Associations Between Early-Life Adversity, Ambient Air Pollution, and Telomere Length in Children.

OBJECTIVE: Examine the independent associations and interaction between early-life adversity and residential ambient air pollution exposure on relative buccal telomere length (rBTL). METHODS: Experiences of abuse, neglect, household challenges, and related life events were identified in a cross-sectional sample of children aged 1 to 11 years ( n = 197) using the 17-item Pediatric ACEs and Related Life Event Screener (PEARLS) tool. The PEARLS tool was analyzed both as a total score and across established domains (Maltreatment, Household Challenges, and Social Context). Ground-level fine particulate matter (PM 2.5 ) concentrations were matched to residential locations for the 1 and 12 months before biospecimen collection. We used multivariable linear regression models to examine for independent associations between continuous PM 2.5 exposure and PEARLS score/domains with rBTL. In addition, effect modification by PEARLS scores and domains on associations between PM 2.5 exposure and rBTL was examined. RESULTS: Study participants were 47% girls, with mean (standard deviation) age of 5.9 (3.4) years, median reported PEARLS score of 2 (interquartile range [IQR], 4), median 12-month prior PM 2.5 concentrations of 11.8 µg/m 3 (IQR, 2.7 µg/m 3 ), median 1-month prior PM 2.5 concentrations of 10.9 µg/m 3 (IQR, 5.8 µg/m 3 ), and rBTL of 0.1 (IQR, 0.03). Mean 12-month prior PM 2.5 exposure was inversely associated with rBTL ( ß = -0.02, 95% confidence interval = -0.04 to -0.01). Although reported PEARLS scores and domains were not independently associated with rBTL, we observed a greater decrement in rBTL with increment of average annual PM 2.5 as reported Social Context domain items increased ( p -interaction < .05). CONCLUSIONS: Our results suggest that adverse Social Context factors may accelerate the association between chronic PM 2.5 exposure on telomere shortening during childhood.

Adverse Childhood Experiences and Related Events are Associated with Asthma Symptoms in Children.

OBJECTIVE: To examine the association between adverse childhood experiences (ACEs) and related events and asthma symptom burden in children. METHODS: This is a cross-sectional study of baseline data from 147 participants with asthma from a cohort of children enrolled in the Pediatric ACEs Screening and Resiliency Study. Participants completed the PEdiatric ACEs and Related Life Events Screener (PEARLS) tool, a 17-item questionnaire, capturing 3 domains of childhood adversity-child maltreatment, household challenges, and social context. Asthma symptom burden was assessed using the International Study of Asthma and Allergies in Childhood core questionnaire, which asks participants to identify the presence and frequency of severe wheezing that limits speech, wheezing with exercise, nocturnal wheezing, and nocturnal cough in the last 12 months. Using multivariable logistical regression models, we examined the relationship between reported PEARLS and asthma symptoms. RESULTS: Of children with asthma, 86% reported at least 1 adversity, with 48% reporting 4 or more. The odds of severe wheeze limiting speech increased by 19% with each additional reported adversity captured by the PEARLS tool (95% confidence intervals (CI) 1.01-1.41). Increasing PEARLS scores were also associated with 16% increased odds of reporting wheeze with exercise (95% CI 1.03-1.31). Wheezing with exercise was associated with the household challenges domain (odds ratio (OR) 1.34; 95% CI 1.05-1.72), while severe wheeze limiting speech was associated with the social context domain (OR 1.75; 95%CI 1.02-3.02). CONCLUSIONS: Childhood adversities are associated with increased asthma symptom burden, suggesting the tool may be helpful in identifying children at risk for poorly controlled asthma.

Biological Burden of Adverse Childhood Experiences in Children.

OBJECTIVE: This study aimed to examine relationships between adverse childhood experiences (ACEs) and related life events and allostatic load (AL)-"wear and tear" from chronic stress-in a pediatric population. METHODS: Children were screened with the PEdiatric ACEs and Related Life Event Screener (PEARLS) tool, a 17-item questionnaire capturing experiences of abuse, neglect, household challenges, and related life events. Biological data were available for 207 participants, and AL was operationalized using clinical or empirical cutoff points across 4 physiological systems (i.e., cardiac, metabolic, inflammatory, neurologic). Covariate-adjusted multivariable regression models were used to examine associations between AL with adversity and health. RESULTS: Children (mean age = 6.5 years, range = 1-11 years) had an average AL score of 1.9 (standard deviation = 1.7), and a U-shaped relationship was observed with child's age. Continuous PEARLS and original ACE scores were not associated with AL. However, children with a reported PEARLS score of 1 to 2 or original ACEs score of 1 to 3 had 1.5 (incidence rate ratio [IRR] = 1.50, 95% confidence interval [CI] = 1.09-2.08) and 1.4 (IRR = 1.41, 95% CI = 1.08-1.84) times greater AL, respectively, compared with participants with none reported. In secondary analyses, caregiver mental illness was associated with higher child AL (adjusted IRR = 1.27, 95% CI = 1.01-1.58). AL was also associated with poorer perceived child general health (adjusted ß = -0.87, 95% CI = -1.58 to -0.15) and greater odds of child obesity (adjusted odds ratio = 1.51, 95% CI = 1.23-1.89). CONCLUSIONS: Measuring AL in a pediatric population requires careful consideration of age. Higher AL was associated with a greater number of reported adversities and worse child health.

Structural racism and its pathways to asthma and atopic dermatitis.

Black, Latinx, and Indigenous people in the United States experience a disproportionate burden of asthma and atopic dermatitis. The study of these disease disparities has focused on proximal socioenvironmental exposures and on the biomechanistic (including genetic) differences between racial and ethnic groups. Although biomedical research in allergy and immunology stands to benefit from the inclusion of diverse study populations, the narrow focus on biologic mechanisms disregards the complexity of interactions across biologic and structural factors, including the effects of structural racism. Structural racism is the totality of ways in which society fosters discrimination by creating and reinforcing inequitable systems through intentional policies and practices sanctioned by government and institutions. It is embedded across multiple levels, including the economic, educational, health care, and judicial systems, which are manifested in inequity in the physical and social environment. In this review, we present a conceptual framework and pull from the literature to demonstrate how structural racism is a root cause of atopic disease disparities by way of residential segregation, socioeconomic position, and mass incarceration, which may lead to aberrations in the innate and adaptive immune response and the augmentation of physiologic stress responses, contributing to a disproportionate disease burden for racial and ethnic populations.

Cell-Based Bioassay to Screen Environmental Chemicals and Human Serum for Total Glucocorticogenic Activity.

Glucocorticoids are steroid hormones that have systemic effects that are mediated by the glucocorticoid receptor. Environmental chemicals that disrupt glucocorticoid receptor signaling and/or glucocorticoid homeostasis could adversely affect the health of human and nonhuman vertebrates. A major challenge in identifying environmental chemicals that alter glucocorticoid receptor signaling and/or glucocorticoid homeostasis is a lack of adequate screening methods. We developed a cell-based bioassay to measure total glucocorticogenic activity (TGA) of environmental chemicals and human serum. Human MDA-MB-231 breast cancer cells were stably transfected with a luciferase reporter gene driven by 3 tandem glucocorticoid-response elements. Dose-response curves for 6 glucocorticoids and 4 non-glucocorticoid steroid hormones were generated to evaluate the specificity of the bioassay. Cells were also optimized to measure TGA of 176 structurally diverse environmental chemicals and human serum samples in a high-throughput format. Reporter activity was glucocorticoid-specific and induced 400-fold by 1 µM dexamethasone. Furthermore, 3 of the screened chemicals (3,4,4'-trichlorocarbanilide, isopropyl-N-phenylcarbamate, and benzothiazole derivative 2-[4-chlorophenyl]-benzothiazole) potentiated cortisol-induced glucocorticoid receptor activity. Serum TGA estimates from the bioassay were highly correlated with a cortisol enzyme-linked immunosorbent assay. The present study establishes an in vitro method to rapidly screen environmental chemicals and human serum for altered glucocorticogenic activity. Future studies can utilize this tool to quantify the joint effect of endogenous glucocorticoids and environmental chemicals. Environ Toxicol Chem 2021;40:177-186. © 2020 SETAC.

Application of generalized concentration addition to predict mixture effects of glucocorticoid receptor ligands.

Environmental exposures often occur in complex mixtures and at low concentrations. Generalized concentration addition (GCA) is a method used to estimate the joint effect of receptor ligands that vary in efficacy. GCA models have been successfully applied to mixtures of aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARγ) ligands, each of which can be modeled as a receptor with a single binding site. Here, we evaluated whether GCA could be applied to homodimer nuclear receptors, which have two binding sites, to predict the combined effect of full glucocorticoid receptor (GR) agonists with partial agonists. We measured transcriptional activation of GR using a cell-based bioassay. Individual concentration-response curves for dexamethasone (full agonist), prednisolone (full agonist), and medroxyprogesterone 17-acetate (partial agonist) were generated and applied in three additivity models, GCA, effect summation (ES), and relative potency factor (RPF), to generate response surfaces. GCA and RPF yielded adequate predictions of the experimental data for two full agonists. However, GCA fit experimental data significantly better than ES and RPF for all other binary mixtures. This work extends the application of GCA to homodimer nuclear receptors and improves prediction accuracy of mixture effects of GR agonists.

Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population.

Inter-individual differences in arsenic metabolism have been linked to arsenic-related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic inorganic arsenic (iAs) metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = -1.9%, 95% CI: -3.3, -0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR = 0.3; 95% CI: 0.1-0.6) and lung cancer (OR = 0.6; 95% CI: 0.2-1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease. Environ. Mol. Mutagen. 58:411-422, 2017. © 2017 Wiley Periodicals, Inc.

Using exposomics to assess cumulative risks and promote health.

Under the exposome paradigm all nongenetic factors contributing to disease are considered to be 'environmental' including chemicals, drugs, infectious agents, and psychosocial stress. We can consider these collectively as environmental stressors. Exposomics is the comprehensive analysis of exposure to all environmental stressors and should yield a more thorough understanding of chronic disease development. We can operationalize exposomics by studying all the small molecules in the body and their influence on biological pathways that lead to impaired health. Here, we describe methods by which this may be achieved and discuss the application of exposomics to cumulative risk assessment in vulnerable populations. Since the goal of cumulative risk assessment is to analyze, characterize, and quantify the combined risks to health from exposures to multiple agents or stressors, it seems that exposomics is perfectly poised to advance this important area of environmental health science. We should therefore support development of tools for exposomic analysis and begin to engage impacted communities in participatory exposome research. A first step may be to apply exposomics to vulnerable populations already studied by more conventional cumulative risk approaches. We further propose that recent migrants, low socioeconomic groups with high environmental chemical exposures, and pregnant women should be high priority populations for study by exposomics. Moreover, exposomics allows us to study interactions between chronic stress and environmental chemicals that disrupt stress response pathways (i.e., 'stressogens'). Exploring the impact of early life exposures and maternal stress may be an interesting and accessible topic for investigation by exposomics using biobanked samples.

Restriction of intestinal stem cell expansion and the regenerative response by YAP.

A remarkable feature of regenerative processes is their ability to halt proliferation once an organ's structure has been restored. The Wnt signalling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. However, the mechanisms that counterbalance Wnt-driven proliferation are poorly understood. Here we demonstrate in mice and humans that yes-associated protein 1 (YAP; also known as YAP1)--a protein known for its powerful growth-inducing and oncogenic properties--has an unexpected growth-suppressive function, restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signalling independently of the AXIN-APC-GSK-3ß complex partly by limiting the activity of dishevelled (DVL). DVL signals in the nucleus of intestinal stem cells, and its forced expression leads to enhanced Wnt signalling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas, and that its expression can restrict the growth of colorectal carcinoma xenografts. Collectively, our work describes a novel mechanistic paradigm for how proliferative signals are counterbalanced in regenerating tissues. Additionally, our findings have important implications for the targeting of YAP in human malignancies.