A blueprint for a new commercial driving epidemiology: An emerging paradigm grounded in integrative exposome and network epistemologies.

Excess health and safety risks of commercial drivers are largely determined by, embedded in, or operate as complex, dynamic, and randomly determined systems with interacting parts. Yet, prevailing epidemiology is entrenched in narrow, deterministic, and static exposure-response frameworks along with ensuing inadequate data and limiting methods, thereby perpetuating an incomplete understanding of commercial drivers' health and safety risks. This paper is grounded in our ongoing research that conceptualizes health and safety challenges of working people as multilayered "wholes" of interacting work and nonwork factors, exemplified by complex-systems epistemologies. Building upon and expanding these assumptions, herein we: (a) discuss how insights from integrative exposome and network-science-based frameworks can enhance our understanding of commercial drivers' chronic disease and injury burden; (b) introduce the "working life exposome of commercial driving" (WLE-CD)-an array of multifactorial and interdependent work and nonwork exposures and associated biological responses that concurrently or sequentially impact commercial drivers' health and safety during and beyond their work tenure; (c) conceptualize commercial drivers' health and safety risks as multilayered networks centered on the WLE-CD and network relational patterns and topological properties-that is, arrangement, connections, and relationships among network components-that largely govern risk dynamics; and (d) elucidate how integrative exposome and network-science-based innovations can contribute to a more comprehensive understanding of commercial drivers' chronic disease and injury risk dynamics. Development, validation, and proliferation of this emerging discourse can move commercial driving epidemiology to the frontier of science with implications for policy, action, other working populations, and population health at large.

A toxicological perspective on climate change and the exposome.

Climate change is accompanied by changes in the exposome, including increased heat, ground-level ozone, and other air pollutants, infectious agents, pollens, and psychosocial stress. These exposures alter the internal component of the exposome and account for some of the health effects of climate change. The adverse outcome pathways describe biological events leading to an unfavorable health outcome. In this perspective study, I propose to use this toxicological framework to better describe the biological steps linking a stressor associated with climate change to an adverse outcome. Such a framework also allows for better identification of possible interactions between stressors related to climate change and others, such as chemical pollution. More generally, I call for the incorporation of climate change as part of the exposome and for improved identification of the biological pathways involved in its health effects.

Understanding the Cardiovascular and Metabolic Health Effects of Air Pollution in the Context of Cumulative Exposomic Impacts.

Poor air quality accounts for more than 9 million deaths a year globally according to recent estimates. A large portion of these deaths are attributable to cardiovascular causes, with evidence indicating that air pollution may also play an important role in the genesis of key cardiometabolic risk factors. Air pollution is not experienced in isolation but is part of a complex system, influenced by a host of other external environmental exposures, and interacting with intrinsic biologic factors and susceptibility to ultimately determine cardiovascular and metabolic outcomes. Given that the same fossil fuel emission sources that cause climate change also result in air pollution, there is a need for robust approaches that can not only limit climate change but also eliminate air pollution health effects, with an emphasis of protecting the most susceptible but also targeting interventions at the most vulnerable populations. In this review, we summarize the current state of epidemiologic and mechanistic evidence underpinning the association of air pollution with cardiometabolic disease and how complex interactions with other exposures and individual characteristics may modify these associations. We identify gaps in the current literature and suggest emerging approaches for policy makers to holistically approach cardiometabolic health risk and impact assessment.

Association of the external environmental exposome and obesity: A comprehensive nationwide study in 2019 among Chinese children and adolescents.

OBJECTIVE: Children and adolescents are particularly vulnerable to the effects of various environmental factors, which could disrupt growth processes and potentially lead to obesity. Currently, comprehensive and systematic assessments of these environmental exposures during developmental periods are lacking. Therefore, this study aims to evaluate the association between external environmental exposures and the incidence of obesity in children and adolescents. METHODS: Data was collected from the 2019 Chinese National Survey on Students' Constitution and Health, including 214,659 Han children aged 7 to 19. Body Mass Index (BMI) and BMI-for-age z-score (zBMI) were the metrics used to assess overweight and obesity prevalence. The study assessed 18 environmental factors, including air pollutants, natural space, land cover, meteorological conditions, built environment, road conditions, and artificial light at night. Exposome-wide association study (ExWAS) to analyze individual exposures' associations with health outcomes, and Weighted Quantile Sum (WQS) to assess cumulative exposure effects. RESULTS: Among the children and adolescents, there were 24.2 % participants classified as overweight or obesity. Notably, 17 out of 18 environmental factors exhibited significant associations with zBMI and overweight/obesity. Seven air pollutants, road conditions, and built density were positively correlated with higher zBMI and obesity risk, while NDVI, forests, and meteorological factors showed negative correlations. Co-exposure analysis highlighted that SO2, ALAN, PM10, and trunk road density significantly increased zBMI, whereas rainfall, grassland, and forest exposure reduced it. Theoretically reduction in the number and prevalence of cases was calculated, indicating potential reductions in prevalence of up to 4.51 % for positive exposures and 5.09 % for negative exposures. Notably, substantial reductions were observed in regions with high pollution levels. CONCLUSION: This large-scale investigation, encompassing various environmental exposures in schools, highlights the significant impact of air pollution, road characteristics, rainfall, and forest coverage on childhood obesity.

Socio-demographic inequalities influence differences in the chemical exposome among Swedish adolescents.

Relatively little is known about the relationship between socio-demographic factors and the chemical exposome in adolescent populations. This knowledge gap hampers global efforts to meet certain UN sustainability goals. The present work addresses this problem in Swedish adolescents by discerning patterns within the chemical exposome and identify demographic groups susceptible to heightened exposures. Enlisting the Riksmaten Adolescents 2016-17 (RMA) study population (N = 1082) in human-biomonitoring, and using proportional odds ordinal logistic regression models, we examined the associations between concentrations of a diverse array of substances (N = 63) with the determinants: gender, age, participant/maternal birth country income per capita level, parental education levels, and geographic place of living (longitude/latitude). Participant/maternal birth country exhibited a significant association with the concentrations of 46 substances, followed by gender (N = 41), and longitude (N = 37). Notably, individuals born in high-income countries by high-income country mothers demonstrated substantially higher estimated adjusted means (EAM) concentrations of polychlorinated biphenyls (PCBs), brominated flame retardants (BFRs) and per- and polyfluoroalkyl substances (PFASs) compared to those born in low-income countries by low-income country mothers. A reverse trend was observed for cobalt (Co), cadmium (Cd), lead (Pb), aluminium (Al), chlorinated pesticides, and phthalate metabolites. Males exhibited higher EAM concentrations of chromium (Cr), mercury (Hg), Pb, PCBs, chlorinated pesticides, BFRs and PFASs than females. In contrast, females displayed higher EAM concentrations of Mn, Co, Cd and metabolites of phthalates and phosphorous flame retardants, and phenolic substances. Geographical disparities, indicative of north-to-south or west-to-east substance concentrations gradients, were identified in Sweden. Only a limited number of lifestyle, physiological and dietary factors were identified as possible drivers of demographic inequalities for specific substances. This research underscores birth country, gender, and geographical disparities as contributors to exposure differences among Swedish adolescents. Identifying underlying drivers is crucial to addressing societal inequalities associated with chemical exposure and aligning with UN sustainability goals.

Environmental Exposome and Atrial Fibrillation: Emerging Evidence and Future Directions.

There has been increased awareness of the linkage between environmental exposures and cardiovascular health and disease. Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting millions of people worldwide and contributing to substantial morbidity and mortality. Although numerous studies have explored the role of genetic and lifestyle factors in the development and progression of atrial fibrillation, the potential impact of environmental determinants on this prevalent condition has received comparatively less attention. This review aims to provide a comprehensive overview of the current evidence on environmental determinants of atrial fibrillation, encompassing factors such as air pollution, temperature, humidity, and other meteorologic conditions, noise pollution, greenspace, and the social environment. We discuss the existing evidence from epidemiological and mechanistic studies, critically evaluating the strengths and limitations of these investigations and the potential underlying biological mechanisms through which environmental exposures may affect atrial fibrillation risk. Furthermore, we address the potential implications of these findings for public health and clinical practice and identify knowledge gaps and future research directions in this emerging field.

Adopting Mechanistic Molecular Biology Approaches in Exposome Research for Causal Understanding.

Through investigating the combined impact of the environmental exposures experienced by an individual throughout their lifetime, exposome research provides opportunities to understand and mitigate negative health outcomes. While current exposome research is driven by epidemiological studies that identify associations between exposures and effects, new frameworks integrating more substantial population-level metadata, including electronic health and administrative records, will shed further light on characterizing environmental exposure risks. Molecular biology offers methods and concepts to study the biological and health impacts of exposomes in experimental and computational systems. Of particular importance is the growing use of omics readouts in epidemiological and clinical studies. This paper calls for the adoption of mechanistic molecular biology approaches in exposome research as an essential step in understanding the genotype and exposure interactions underlying human phenotypes. A series of recommendations are presented to make the necessary and appropriate steps to move from exposure association to causation, with a huge potential to inform precision medicine and population health. This includes establishing hypothesis-driven laboratory testing within the exposome field, supported by appropriate methods to read across from model systems research to human.

Geospatial Science for the Environmental Epidemiology of Cancer in the Exposome Era.

Geospatial science is the science of location or place that harnesses geospatial tools, such as geographic information systems (GIS), to understand the features of the environment according to their locations. Geospatial science has been transformative for cancer epidemiologic studies through enabling large-scale environmental exposure assessments. As the research paradigm for the exposome, or the totality of environmental exposures across the life course, continues to evolve, geospatial science will serve a critical role in determining optimal practices for how to measure the environment as part of the external exposome. The objectives of this article are to provide a summary of key concepts, present a conceptual framework that illustrates how geospatial science is applied to environmental epidemiology in practice and through the lens of the exposome, and discuss the following opportunities for advancing geospatial science in cancer epidemiologic research: enhancing spatial and temporal resolutions and extents for geospatial data; geospatial methodologies to measure climate change factors; approaches facilitating the use of patient addresses in epidemiologic studies; combining internal exposome data and geospatial exposure models of the external exposome to provide insights into biological pathways for environment-disease relationships; and incorporation of geospatial data into personalized cancer screening policies and clinical decision making.

Hair-Derived Exposome Exploration of Cardiometabolic Health: Piloting a Bayesian Multitrait Variable Selection Approach.

Cardiometabolic health is complex and characterized by an ensemble of correlated and/or co-occurring conditions including obesity, dyslipidemia, hypertension, and diabetes mellitus. It is affected by social, lifestyle, and environmental factors, which in-turn exhibit complex correlation patterns. To account for the complexity of (i) exposure profiles and (ii) health outcomes, we propose to use a multitrait Bayesian variable selection approach and identify a sparse set of exposures jointly explanatory of the complex cardiometabolic health status. Using data from a subset (N = 941 participants) of the nutrition, environment, and cardiovascular health (NESCAV) study, we evaluated the link between measurements of the cumulative exposure to (N = 33) pollutants derived from hair and cardiometabolic health as proxied by up to nine measured traits. Our multitrait analysis showed increased statistical power, compared to single-trait analyses, to detect subtle contributions of exposures to a set of clinical phenotypes, while providing parsimonious results with improved interpretability. We identified six exposures that were jointly explanatory of cardiometabolic health as modeled by six complementary traits, of which, we identified strong associations between hexachlorobenzene and trifluralin exposure and adverse cardiometabolic health, including traits of obesity, dyslipidemia, and hypertension. This supports the use of this type of approach for the joint modeling, in an exposome context, of correlated exposures in relation to complex and multifaceted outcomes.

Association between Ambient Volatile Organic Compounds Exposome and Emergency Hospital Admissions for Cardiovascular Disease.

The limited research on volatile organic compounds (VOCs) has not taken into account the interactions between constituents. We used the weighted quantile sum (WQS) model and generalized linear model (GLM) to quantify the joint effects of ambient VOCs exposome and identify the substances that play key roles. For a 0 day lag, a quartile increase of WQS index for n-alkanes, iso/anti-alkanes, aromatic, halogenated aromatic hydrocarbons, halogenated saturated chain hydrocarbons, and halogenated unsaturated chain hydrocarbons were associated with 1.09% (95% CI: 0.13, 2.06%), 0.98% (95% CI: 0.22, 1.74%), 0.92% (95% CI: 0.14, 1.69%), 1.03% (95% CI: 0.14, 1.93%), 1.69% (95% CI: 0.48, 2.91%), and 1.85% (95% CI: 0.93, 2.79%) increase in cardiovascular disease (CVD) emergency hospital admissions, respectively. Independent effects of key substances on CVD-related emergency hospital admissions were also reported. In particular, an interquartile range increase in 1,1,1-trichloroethane, methylene chloride, styrene, and methylcyclohexane is associated with a greater risk of CVD-associated emergency hospital admissions [3.30% (95% CI: 1.93, 4.69%), 3.84% (95% CI: 1.21, 6.53%), 5.62% (95% CI: 1.35, 10.06%), 8.68% (95% CI: 3.74, 13.86%), respectively]. We found that even if ambient VOCs are present at a considerably low concentration, they can cause cardiovascular damage. This should prompt governments to establish and improve concentration standards for VOCs and their sources. At the same time, policies should be introduced to limit VOCs emission to protect public health.

An exposome atlas of serum reveals the risk of chronic diseases in the Chinese population.

Although adverse environmental exposures are considered a major cause of chronic diseases, current studies provide limited information on real-world chemical exposures and related risks. For this study, we collected serum samples from 5696 healthy people and patients, including those with 12 chronic diseases, in China and completed serum biomonitoring including 267 chemicals via gas and liquid chromatography-tandem mass spectrometry. Seventy-four highly frequently detected exposures were used for exposure characterization and risk analysis. The results show that region is the most critical factor influencing human exposure levels, followed by age. Organochlorine pesticides and perfluoroalkyl substances are associated with multiple chronic diseases, and some of them exceed safe ranges. Multi-exposure models reveal significant risk effects of exposure on hyperlipidemia, metabolic syndrome and hyperuricemia. Overall, this study provides a comprehensive human serum exposome atlas and disease risk information, which can guide subsequent in-depth cause-and-effect studies between environmental exposures and human health.

Associations of environmental factors with neurodegeneration: An exposome-wide Mendelian randomization investigation.

Neurodegenerative diseases (NDDs) remain a global health challenge. Previous studies have reported potential links between environmental factors and NDDs, however, findings remain controversial across studies and elusive to be interpreted as evidence of robust causal associations. In this study, we comprehensively explored the causal associations of the common environmental factors with major NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), based on updated large-scale genome-wide association study data through two-sample Mendelian randomization (MR) approach. Our results indicated that, overall, 28 significant sets of exposure-outcome causal association evidence were detected, 12 of which were previously underestimated and newly identified, including average weekly beer plus cider intake, strenuous sports or other exercises, diastolic blood pressure, and body fat percentage with AD, alcohol intake frequency with PD, apolipoprotein B, systolic blood pressure, and forced expiratory volume in 1 s (FEV1) with ALS, and alcohol intake frequency, hip circumference, forced vital capacity, and FEV1 with MS. Moreover, the causal effects of several environmental factors on NDDs were found to overlap. From a triangulation perspective, our investigation provided insights into understanding the associations of environmental factors with NDDs, providing causality-oriented evidence to establish the risk profile of NDDs.

Nature-versus-nurture considered harmful: Actionability as an alternative tool for understanding the exposome from an ethical perspective.

Exposome research is put forward as a major tool for solving the nature-versus-nurture debate because the exposome is said to represent "the nature of nurture." Against this influential idea, we argue that the adoption of the nature-versus-nurture debate into the exposome research program is a mistake that needs to be undone to allow for a proper bioethical assessment of exposome research. We first argue that this adoption is originally based on an equivocation between the traditional nature-versus-nurture debate and a debate about disease prediction/etiology. Second, due to this mistake, exposome research is pushed to adopt a limited conception of agential control that is harmful to one's thinking about the good that exposome research can do for human health and wellbeing. To fully excise the nature-versus-nurture debate from exposome research, we argue that exposome researchers and bioethicists need to think about the exposome afresh from the perspective of actionability. We define the concept of actionability and related concepts and show how these can be used to analyze the ethical aspects of the exposome. In particular, we focus on refuting the popular "gun analogy" in exposome research, returning results to study participants and risk-taking in the context of a well-lived life.

Longitudinal Mapping of Personal Biotic and Abiotic Exposomes and Transcriptome in Underwater Confined Space Using Wearable Passive Samplers.

Silicone-based passive samplers, commonly paired with gas chromatography-mass spectrometry (GC-MS) analysis, are increasingly utilized for personal exposure assessments. However, its compatibility with the biotic exposome remains underexplored. In this study, we introduce the wearable silicone-based AirPie passive sampler, coupled with nontargeted liquid chromatography with high-resolution tandem mass spectrometry (LC-HRMS/MS), GC-HRMS, and metagenomic shotgun sequencing methods, offering a comprehensive view of personalized airborne biotic and abiotic exposomes. We applied the AirPie samplers to 19 participants in a unique deep underwater confined environment, annotating 4,390 chemical and 2,955 microbial exposures, integrated with corresponding transcriptomic data. We observed significant shifts in environmental exposure and gene expression upon entering this unique environment. We noted increased exposure to pollutants, such as benzenoids, polycyclic aromatic hydrocarbons (PAHs), opportunistic pathogens, and associated antibiotic-resistance genes (ARGs). Transcriptomic analyses revealed the activation of neurodegenerative disease-related pathways, mostly related to chemical exposure, and the repression of immune-related pathways, linked to both biological and chemical exposures. In summary, we provided a comprehensive, longitudinal exposome map of the unique environment and underscored the intricate linkages between external exposures and human health. We believe that the AirPie sampler and associated analytical methods will have broad applications in exposome and precision medicine.

Medication use and risk of amyotrophic lateral sclerosis: using machine learning for an exposome-wide screen of a large clinical database.

BACKGROUND: Accumulating evidence suggests that non-genetic factors have important etiologic roles in amyotrophic lateral sclerosis (ALS), yet identification of specific culprit factors has been challenging. Many medications target biological pathways implicated in ALS pathogenesis, and screening large pharmacologic datasets for signals could greatly accelerate the identification of risk-modulating pharmacologic factors for ALS. METHOD: We conducted a high-dimensional screening of patients' history of medication use and ALS risk using an advanced machine learning approach based on gradient-boosted decision trees coupled with Bayesian model optimization and repeated data sampling. Clinical and medication dispensing data were obtained from a large Israeli health fund for 501 ALS cases and 4,998 matched controls using a lag period of 3 or 5 years prior to ALS diagnosis for ascertaining medication exposure. RESULTS: Of over 1,000 different medication classes, we identified 8 classes that were consistently associated with increased ALS risk across independently trained models, where most are indicated for control of symptoms implicated in ALS. Some suggestive protective effects were also observed, notably for vitamin E. DISCUSSION: Our results indicate that use of certain medications well before the typically recognized prodromal period was associated with ALS risk. This could result because these medications increase ALS risk or could indicate that ALS symptoms can manifest well before suggested prodromal periods. The results also provide further evidence that vitamin E may be a protective factor for ALS. Targeted studies should be performed to elucidate the possible pathophysiological mechanisms while providing insights for therapeutics design.

Environmental Interventions for Preventing Atopic Diseases.

PURPOSE OF REVIEW: In this review, we detail the exposome (consisting of environmental factors such as diet, microbial colonization, allergens, pollutants, and stressors), mechanistic and clinical research supporting its influence on atopic disease, and potentiation from climate change. We highlight contemporary environmental interventions and available evidence substantiating their roles in atopic disease prevention, from observational cohorts to randomized controlled trials, when available. RECENT FINDINGS: Early introduction to allergenic foods is an effective primary prevention strategy to reduce food allergy. Diverse dietary intake also appears to be a promising strategy for allergic disease prevention, but additional study is necessary. Air pollution and tobacco smoke are highly associated with allergic disease, among other medical comorbidities, paving the way for campaigns and legislation to reduce these exposures. There is no clear evidence that oral vitamin D supplementation, prebiotic or probiotic supplementation, daily emollient application, and antiviral prophylaxis are effective in preventing atopic disease, but these interventions require further study. While some environmental interventions have a well-defined role in the prevention of atopic disease, additional study of many remaining interventions is necessary to enhance our understanding of their role in disease prevention. Alignment of research findings from randomized controlled trials with public policy is essential to develop meaningful public health outcomes and prevent allergic disease on the population level.

Two cosmoses, one universe: a narrative review exploring the gut microbiome's role in the effect of urban risk factors on vascular ageing.

In the face of rising global urbanisation, understanding how the associated environment and lifestyle impact public health is a cornerstone for prevention, research, and clinical practice. Cardiovascular disease is the leading cause of morbidity and mortality worldwide, with urban risk factors contributing greatly to its burden. The current narrative review adopts an exposome approach to explore the effect of urban-associated physical-chemical factors (such as air pollution) and lifestyle on cardiovascular health and ageing. In addition, we provide new insights into how these urban-related factors alter the gut microbiome, which has been associated with an increased risk of cardiovascular disease. We focus on vascular ageing, before disease onset, to promote preventative research and practice. We also discuss how urban ecosystems and social factors may interact with these pathways and provide suggestions for future research, precision prevention and management of vascular ageing. Most importantly, future research and decision-making would benefit from adopting an exposome approach and acknowledging the diverse and boundless universe of the microbiome.

Modeling the impact of urban and hospital eco-exposomes on antibiotic-resistance dynamics in wastewaters.

The emergence and selection of antibiotic resistance is a major public health problem worldwide. The presence of antibiotic-resistant bacteria (ARBs) in natural and anthropogenic environments threatens the sustainability of efforts to reduce resistance in human and animal populations. Here, we use mathematical modeling of the selective effect of antibiotics and contaminants on the dynamics of bacterial resistance in water to analyze longitudinal spatio-temporal data collected in hospital and urban wastewater between 2012 and 2015. Samples were collected monthly during the study period at four different sites in Haute-Savoie, France: hospital and urban wastewater, before and after water treatment plants. Three different categories of exposure variables were collected simultaneously: 1) heavy metals, 2) antibiotics and 3) surfactants for a total of 13 drugs/molecules; in parallel to the normalized abundance of 88 individual genes and mobile genetic elements, mostly conferring resistance to antibiotics. A simple hypothesis-driven model describing weekly antibiotic resistance gene (ARG) dynamics was proposed to fit the available data, assuming that normalized gene abundance is proportional to antibiotic resistant bacteria (ARB) populations in water. The detected compounds were found to influence the dynamics of 17 genes found at multiple sites. While mercury and vancomycin were associated with increased ARG and affected the dynamics of 10 and 12 identified genes respectively, surfactants antagonistically affected the dynamics of three genes. The models proposed here make it possible to analyze the relationship between the persistence of resistance genes in the aquatic environment and specific compounds associated with human activities from longitudinal data. Our analysis of French data over 2012-2015 identified mercury and vancomycin as co-selectors for some ARGs.

Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions.

Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways.

Organisms adapt to their environment through different pathways. In vertebrates, xenobiotics are detected, metabolized and eliminated through the inducible xenobiotic-metabolizing pathways (XMP) which can also generate reactive toxic intermediates. In this review, we will discuss the impacts of the chemical exposome complexity on the balance between detoxication and side effects. There is a large discrepancy between the limited number of proteins involved in these pathways (few dozens) and the diversity and complexity of the chemical exposome (tens of thousands of chemicals). Several XMP proteins have a low specificity which allows them to bind and/or metabolize a large number of chemicals. This leads to undesired consequences, such as cross-inhibition, inefficient metabolism, release of toxic intermediates, etc. Furthermore, several XMP proteins have endogenous functions that may be disrupted upon exposure to exogenous chemicals. The gut microbiome produces a very large number of metabolites that enter the body and are part of the chemical exposome. It can metabolize xenobiotics and either eliminate them or lead to toxic derivatives. The complex interactions between chemicals of different origins will be illustrated by the diverse roles of the aryl hydrocarbon receptor which binds and transduces the signals of a large number of xenobiotics, microbiome metabolites, dietary chemicals and endogenous compounds. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'.