travelled from the blood to tears by crossing the blood-tear barrier. This review demonstrates that tear fluid can be used to identify hazardous chemicals from the external environment and differentiate exposure groups.

Current research on the epigenetic repercussions of exposure to a combination of pollutants is limited. This study aims to discern DNA methylation probes associated with exposure to multiple pollutants, serving as early effect markers, and single-nucleotide polymorphisms (SNPs) as surrogate indicators for population susceptibility. The investigation involved the analysis of urine exposure biomarkers for 11 heavy metals (vanadium, arsenic, mercury, cadmium, chromium, nickel, lead, manganese, copper, strontium, thallium), polycyclic aromatic hydrocarbon (PAHs) (1-hydroxypyrene), genome-wide DNA methylation sequencing, and SNPs array on all study participants. The data were integrated with metabolomics information and analyzed both at a community level based on proximity to home addresses relative to the complex and at an individual level based on exposure biomarker concentrations.

On a community level, 67 exposure-related CpG probes were identified, while 70 CpG probes were associated with urine arsenic concentration, 2 with mercury, and 46 with vanadium on an individual level. These probes were annotated to genes implicated in cancers and chronic kidney disease. Weighted quantile sum regression analysis revealed that vanadium, mercury, and 1-hydroxypyrene contributed the most to cg08238319 hypomethylation. cg08238319 is annotated to the aryl hydrocarbon receptor repressor (AHRR) gene, and AHRR hypomethylation was correlated with an elevated risk of lung cancer. AHRR was further linked to deregulations in phenylalanine metabolism, alanine, aspartate, and glutamate metabolism, along with heightened oxidative stress. Additionally, three SNPs (rs11085020, rs199442, and rs10947050) corresponding to exposure-related CpG probes exhibited significant interaction effects with multiple heavy metals and PAHs exposure, and have been implicated in cancer progression and respiratory diseases.

Our findings underscore the pivotal role of AHRR methylation in gene-environment interactions and highlight SNPs that could potentially serve as indicators of population susceptibility in regions exposed to multiple heavy metals and PAHs.

Numbers of aggressive prostate cancer (aPC) cases are rising, but only a few risk factors have been identified. In this study, we introduce a systematic approach to integrate geospatial data into external exposome research using aPC cases from Pennsylvania. We demonstrate the association between several area-level exposome measures across five Social Determinants of Health domains (SDOH) and geographic areas identified as having elevated odds of aPC. Residential locations of Pennsylvania men diagnosed with aPC from 2005 to 2017 were linked to 37 county-/tract-level SDOH exosome measures. Variable reduction processes adopted from neighborhood-wide association study along with Bayesian geoadditive logistic regression were used to identify areas with elevated odds of aPC and exposome factors that significantly attenuated the odds and reduced the size of identified areas. Areas with significantly higher odds of aPC were explained by various SDOH exposome measures, though the extent of the reduction depended on geographic location. Some areas were associated with race (social context), health insurance (access), or tract-level poverty (economics), while others were associated with either county-level water quality or a combination of factors. Area-level exposome measures can guide future patient-level external exposome research and help design targeted interventions to reduce local cancer burden.

Interventions are needed to help people reduce exposure to harmful chemicals from everyday products and lifestyle habits. Report-back of individual exposures is a potential pathway to increasing environmental health literacy (EHL) and readiness to reduce exposures.

Our objective was to determine if report-back of endocrine-disrupting chemicals (EDCs) can reduce EDC exposure, increase EHL, and increase readiness to change (i.e., to implement EDC exposure-reduction behaviors).

Participants in the Healthy Nevada Project completed EHL and readiness-to-change surveys before (n = 424) and after (n = 174) a report-back intervention. Participants used mail-in kits to measure urinary biomarkers of EDCs. The report-back of results included urinary levels, information about health effects, sources of exposure, and personalized recommendations to reduce exposure.

EHL was generally very high at baseline, especially for questions related to the general pollution. For questions related to chemical exposures, responses varied across several demographics. Statistically reliable improvements in EHL responses were seen after report-back. For readiness to change, 72% were already or planning to change their behaviors. Post-intervention, women increased their readiness (p = 0.053), while men decreased (p = 0.007). When asked what challenges they faced in reducing exposure, 79% cited not knowing what to do. This dropped to 35% after report-back. Participants with higher propylparaben were younger (p = 0.03) and women and participants who rated themselves in better health had higher levels of some phthalates (p = 0.02-0.003 and p = 0.001-0.003, respectively). After report-back, monobutyl phthalate decreased among the 48 participants who had valid urine tests before and after the intervention (p < 0.001).

The report-back intervention was successful as evidenced by increased EHL behaviors, increased readiness to change among women, and a decrease in monobutyl phthalate. An EHL questionnaire more sensitive to chemical exposures would help differentiate high and low literacy. Future research will focus on understanding why men decreased their readiness to change and how the intervention can be improved for all participants.

Understanding the complex interplay of genetic and environmental factors in disease etiology and the role of gene-environment interactions (GEIs) across human development stages is important. We review the state of GEI research, including challenges in measuring environmental factors and advantages of GEI analysis in understanding disease mechanisms. We discuss the evolution of GEI studies from candidate gene-environment studies to genome-wide interaction studies (GWISs) and the role of multi-omics in mediating GEI effects. We review advancements in GEI analysis methods and the importance of large-scale datasets. We also address the translation of GEI findings into precision environmental health (PEH), showcasing real-world applications in healthcare and disease prevention. Additionally, we highlight societal considerations in GEI research, including environmental justice, the return of results to participants, and data privacy. Overall, we underscore the significance of GEI for disease prediction and prevention and advocate for integrating the exposome into PEH omics studies.

Pollutants in human milk are critical for evaluating maternal internal exposure and infant external exposure. However, most studies have focused on a limited range of pollutants. Here, 15 pooled samples (prepared from 467 individual samples) of human milk from three areas of the Yangtze River Delta (YRD) in China were analyzed by gas chromatography quadrupole time-of-flight mass spectrometry. In total, 171 compounds of nine types were preliminarily identified. Among these, 16 compounds, including 2,5-di-tert-butylhydroquinone and 2-tert-butyl-1,4-benzoquinone, were detected in human milk for the first time. Partial least-squares discriminant analysis identified ten area-specific pollutants, including 2-naphthylamine, 9-fluorenone, 2-isopropylthianthrone, and benzo[a]pyrene, among pooled human milk samples from Shanghai (n = 3), Jiangsu Province (n = 6), and Zhejiang Province (n = 6). Risk index (RI) values were calculated and indicated that legacy polycyclic aromatic hydrocarbons (PAHs) contributed only 20% of the total RIs for the identified PAHs and derivatives, indicating that more attention should be paid to PAHs with various functional groups. Nine priority pollutants in human milk from the YRD were identified. The most important were 4-tert-amylphenol, caffeine, and 2,6-di-tert-butyl-p-benzoquinone, which are associated with apoptosis, oxidative stress, and other health hazards. The results improve our ability to assess the health risks posed by pollutants in human milk.

The National Institute of Environmental Health Sciences (NIEHS) continues to prioritize research to better understand the health effects resulting from exposure to mixtures of chemical and nonchemical stressors. Mixtures research activities over the last decade were informed by expert input during the development and deliberations of the 2011 NIEHS Workshop "Advancing Research on Mixtures: New Perspectives and Approaches for Predicting Adverse Human Health Effects." NIEHS mixtures research efforts since then have focused on key themes including a) prioritizing mixtures for study, b) translating mixtures data from in vitro and in vivo studies, c) developing cross-disciplinary collaborations, d) informing component-based and whole-mixture assessment approaches, e) developing sufficient similarity methods to compare across complex mixtures, f) using systems-based approaches to evaluate mixtures, and g) focusing on management and integration of mixtures-related data.

We aimed to describe NIEHS driven research on mixtures and combined exposures over the last decade and present areas for future attention.

Intramural and extramural mixtures research projects have incorporated a diverse array of chemicals (e.g., polycyclic aromatic hydrocarbons, botanicals, personal care products, wildfire emissions) and nonchemical stressors (e.g., socioeconomic factors, social adversity) and have focused on many diseases (e.g., breast cancer, atherosclerosis, immune disruption). We have made significant progress in certain areas, such as developing statistical methods for evaluating multiple chemical associations in epidemiology and building translational mixtures projects that include both in vitro and in vivo models.

Moving forward, additional work is needed to improve mixtures data integration, elucidate interactions between chemical and nonchemical stressors, and resolve the geospatial and temporal nature of mixture exposures. Continued mixtures research will be critical to informing cumulative impact assessments and addressing complex challenges, such as environmental justice and climate change. https://doi.org/10.1289/EHP14340.

Exposome studies are advancing in high-income countries to understand how multiple environmental exposures impact health. However, there is a significant research gap in low- and middle-income and tropical countries. We aimed to describe the spatiotemporal variation of the external exposome, its correlation structure between and within exposure groups, and its dimensionality. A one-year follow-up cohort study of 506 children under 5 in two cities in Colombia was conducted to evaluate asthma, acute respiratory infections, and DNA damage. We examined 48 environmental exposures during pregnancy and 168 during childhood in eight exposure groups, including atmospheric pollutants, natural spaces, meteorology, built environment, traffic, indoor exposure, and socioeconomic capital. The exposome was estimated using geographic information systems, remote sensing, spatiotemporal modeling, and questionnaires. The median age of children at study entry was 3.7 years (interquartile range: 2.9-4.3). Air pollution and natural spaces exposure decreased from pregnancy to childhood, while socioeconomic capital increased. The highest median correlations within exposure groups were observed in meteorology (r = 0.85), traffic (r = 0.83), and atmospheric pollutants (r = 0.64). Important correlations between variables from different exposure groups were found, such as atmospheric pollutants and meteorology (r = 0.76), natural spaces (r = -0.34), and the built environment (r = 0.53). Twenty principal components explained 70%, and 57 explained 95% of the total variance in the childhood exposome. Our findings show that there is an important spatiotemporal variation in the exposome of children under 5. This is the first characterization of the external exposome in urban areas of Latin America and highlights its complexity, but also the need to better characterize and understand the exposome in order to optimize its analysis and applications in local interventions aimed at improving the health conditions and well-being of the child population and contributing to environmental health decision-making.

The biological mechanisms linking environmental exposures with cardiovascular disease pathobiology are incompletely understood. We sought to identify circulating proteomic signatures of environmental exposures and examine their associations with cardiometabolic and respiratory disease in observational cohort studies.

We tested the relations of >6500 circulating proteins with 29 environmental exposures across the built environment, green space, air pollution, temperature, and social vulnerability indicators in ≈3000 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults) across 4 centers using penalized and ordinary linear regression. In >3500 participants from FHS (Framingham Heart Study) and JHS (Jackson Heart Study), we evaluated the prospective relations of proteomic signatures of the envirome with cardiovascular disease and mortality using Cox models.

Proteomic signatures of the envirome identified novel/established cardiovascular disease-relevant pathways including DNA damage, fibrosis, inflammation, and mitochondrial function. The proteomic signatures of the envirome were broadly related to cardiometabolic disease and respiratory phenotypes (eg, body mass index, lipids, and left ventricular mass) in CARDIA, with replication in FHS/JHS. A proteomic signature of social vulnerability was associated with a composite of cardiovascular disease/mortality (1428 events; FHS: hazard ratio, 1.16 [95% CI, 1.08-1.24]; P=1.77×10-5; JHS: hazard ratio, 1.25 [95% CI, 1.14-1.38]; P=6.38×10-6; hazard ratio expressed as per 1 SD increase in proteomic signature), robust to adjustment for known clinical risk factors.

Environmental exposures are related to an inflammatory-metabolic proteome, which identifies individuals with cardiometabolic disease and respiratory phenotypes and outcomes. Future work examining the dynamic impact of the environment on human cardiometabolic health is warranted.

The quantification of arsenic, mercury, cadmium and lead in the human bloodstream is routinely used today to assess exposure to these toxic metal(loid)s, but the interpretation of the obtained data in terms of their cumulative health relevance remains problematic. Seemingly unrelated to this, epidemiological studies strongly suggest that the simultaneous chronic exposure to these environmental pollutants is associated with the etiology of autism, type 2 diabetes, irritable bowel disease and other diseases. This from a public health point of view undesirable situation urgently requires research initiatives to establish functional connections between human exposure to multiple toxic metal(loid) species and adverse health effects. One way to establish causal exposure-response relationships is a molecular toxicology approach, which requires one to unravel the biomolecular mechanisms that unfold after individual toxic metal(loid)s enter the bloodstream/organ nexus as these interactions ultimately determine which metabolites impinge on target organs and thus provide mechanistic links to diseases of unknown etiology. In an attempt to underscore the importance of the toxicological chemistry of metal(loid)s in the bloodstream, this review summarizes recent progress into relevant bioinorganic processes that are implicated in the etiology of adverse organ-based health effects and possibly diseases. A better understanding of these bioinorganic processes will not only help to improve the regulatory framework to better protect humans from the adverse effects of toxic metal(loid) species, but also represents an important starting point for the development of treatments to ameliorate pollution-induced adverse health effects on human populations, including pregnant women, the fetus and children.

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action-eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen-immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients.

Contaminants may induce immune response polarization, leading to immune diseases, such as allergic diseases. Evidence concerning the effects of chlorinated paraffins (CPs), an emerging persistent organic pollutant, on immune system is scarce, particularly for epidemiological evidence. This study explores the association between CPs exposure and allergic diseases (allergic rhinitis, atopic eczema, and allergic conjunctivitis) in children and adolescents in the Pearl River Delta (PRD) in China. Herein, 131,304 children and adolescents from primary and secondary schools in the PRD were included and completed the questionnaire survey. The particulate matter (PM) samples were collected in the PRD and the PM2.5-bound CP concentrations were analyzed. In the multivarious adjustment mixed effect model (MEM), an IQR increase in ∑CPs was significantly associated with allergic diseases (rhinitis, eczema, and conjunctivitis) with the estimated odds ratios (ORs) for 1.11 (95% CI: 1.10, 1.13), 1.17 (95% CI: 1.15, 1.19), and 1.82 (95% CI: 1.76, 1.88), respectively. Interaction analysis indicated that overweight and obese individuals might have greater risk. Similar effect estimates were observed in several sensitivity analyses. This study provided epidemiological evidence on the immunotoxicity of CPs. More studies to confirm our findings and investigate mechanisms are needed.