Mechanisms of Pediatric Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, is characterized by chronic intestinal inflammation due to a complex interaction of genetic determinants, disruption of mucosal barriers, aberrant inflammatory signals, loss of tolerance, and environmental triggers. Importantly, the incidence of pediatric IBD is rising, particularly in children younger than 10 years. In this review, we discuss the clinical presentation of these patients and highlight environmental exposures that may affect disease risk, particularly among people with a background genetic risk. With regard to both children and adults, we review advancements in understanding the intestinal epithelium, the mucosal immune system, and the resident microbiota, describing how dysfunction at any level can lead to diseases like IBD. We conclude with future directions for applying advances in IBD genetics to better understand pathogenesis and develop therapeutics targeting key pathogenic nodes.

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.

Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.

Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.

The MRGPR family of receptors in immunity.

The discovery of Mas-related G protein-coupled receptors (Mrgprs) has opened a compelling chapter in our understanding of immunity and sensory biology. This family of receptors, with their unique expression and diverse ligands, has emerged as key players in inflammatory states and hold the potential to alleviate human diseases. This review will focus on the members of this receptor family expressed on immune cells and how they govern immune and neuro-immune pathways underlying various physiological and pathological states. Immune cell-specific Mrgprs have been shown to control a variety of manifestations, including adverse drug reactions, inflammatory conditions, bacterial immunity, and the sensing of environmental exposures like allergens and irritants.

Dynamic Human Environmental Exposome Revealed by Longitudinal Personal Monitoring.

Human health is dependent upon environmental exposures, yet the diversity and variation in exposures are poorly understood. We developed a sensitive method to monitor personal airborne biological and chemical exposures and followed the personal exposomes of 15 individuals for up to 890 days and over 66 distinct geographical locations. We found that individuals are potentially exposed to thousands of pan-domain species and chemical compounds, including insecticides and carcinogens. Personal biological and chemical exposomes are highly dynamic and vary spatiotemporally, even for individuals located in the same general geographical region. Integrated analysis of biological and chemical exposomes revealed strong location-dependent relationships. Finally, construction of an exposome interaction network demonstrated the presence of distinct yet interconnected human- and environment-centric clouds, comprised of interacting ecosystems such as human, flora, pets, and arthropods. Overall, we demonstrate that human exposomes are diverse, dynamic, spatiotemporally-driven interaction networks with the potential to impact human health.

Autoimmunity and organ damage in systemic lupus erythematosus.

Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune system contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigenetic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique 'interactome', which will dictate specific treatment.

Environmental pollutants and the immune response.

Environmental pollution is one of the most serious challenges to health in the modern world. Pollutants alter immune responses and can provoke immunotoxicity. In this Review, we summarize the major environmental pollutants that are attracting wide-ranging concern and the molecular basis underlying their effects on the immune system. Xenobiotic receptors, including the aryl hydrocarbon receptor (AHR), sense and respond to a subset of environmental pollutants by activating the expression of detoxification enzymes to protect the body. However, chronic activation of the AHR leads to immunotoxicity. KEAP1-NRF2 is another important system that protects the body against environmental pollutants. KEAP1 is a sensor protein that detects environmental pollutants, leading to activation of the transcription factor NRF2. NRF2 protects the body from immunotoxicity by inducing the expression of genes involved in detoxification, antioxidant and anti-inflammatory activities. Intervening in these sensor-response systems could protect the body from the devastating immunotoxicity that can be induced by environmental pollutants.

Locally instructed CXCR4hi neutrophils trigger environment-driven allergic asthma through the release of neutrophil extracellular traps.

Low exposure to microbial products, respiratory viral infections and air pollution are major risk factors for allergic asthma, yet the mechanistic links between such conditions and host susceptibility to type 2 allergic disorders remain unclear. Through the use of single-cell RNA sequencing, we characterized lung neutrophils in mice exposed to a pro-allergic low dose of lipopolysaccharide (LPS) or a protective high dose of LPS before exposure to house dust mites. Unlike exposure to a high dose of LPS, exposure to a low dose of LPS instructed recruited neutrophils to upregulate their expression of the chemokine receptor CXCR4 and to release neutrophil extracellular traps. Low-dose LPS-induced neutrophils and neutrophil extracellular traps potentiated the uptake of house dust mites by CD11b+Ly-6C+ dendritic cells and type 2 allergic airway inflammation in response to house dust mites. Neutrophil extracellular traps derived from CXCR4hi neutrophils were also needed to mediate allergic asthma triggered by infection with influenza virus or exposure to ozone. Our study indicates that apparently unrelated environmental risk factors can shape recruited lung neutrophils to promote the initiation of allergic asthma.

Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19.

CD4+ T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4+ T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4+ memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4+ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4+ T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.

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.

Lung adenocarcinoma promotion by air pollutants.

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 µm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1ß. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM2.5 air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

Proteome plasticity in response to persistent environmental change.

Temperature is a variable component of the environment, and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses, resulting in refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to reduction of temperature-sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find that many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and, importantly, cellular functions. We postulate that, in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.

The cellular composition of the human immune system is shaped by age and cohabitation.

Detailed population-level description of the human immune system has recently become achievable. We used a 'systems-level' approach to establish a resource of cellular immune profiles of 670 healthy individuals. We report a high level of interindividual variation, with low longitudinal variation, at the level of cellular subset composition of the immune system. Despite the profound effects of antigen exposure on individual antigen-specific clones, the cellular subset structure proved highly elastic, with transient vaccination-induced changes followed by a return to the individual's unique baseline. Notably, the largest influence on immunological variation identified was cohabitation, with 50% less immunological variation between individuals who share an environment (as parents) than between people in the wider population. These results identify local environmental conditions as a key factor in shaping the human immune system.

Air pollution exposure disparities across US population and income groups.

Air pollution contributes to the global burden of disease, with ambient exposure to fine particulate matter of diameters smaller than 2.5 µm (PM2.5) being identified as the fifth-ranking risk factor for mortality globally1. Racial/ethnic minorities and lower-income groups in the USA are at a higher risk of death from exposure to PM2.5 than are other population/income groups2-5. Moreover, disparities in exposure to air pollution among population and income groups are known to exist6-17. Here we develop a data platform that links demographic data (from the US Census Bureau and American Community Survey) and PM2.5 data18 across the USA. We analyse the data at the tabulation area level of US zip codes (N is approximately 32,000) between 2000 and 2016. We show that areas with higher-than-average white and Native American populations have been consistently exposed to average PM2.5 levels that are lower than areas with higher-than-average Black, Asian and Hispanic or Latino populations. Moreover, areas with low-income populations have been consistently exposed to higher average PM2.5 levels than areas with high-income groups for the years 2004-2016. Furthermore, disparities in exposure relative to safety standards set by the US Environmental Protection Agency19 and the World Health Organization20 have been increasing over time. Our findings suggest that more-targeted PM2.5 reductions are necessary to provide all people with a similar degree of protection from environmental hazards. Our study is observational and cannot provide insight into the drivers of the identified disparities.

Environmental radiation exposure at Chornobyl has not systematically affected the genomes or chemical mutagen tolerance phenotypes of local worms.

The 1986 disaster at the Chornobyl Nuclear Power Plant transformed the surrounding region into the most radioactive landscape known on the planet. Whether or not this sudden environmental shift selected for species, or even individuals within a species, that are naturally more resistant to mutagen exposure remains an open question. In this study, we collected, cultured, and cryopreserved 298 wild nematode isolates from areas varying in radioactivity within the Chornobyl Exclusion Zone. We sequenced and assembled genomes de novo for 20 Oscheius tipulae strains, analyzed their genomes for evidence of recent mutation acquisition in the field, and observed no evidence of an association between mutation and radioactivity at the sites of collection. Multigenerational exposure of each of these strains to several chemical mutagens in the lab revealed that strains vary heritably in tolerance to each mutagen, but mutagen tolerance cannot be predicted based on the radiation levels at collection sites, and Chornobyl isolates were not systematically more resistant than strains from undisturbed habitats. In sum, the absence of mutational signatures does not reflect unique capacity for tolerating DNA damage.

Childhood PM2.5 exposure and upward mobility in the United States.

Although it is well documented that exposure to fine particulate matter (PM2.5) increases the risk of several adverse health outcomes, less is known about its relationship with economic opportunity. Previous studies have relied on regression modeling, which implied strict assumptions regarding confounding adjustments and did not explore geographical heterogeneity. We obtained data for 63,165 US census tracts (86% of all census tracts in the United States) on absolute upward mobility (AUM) defined as the mean income rank in adulthood of children born to families in the 25th percentile of the national income distribution. We applied and compared several state-of-the-art confounding adjustment methods to estimate the overall and county-specific associations of childhood exposure to PM2.5 and AUM controlling for many census tract-level confounders. We estimate that census tracts with a 1 µg/m3 higher PM2.5 concentrations in 1982 are associated with a statistically significant 1.146% (95% CI: 0.834, 1.458) lower AUM in 2015, on average. We also showed evidence that this relationship varies spatially between counties, exhibiting a more pronounced negative relationship in the Midwest and the South.

Global fishing patterns amplify human exposures to methylmercury.

Global pollution has exacerbated accumulation of toxicants like methylmercury (MeHg) in seafood. Human exposure to MeHg has been associated with long-term neurodevelopmental delays and impaired cardiovascular health, while many micronutrients in seafood are beneficial to health. The largest MeHg exposure source for many general populations originates from marine fish that are harvested from the global ocean and sold in the commercial seafood market. Here, we use high-resolution catch data for global fisheries and an empirically constrained spatial model for seafood MeHg to examine the spatial origins and magnitudes of MeHg extracted from the ocean. Results suggest that tropical and subtropical fisheries account for >70% of the MeHg extracted from the ocean because they are the major fishing grounds for large pelagic fishes and the natural biogeochemistry in this region facilitates seawater MeHg production. Compounding this issue, micronutrients (selenium and omega-3 fatty acids) are lowest in seafood harvested from warm, low-latitude regions and may be further depleted by future ocean warming. Our results imply that extensive harvests of large pelagic species by industrial fisheries, particularly in the tropics, drive global public health concerns related to MeHg exposure. We estimate that 84 to 99% of subsistence fishing entities globally likely exceed MeHg exposure thresholds based on typical rates of subsistence fish consumption. Results highlight the need for both stringent controls on global pollution and better accounting for human nutrition in fishing choices.

Climate change and public health in California: A structured review of exposures, vulnerable populations, and adaptation measures.

California faces several serious direct and indirect climate exposures that can adversely affect public health, some of which are already occurring. The public health burden now and in the future will depend on atmospheric greenhouse gas concentrations, underlying population vulnerabilities, and adaptation efforts. Here, we present a structured review of recent literature to examine the leading climate risks to public health in California, including extreme heat, extreme precipitation, wildfires, air pollution, and infectious diseases. Comparisons among different climate-health pathways are difficult due to inconsistencies in study design regarding spatial and temporal scales and health outcomes examined. We find, however, that the current public health burden likely affects thousands of Californians each year, depending on the exposure pathway and health outcome. Further, while more evidence exists for direct and indirect proximal health effects that are the focus of this review, distal pathways (e.g., impacts of drought on nutrition) are more uncertain but could add to this burden. We find that climate adaptation measures can provide significant health benefits, particularly in disadvantaged communities. We conclude with priority recommendations for future analyses and solution-driven policy actions.

Measuring long-term exposure to wildfire PM2.5 in California: Time-varying inequities in environmental burden.

Wildfires have become more frequent and intense due to climate change and outdoor wildfire fine particulate matter (PM2.5) concentrations differ from relatively smoothly varying total PM2.5. Thus, we introduced a conceptual model for computing long-term wildfire PM2.5 and assessed disproportionate exposures among marginalized communities. We used monitoring data and statistical techniques to characterize annual wildfire PM2.5 exposure based on intermittent and extreme daily wildfire PM2.5 concentrations in California census tracts (2006 to 2020). Metrics included: 1) weeks with wildfire PM2.5 < 5 µg/m3; 2) days with non-zero wildfire PM2.5; 3) mean wildfire PM2.5 during peak exposure week; 4) smoke waves (≥2 consecutive days with <15 µg/m3 wildfire PM2.5); and 5) mean annual wildfire PM2.5 concentration. We classified tracts by their racial/ethnic composition and CalEnviroScreen (CES) score, an environmental and social vulnerability composite measure. We examined associations of CES and racial/ethnic composition with the wildfire PM2.5 metrics using mixed-effects models. Averaged 2006 to 2020, we detected little difference in exposure by CES score or racial/ethnic composition, except for non-Hispanic American Indian and Alaska Native populations, where a 1-SD increase was associated with higher exposure for 4/5 metrics. CES or racial/ethnic × year interaction term models revealed exposure disparities in some years. Compared to their California-wide representation, the exposed populations of non-Hispanic American Indian and Alaska Native (1.68×, 95% CI: 1.01 to 2.81), white (1.13×, 95% CI: 0.99 to 1.32), and multiracial (1.06×, 95% CI: 0.97 to 1.23) people were over-represented from 2006 to 2020. In conclusion, during our study period in California, we detected disproportionate long-term wildfire PM2.5 exposure for several racial/ethnic groups.