Hallmarks of environmental insults.

Environmental insults impair human health around the world. Contaminated air, water, soil, food, and occupational and household settings expose humans of all ages to a plethora of chemicals and environmental stressors. We propose eight hallmarks of environmental insults that jointly underpin the damaging impact of environmental exposures during the lifespan. Specifically, they include oxidative stress and inflammation, genomic alterations and mutations, epigenetic alterations, mitochondrial dysfunction, endocrine disruption, altered intercellular communication, altered microbiome communities, and impaired nervous system function. They provide a framework to understand why complex mixtures of environmental exposures induce severe health effects even at relatively modest concentrations.

Molecular mechanisms of environmental exposures and human disease.

A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome - the cumulative measure of environmental influences over the lifespan - and its integration into future environmental health research.

Outdoor air pollution and cancer: An overview of the current evidence and public health recommendations.

Outdoor air pollution is a major contributor to the burden of disease worldwide. Most of the global population resides in places where air pollution levels, because of emissions from industry, power generation, transportation, and domestic burning, considerably exceed the World Health Organization's health-based air-quality guidelines. Outdoor air pollution poses an urgent worldwide public health challenge because it is ubiquitous and has numerous serious adverse human health effects, including cancer. Currently, there is substantial evidence from studies of humans and experimental animals as well as mechanistic evidence to support a causal link between outdoor (ambient) air pollution, and especially particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. It is estimated that hundreds of thousands of lung cancer deaths annually worldwide are attributable to PM air pollution. Epidemiological evidence on outdoor air pollution and the risk of other types of cancer, such as bladder cancer or breast cancer, is more limited. Outdoor air pollution may also be associated with poorer cancer survival, although further research is needed. This report presents an overview of outdoor air pollutants, sources, and global levels, as well as a description of epidemiological evidence linking outdoor air pollution with cancer incidence and mortality. Biological mechanisms of air pollution-derived carcinogenesis are also described. This report concludes by summarizing public health/policy recommendations, including multilevel interventions aimed at individual, community, and regional scales. Specific roles for medical and health care communities with regard to prevention and advocacy and recommendations for further research are also described.

Epigenome-wide meta-analysis of BMI in nine cohorts: Examining the utility of epigenetically predicted BMI.

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E-7) and 1,238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European and African descent, as defined by self-reported race/ethnicity. We found that five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log-normalized BMI in the WHI (80% training/20% testing). This model found that 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides and lower HDL cholesterol and LDL cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL cholesterol and lower glucose and triglycerides. This study confirmed 553 and identified 685 CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health, suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.

Epigenetics of Early Cardiometabolic Disease: Mechanisms and Precision Medicine.

Epigenetics has transformed our understanding of the molecular basis of complex diseases, including cardiovascular and metabolic disorders. This review offers a comprehensive overview of the current state of knowledge on epigenetic processes implicated in cardiovascular and metabolic diseases, highlighting the potential of DNA methylation as a precision medicine biomarker and examining the impact of social determinants of health, gut bacterial epigenomics, noncoding RNA, and epitranscriptomics on disease development and progression. We discuss challenges and barriers to advancing cardiometabolic epigenetics research, along with the opportunities for novel preventive strategies, targeted therapies, and personalized medicine approaches that may arise from a better understanding of epigenetic processes. Emerging technologies, such as single-cell sequencing and epigenetic editing, hold the potential to further enhance our ability to dissect the complex interplay between genetic, environmental, and lifestyle factors. To translate research findings into clinical practice, interdisciplinary collaborations, technical and ethical considerations, and accessibility of resources and knowledge are crucial. Ultimately, the field of epigenetics has the potential to revolutionize the way we approach cardiovascular and metabolic diseases, paving the way for precision medicine and personalized health care, and improving the lives of millions of individuals worldwide affected by these conditions.

Cumulative Stress Across the Life Course and Biological Aging in Adulthood.

OBJECTIVE: Psychosocial stressors have been linked with accelerated biological aging in adults; however, few studies have examined stressors across the life course in relation to biological aging. METHODS: In 359 individuals (57% White, 34% Black) from the Child Health and Development Studies Disparities study, economic (income, education, financial strain), social (parent-child relations, caretaker responsibilities) and traumatic (death of a sibling or child, violence exposure) stressors were assessed at multiple time points (birth and ages 9, 15, and 50 years). Experiences of major discrimination were assessed at age 50. Life period stress scores were then assessed as childhood (birth-age 15 years) and adulthood (age 50 years). At age 50 years, participants provided blood samples, and DNA methylation was assessed with the EPIC BeadChip. Epigenetic age was estimated using six epigenetic clocks (Horvath, Hannum, Skin and Blood age, PhenoAge, GrimAge, Dunedin Pace of Aging). Age acceleration was determined using residuals from regressing chronologic age on each of the epigenetic age metrics. Telomere length was assessed using the quantitative polymerase chain reaction-based methods. RESULTS: In linear regression models adjusted for race and gender, total life stress, and childhood and adult stress independently predicted accelerated aging based on GrimAge and faster pace of aging based on the DunedinPace. Associations were attenuated after adjusting for smoking status. In sex-stratified analyses, greater childhood stress was associated with accelerated epigenetic aging among women but not men. No associations were noted with telomere length. CONCLUSIONS: We found that cumulative stressors across the life course were associated with accelerated epigenetic age, with differences by sex (e.g., accelerated among women). Further research of this association in large and diverse samples is needed.

White matter microstructural variability linked to differential attentional skills and impulsive behavior in a pediatric population.

Structural and functional magnetic resonance imaging (MRI) studies have suggested a neuroanatomical basis that may underly attention-deficit-hyperactivity disorder (ADHD), but the anatomical ground truth remains unknown. In addition, the role of the white matter (WM) microstructure related to attention and impulsivity in a general pediatric population is still not well understood. Using a state-of-the-art structural connectivity pipeline based on the Brainnetome atlas extracting WM connections and its subsections, we applied dimensionality reduction techniques to obtain biologically interpretable WM measures. We selected the top 10 connections-of-interests (located in frontal, parietal, occipital, and basal ganglia regions) with robust anatomical and statistical criteria. We correlated WM measures with psychometric test metrics (Conner's Continuous Performance Test 3) in 171 children (27 Dx ADHD, 3Dx ASD, 9-13 years old) from the population-based GESTation and Environment cohort. We found that children with lower microstructural complexity and lower axonal density show a higher impulsive behavior on these connections. When segmenting each connection in subsections, we report WM alterations localized in one or both endpoints reflecting a specific localization of WM alterations along each connection. These results provide new insight in understanding the neurophysiology of attention and impulsivity in a general population.

Per- and polyfluoroalkyl substances, polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers and dysregulation of MicroRNA expression in humans and animals-A systematic review.

BACKGROUND: Persistent organic pollutants (POPs) are chemicals characterized by their environmental persistence. Evidence suggests that exposure to POPs, which is ubiquitous, is associated with microRNA (miRNA) dysregulation. miRNA are key regulators in many physiological processes. It is thus of public health concern to understand the relationships between POPs and miRNA as related to health outcomes. OBJECTIVES: This systematic review evaluated the relationship between widely recognized, intentionally manufactured, POPs, including per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (dichlorodiphenyltrichloroethane [DDT], dichlorodiphenyldichloroethylene [DDE], hexachlorobenzene [HCB]), with miRNA expression in both human and animal studies. METHODS: We used PubMed and Embase to systematically search the literature up to September 29th, 2023. Search results for human and animal studies were included if they incorporated at least one POP of interest in relation to at least one miRNA. Data were synthesized to determine the direction and significance of associations between POPs and miRNA. We utilized ingenuity pathway analysis to review disease pathways for miRNA that were associated with POPs. RESULTS: Our search identified 38 eligible studies: 9 in humans and 29 in model organisms. PFAS were associated with decreased expression of miR-19, miR-193b, and miR-92b, as well as increased expression of miR-128, miR-199a-3p, and miR-26b across species. PCBs were associated with increased expression of miR-15a, miR-1537, miR-21, miR-22-3p, miR-223, miR-30b, and miR-34a, as well as decreased expression of miR-130a and let-7b in both humans and animals. Pathway analysis for POP-associated miRNA identified pathways related to carcinogenesis. DISCUSSION: This is the first systematic review of the association of POPs with miRNA in humans and model organisms. Large-scale prospective human studies are warranted to examine the role of miRNA as mediators between POPs and health outcomes.

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans. OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children. METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 16.6 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs. RESULTS: Plasma PFAS concentrations were associated with alterations in 476 miRNAs in the Teen-LABs study and 13 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis. CONCLUSION: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.

Establishing non-fasting reference values for plasma lipids levels based on age, sex, and puberty stage in a French-Canadian pediatric population.

BACKGROUND: Dyslipidemias, including familial hypercholesterolemia (FH), are a significant risk factor for cardiovascular diseases. FH is a genetic disorder resulting in elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased probability of early cardiovascular disorders. Heterozygous familial hypercholesterolemia (HeFH) is the most common form, affecting approximately 1 in 250 individuals worldwide, with a higher prevalence among the French-Canadian population. Childhood is a critical period for screening risk factors, but the recommendation for non-fasting screening remains controversial due to a lack of specific reference values for this state. This study aims to establish reference values for lipid levels in non-fasting children from Sherbrooke, Quebec, Canada, that will be specific for sex, age, and pubertal stages. METHODS: Blood samples and corresponding anthropometric data were collected from 356 healthy children aged from 6 to 13. They were categorized either into two age groups: Cohort 6-8 and Cohort 9-13, or into pubertal stages. Reference values, specifically the 2.5th, 5th, 10th, 50th, 90th, 95th, and 97.5th percentiles were determined using the CLSI C28-A3 guidelines. RESULTS: Lipid profiles did not significantly differ between sexes, except for higher levels of high-density lipoprotein (HDL-C) in boys within Cohort 6-8. HDL-C levels significantly increased, while LDL-C and non-HDL-C levels significantly decreased in both sexes with age. Non-fasting age- and pubertal stages-specific reference values were established. CONCLUSION: This study established reference intervals for lipid markers in non-fasting state within the pediatric French-Canadian population. These findings could be used in dyslipidemia screening in daily practice.

Extracellular Vesicle-Encapsulated microRNAs as Novel Biomarkers of Lung Health.

Rationale: Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of early lung injury. Objectives: Evaluate associations of plasma EV-miRNAs with lung function. Methods: The prospective NAS (Normative Aging Study) collected plasma EV-miRNA measurements from 1996-2015 and spirometry every 3-5 years through 2019. Associations of EV-miRNAs with baseline lung function were modeled using linear regression. To complement the individual miRNA approach, unsupervised machine learning was used to identify clusters of participants with distinct EV-miRNA profiles. Associations of EV-miRNA profiles with multivariate latent longitudinal lung function trajectories were modeled using log binomial regression. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the HEALS (Health Effects of Arsenic Longitudinal Study). Measurements and Main Results: In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function (false discovery rate-adjusted P value < 0.05), 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort. A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample. Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity. Conclusions: Plasma EV-miRNAs may represent a robust biomarker of subclinical lung injury and may facilitate early identification and treatment of patients at risk of developing overt lung disease.

Endocrine-disrupting chemical concentrations in follicular fluid and follicular reproductive hormone levels.

PURPOSE: To determine correlations between chemicals in follicular fluid (FF) and follicular reproductive hormone levels. METHODS: The analysis was part of a larger cohort study to determine associations between exposure to EDCs and in vitro fertilization (IVF) outcomes. FF was aspirated from a single leading follicle per participant. Demographics and data on exposure to EDCs were self-reported by the participants using a questionnaire. The concentrations of estradiol (E2), progesterone (PG), anti-Mullerian hormone (AMH), and inhibin B, as well as that of 12 phthalate metabolites and 12 phenolic chemicals were measured in each FF sample. Multivariate linear regression model was used to identify the drivers of hormone levels based on participant's age, BMI, smoking status, and chemical exposure for the monitored chemicals detected in more than 50% of the samples. Benjamini-Hochberg false discovery rate (FDR) correction was applied on the resulting p values (q value). RESULTS: FF samples were obtained from 72 women (mean age 30.9 years). Most of the phthalates and phenolic substances monitored (21/24, 88%) were identified in FF. Ten compounds (7 phthalate metabolites, 3 phenols) were found in more than 50% of samples. In addition, there were positive associations between E2 levels and mono-n-butyl phthalate (MnBP) (beta = 0.01) and mono-isobutyl phthalate (MiBP) (beta = 0.03) levels (q value < 0.05). CONCLUSION: Higher concentrations of several phthalate metabolites, present among others in personal care products, were associated with increased E2 levels in FF. The results emphasize the need to further investigate the mechanisms of action of such EDCs on hormonal cyclicity and fertility in women.

Ozone pollution and hospital admissions for cardiovascular events.

AIMS: The available literature on morbidity risk of cardiovascular diseases associated with ambient ozone pollution is still limited. This study examined the potential acute effects of exposure to ambient ozone pollution on hospital admissions of cardiovascular events in China. METHODS AND RESULTS: A two-stage multi-city time-series study approach was used to explore the associations of exposure to ambient ozone with daily hospital admissions (n = 6 444 441) for cardiovascular events in 70 Chinese cities of prefecture-level or above during 2015-17. A 10 µg/m3 increment in 2-day average daily 8 h maximum ozone concentrations was associated with admission risk increases of 0.46% [95% confidence interval (CI): 0.28%, 0.64%] in coronary heart disease, 0.45% (95% CI: 0.13%, 0.77%) in angina pectoris, 0.75% (95% CI: 0.38%, 1.13%) in acute myocardial infarction (AMI), 0.70% (95% CI: 0.41%, 1.00%) in acute coronary syndrome, 0.50% (95% CI: 0.24%, 0.77%) in heart failure, 0.40% (95% CI: 0.23%, 0.58%) in stroke and 0.41% (95% CI: 0.22%, 0.60%) in ischemic stroke, respectively. The excess admission risks for these cardiovascular events associated with high ozone pollution days (with 2-day average 8-h maximum concentrations ≥100 µg/m3 vs. < 70 µg/m3) ranged from 3.38% (95% CI: 1.73%, 5.06%) for stroke to 6.52% (95% CI: 2.92%, 10.24%) for AMI. CONCLUSION: Ambient ozone was associated with increased hospital admission risk for cardiovascular events. Greater admission risks for cardiovascular events were observed under high ozone pollution days. These results provide evidence for the harmful cardiovascular effects of ambient ozone and call for special attention on the control of high ozone pollution.

Testing cell-type-specific mediation effects in genome-wide epigenetic studies.

Epigenome-wide mediation analysis aims to identify DNA methylation CpG sites that mediate the causal effects of genetic/environmental exposures on health outcomes. However, DNA methylations in the peripheral blood tissues are usually measured at the bulk level based on a heterogeneous population of white blood cells. Using the bulk level DNA methylation data in mediation analysis might cause confounding bias and reduce study power. Therefore, it is crucial to get fine-grained results by detecting mediation CpG sites in a cell-type-specific way. However, there is a lack of methods and software to achieve this goal. We propose a novel method (Mediation In a Cell-type-Specific fashion, MICS) to identify cell-type-specific mediation effects in genome-wide epigenetic studies using only the bulk-level DNA methylation data. MICS follows the standard mediation analysis paradigm and consists of three key steps. In step1, we assess the exposure-mediator association for each cell type; in step 2, we assess the mediator-outcome association for each cell type; in step 3, we combine the cell-type-specific exposure-mediator and mediator-outcome associations using a multiple testing procedure named MultiMed [Sampson JN, Boca SM, Moore SC, et al. FWER and FDR control when testing multiple mediators. Bioinformatics 2018;34:2418-24] to identify significant CpGs with cell-type-specific mediation effects. We conduct simulation studies to demonstrate that our method has correct FDR control. We also apply the MICS procedure to the Normative Aging Study and identify nine DNA methylation CpG sites in the lymphocytes that might mediate the effect of cigarette smoking on the lung function.

Aclust2.0: a revamped unsupervised R tool for Infinium methylation beadchips data analyses.

MOTIVATION: A wide range of computational packages has been developed for regional DNA methylation analyses of Illumina's Infinium array data. Aclust, one of the first unsupervised algorithms, was originally designed to analyze regional methylation of Infinium's 27K and 450K arrays by clustering neighboring methylation sites prior to downstream analyses. However, Aclust relied on outdated packages that rendered it largely non-operational especially with the newer Infinium EPIC and mouse arrays. RESULTS: We have created Aclust2.0, a streamlined pipeline that involves five steps for the analyses of human (450K and EPIC) and mouse array data. Aclust2.0 provides a user-friendly pipeline and versatile for regional DNA methylation analyses for molecular epidemiological and mouse studies. AVAILABILITY AND IMPLEMENTATION: Aclust2.0 is freely available on Github (https://github.com/OluwayioseOA/Alcust2.0.git).

Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men.

OBJECTIVE: Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic. METHODS: Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities ( n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the "number of independent degrees of freedom" approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software. RESULTS: We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders. CONCLUSION: Our findings provide new insights into possible mechanisms underlying optimism and health.

Maternal age at birth and child attention-deficit hyperactivity disorder: causal association or familial confounding?

BACKGROUND: Causal explanations for the association of young motherhood with increased risk for child attention-deficit hyperactivity disorder (ADHD) remain unclear. METHODS: The ABCD Study recruited 11,878 youth from 22 sites across the United States between June 1, 2016 and October 15, 2018. This cross-sectional analysis of 8,514 children aged 8-11 years excluded 2,260 twins/triplets, 265 adopted children, and 839 younger siblings. We examined associations of maternal age with ADHD clinical range diagnoses based on the Child Behavior Checklist and NIH Toolbox Flanker Attention Scores using mixed logistic and linear regression models, respectively. We conducted confounding and causal mediation analyses using genotype array, demographic, socioeconomic, and prenatal environment data to investigate which genetic and environmental variables may explain the association between young maternal age and child ADHD. RESULTS: In crude models, each 10-year increase in maternal age was associated with 32% decreased odds of ADHD clinical range diagnosis (OR = 0.68; 95% CI [0.59, 0.78]) and 1.09-points increased NIH Flanker Attention Scores (ß = 1.09; 95% CI [0.76, 1.41]), indicating better child visual selective attention. However, adjustment for confounders weakened these associations. The strongest confounders were family income, caregiver education, and ADHD polygenic risk score for ADHD clinical range diagnoses, and family income, caregiver education, and race/ethnicity for NIH Flanker Attention Scores. Breastfeeding duration, prenatal alcohol exposure, and prenatal tobacco exposure were responsible for up to 18%, 6%, and 4% mediation, respectively. CONCLUSIONS: Socioeconomic disadvantages were likely the primary explanation for the association of young maternal age with child ADHD, although genetics and modifiable environmental factors also played a role. Public policies aimed at reducing the burden of ADHD associated with young motherhood should target socioeconomic inequalities and support young pregnant women by advocating for reduced prenatal tobacco exposure and healthy breastfeeding practices after childbirth.

Cohort Network: A Knowledge Graph toward Data Dissemination and Knowledge-Driven Discovery for Cohort Studies.

Contemporary environmental health sciences draw on large-scale longitudinal studies to understand the impact of environmental exposures and behavior factors on the risk of disease and identify potential underlying mechanisms. In such studies, cohorts of individuals are assembled and followed up over time. Each cohort generates hundreds of publications, which are typically neither coherently organized nor summarized, hence limiting knowledge-driven dissemination. Hence, we propose a Cohort Network, a multilayer knowledge graph approach to extract exposures, outcomes, and their connections. We applied the Cohort Network on 121 peer-reviewed papers published over the past 10 years from the Veterans Affairs (VA) Normative Aging Study (NAS). The Cohort Network visualized connections between exposures and outcomes across different publications and identified key exposures and outcomes, such as air pollution, DNA methylation, and lung function. We demonstrated the utility of the Cohort Network for new hypothesis generation, e.g., identification of potential mediators of exposure-outcome associations. The Cohort Network can be used by investigators to summarize the cohort's research and facilitate knowledge-driven discovery and dissemination.

Characterization of childhood exposure to environmental contaminants using stool in a semi-urban middle-class cohort from eastern Canada.

Children are exposed to various environmental organic and inorganic contaminants with effects on health outcomes still largely unknown. Many matrices (e.g., blood, urine, nail, hair) have been used to characterize exposure to organic and inorganic contaminants. The sampling of feces presents several advantages; it is non-invasive and provides a direct evaluation of the gut microbiome exposure to contaminants. The gut microbiome is a key factor in neurological development through the brain-gut axis. Its composition and disturbances can affect the neurodevelopment of children. Characterization of children exposure to contaminants is often performed on vulnerable populations (e.g., from developing countries, low-income neighborhoods, and large urban centers). Data on the exposure of children from middle-class, semi-urban, and mid-size populations to contaminants is scarce despite representing a significant fraction of the population in North America. In this study, 73 organics compounds from different chemical classes and 22 elements were analyzed in 6 years old (n = 84) and 10 years old (n = 119) children's feces from a middle-class, semi-urban, mid-size population cohort from Eastern Canada. Results show that 67 out of 73 targeted organics compounds and all elements were at least detected in one child's feces. Only caffeine (97% & 80%) and acetaminophen (28% & 48%) were detected in more than 25% of the children's feces, whereas all elements besides titanium were detected in more than 50% of the children.

Intermediate and long-term exposure to air pollution and temperature and the extracellular microRNA profile of participants in the normative aging study (NAS).

BACKGROUND: The molecular effects of intermediate and long-term exposure to air pollution and temperature, such as those on extracellular microRNA (ex-miRNA) are not well understood but may have clinical consequences. OBJECTIVES: To assess the association between exposure to ambient air pollution and temperature and ex-miRNA profiles. METHODS: Our study population consisted of 734 participants in the Normative Aging Study (NAS) between 1999 and 2015. We used high-resolution models to estimate four-week, eight-week, twelve-week, six-month, and one-year moving averages of PM2.5, O3, NO2, and ambient temperature based on geo-coded residential addresses. The outcome of interest was the extracellular microRNA (ex-miRNA) profile of each participant over time. We used a longitudinal quantile regression approach to estimate the association between the exposures and each ex-miRNA. Results were corrected for multiple comparisons and ex-miRNAs that were still significantly associated with the exposures were further analyzed using KEGG pathway analysis and Ingenuity Pathway Analysis. RESULTS: We found 151 significant associations between levels of PM2.5, O3, NO2, and ambient temperature and 82 unique ex-miRNAs across multiple quantiles. Most of the significant results were associations with intermediate-term exposure to O3, long-term exposure to PM2.5, and both intermediate and long-term exposure to ambient temperature. The exposures were most often associated with the 75th and 90th percentile of the outcomes. Pathway analyses of significant ex-miRNAs revealed their involvement in biological pathways involving cell function and communication as well as clinical diseases such as cardiovascular disease, respiratory disease, and neurological disease. CONCLUSION: Our results show that intermediate and long-term exposure to all our exposures of interest were associated with changes in the ex-miRNA profile of study participants. Further studies on environmental risk factors and ex-miRNAs are warranted.