External Exposome Research Articles

Exposome, oxidative stress and inflammation in multiple sclerosis: the EXPOSITION study protocol

Abstract Background The functional exposome approach examines the relationship between biological effects (internal exposome) and the sum of environmental exposures (external exposome). Multiple sclerosis (MS) is characterized by selective demyelination and acute inflammation; miRNAs and microbiota are emerging in the pathogenesis as inflammation and oxidative stress biomarkers. The EXPOSITION study protocol has been designed to study such biomarkers variation in response to the external exposome (air pollution, urbanization, lifestyles) in people with MS (pwMS). Methods EXPOSITION is a cross-sectional observational study collecting a sample of 200 pwMS residing in Lombardy, Northern Italy. Sample size is based on the prediction of differential expression of candidate miRNAs through bioinformatic analyses. All participants will be investigated for social, demographic and clinical data as well as general and specific external exposome factors. The internal exposome factors will be collected for each participant from blood and stool samples, as well as from nasal swabs. Exposome clustering and correlation statistical techniques will be applied and variation of miRNA and microbiota will be tested in association with the variation of the external exposome in urban and extra-urban environments. Results and conclusions The expected results will help pwMS and researchers understanding which biomarkers and which components of the external exposome are associated to oxidative stress and inflammation, to improve precision medicine and contrast disease progression. The relationship between urban exposome and biodiversity is an important dimension in the study of environmental impact on human health. This study may provide preliminary data to assess which nature-based solutions are suitable for enhancing the biodiversity of urban areas. Key messages • The functional exposome approach could be used to link environmental risk factors and disease biomarkers using the right methology. • EXPOSITION will quantify the variation of miRNA and microbiota in association with the variation of external exposome, in urban and extra-urban environments.

Lifestyle differences between co-twins are associated with decreased similarity in their internal and external exposome profiles

Whether differences in lifestyle between co-twins are reflected in differences in their internal or external exposome profiles remains largely underexplored. We therefore investigated whether within-pair differences in lifestyle were associated with within-pair differences in exposome profiles across four domains: the external exposome, proteome, metabolome and epigenetic age acceleration (EAA). For each domain, we assessed the similarity of co-twin profiles using Gaussian similarities in up to 257 young adult same-sex twin pairs (54% monozygotic). We additionally tested whether similarity in one domain translated into greater similarity in another. Results suggest that a lower degree of similarity in co-twins' exposome profiles was associated with greater differences in their behavior and substance use. The strongest association was identified between excessive drinking behavior and the external exposome. Overall, our study demonstrates how social behavior and especially substance use are connected to the internal and external exposomes, while controlling for familial confounders.

Socioeconomic position during pregnancy and pre-school exposome in children from eight European birth cohort studies

Distribution of environmental hazards and vulnerability to their effects vary across socioeconomic groups. Our objective was to analyse the relationship between child socioeconomic position (SEP) at birth and the external exposome at pre-school age (0–4 years).This study included more than 60,000 children from eight cohorts in eleven European cities (Oslo, Copenhagen, Bristol, Bradford, Rotterdam, Nancy, Poitiers, Gipuzkoa, Sabadell, Valencia and Turin). SEP was measured through maternal education and a standardised indicator of household income. Three child exposome domains were investigated: behavioral, diet and urban environment. We fitted separate logistic regression model for each exposome variable - dichotomised using the city-specific median - on SEP (medium/low vs high) adjusting for maternal age, country of birth and parity. Analyses were carried out separately in each study-area.Low-SEP children had, consistently across study-areas, lower Odds Ratios (ORs) of breastfeeding, consumption of eggs, fish, fruit, vegetables and higher ORs of TV screen time, pet ownership, exposure to second-hand smoke, consumption of dairy, potatoes, sweet beverages, savory biscuits and crisps, fats and carbohydrates. For example, maternal education-breastfeeding OR (95% Confidence Interval (CI)) ranged from 0.18 (0.14–0.24) in Bristol to 0.73 (0.58–0.90) in Oslo. SEP was also strongly associated with the urban environment with marked between-city heterogeneity. For example, income-PM2.5 OR (95%CI) ranged from 0.69 (0.47–1.02) in Sabadell to 2.44 (2.16–2.72) in Oslo.Already at pre-school age, children with lower SEP have consistently poorer diets and behaviours, which might influence their future health and wellbeing. SEP-urban environment relationships are strongly context-dependent.

Relationships between the external exposome and proteome linked to mental health risk in adolescents

Relationships between the external exposome and proteome linked to mental health risk in adolescents

An exploratory analysis of the impact of area-level exposome on geographic disparities in aggressive prostate cancer

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

The Chilean exposome-based system for ecosystems (CHiESS): a framework for national data integration and analytics platform.

The double burden of diseases and scarce resources in developing countries highlight the need to change the conceptualization of health problems and translational research. Contrary to the traditional paradigm focused on genetics, the exposome paradigm proposed in 2005 that complements the genome is an innovative theory. It involves a holistic approach to understanding the complexity of the interactions between the human being’s environment throughout their life and health. This paper outlines a scalable framework for exposome research, integrating diverse data sources for comprehensive public health surveillance and policy support. The Chilean exposome-based system for ecosystems (CHiESS) project proposes a conceptual model based on the ecological and One Health approaches, and the development of a technological dynamic platform for exposome research, which leverages available administrative data routinely collected by national agencies, in clinical records, and by biobanks. CHiESS considers a multilevel exposure for exposome operationalization, including the ecosystem, community, population, and individual levels. CHiESS will include four consecutive stages for development into an informatic platform: (1) environmental data integration and harmonization system, (2) clinical and omics data integration, (3) advanced analytical algorithm development, and (4) visualization interface development and targeted population-based cohort recruitment. The CHiESS platform aims to integrate and harmonize available secondary administrative data and provide a complete geospatial mapping of the external exposome. Additionally, it aims to analyze complex interactions between environmental stressors of the ecosystem and molecular processes of the human being and their effect on human health. Moreover, by identifying exposome-based hotspots, CHiESS allows the targeted and efficient recruitment of population-based cohorts for translational research and impact evaluation. Utilizing advanced technologies such as Artificial Intelligence (AI), Internet of Things (IoT), and blockchain, this framework enhances data security, real-time monitoring, and predictive analytics. The CHiESS model is adaptable for international use, promoting global health collaboration and supporting sustainable development goals.

Early-life external exposome in children 2–5 years old in Colombia

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

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.

Recent Advancements in the Atopic Dermatitis Mechanism.

Atopic dermatitis (AD) is a recurrent, chronic, inflammatory, itchy skin disorder that affects up to 20% of the pediatric population and 10% of the adult population worldwide. Onset typically occurs early in life, and although cardinal disease features are similar across all ages, different age groups and ethnicities present distinct clinical characteristics. The disease imposes a significant burden in all health-related quality of life domains, both in children and adults, and a substantial economic cost both at individual and national levels. The pathophysiology of AD includes a complex and multifaceted interplay between the impaired dysfunctional epidermal barrier, genetic predisposition, and environmental contributors, such as chemical and/or biological pollutants and allergens, in the context of dysregulated TH2 and TH17 skewed immune response. Regarding the genetic component, the loss of function mutations encoding structural proteins such as filaggrin, a fundamental epidermal protein, and the more recently identified variations in the epidermal differentiation complex are well-established determinants resulting in an impaired skin barrier in AD. More recently, epigenetic factors have facilitated AD development, including the dysbiotic skin microbiome and the effect of the external exposome, combined with dietary disorders. Notably, the interleukin (IL)-31 network, comprising several cell types, including macrophages, basophils, and the generated cytokines involved in the pathogenesis of itch in AD, has recently been explored. Unraveling the specific AD endotypes, highlighting the implicated molecular pathogenetic mechanisms of clinically relevant AD phenotypes, has emerged as a crucial step toward targeted therapies for personalized treatment in AD patients. This review aims to present state-of-the-art knowledge regarding the multifactorial and interactive pathophysiological mechanisms in AD.

Plaque Psoriasis Exacerbation and COVID-19 Vaccination: Assessing the Characteristics of the Flare and the Exposome Parameters.

The diverse patient population and widespread vaccination in the COVD-19 era make vaccine-triggered episodes of psoriasis an ideal model of exposome research. This scenario explores the fine balance between protective and exacerbating factors, providing insights into the complex relationship between environmental exposure and psoriasis immunopathogenesis when a trigger appears, such as that of the hyperinflammatory state induced by the COVID-19 vaccine. Analyzing interactions between vaccine-induced phenomena and exposome parameters may provide clinically relevant information important for personalized medicine decision-making. We performed a literature review seeking patients with plaque psoriasis flares or new onset or change in plaque psoriasis into another psoriasis subtype, such as pustular or erythrodermic flare, focusing on the inner and external exposome traits of patients. We identified 71 patients with plaque psoriasis flares, 12 patients with new-onset psoriasis, and 17 with plaque psoriasis subtype change, and assessed the COVID-19 vaccine-induced plaque psoriasis in terms of clinical presentation, post-vaccination flare period and treatment status, as well as inner exposome parameters (genomics, oxidative stress, hormonal impact due to gender, aging, skin color) and external parameters (UV, infectomics). Novel data on psoriasis flares following COVID-19 vaccination are primarily obtained by combining exposome and vaccine-triggered episode features and characteristics and comparing them with similar psoriasis flares unrelated to COVID-19 vaccination.

360° approach to the patient with mite allergy: from scientific evidence to clinical practice.

In the recent years, several important advances have been made in the diagnosis of allergy using molecular techniques. The aetiological diagnosis of allergy using molecular components of allergens allows a more precise definition of the patient's IgE repertoire. Precision medicine is a structural model aimed at personalising healthcare and places the patient at the centre of the specialist's decision-making process. To this end, an accurate characterisation of the external exposome at a molecular level and their putative role as clinically relevant allergens is essential to elucidate the phenotypic diversity of atopic disease, with a view to personalising diagnosis and therapy. It has been proposed a decision algorithm, the Top-Down approach, where the clinical history is set first and is followed by the use of skin tests or specific IgE techniques, which facilitates the clinicians to make decisions. The therapeutic intervention driven by the standard diagnostic approach, but supported by these innovative tools, can lead to a better phenotyping of highly complex patients, and a more appropriate prescription of AIT. To this end, the allergen extracts used for diagnosis require to be of proven quality and contain the most relevant allergens. Likewise, allergen vaccines must gather efficacy, safety, duration, and patient compliance, hence the demand for new vaccines to overcome these drawbacks.

External exposome and all-cause mortality in European cohorts: the EXPANSE project.

Many studies reported associations between long-term exposure to environmental factors and mortality; however, little is known on the combined effects of these factors and health. We aimed to evaluate the association between external exposome and all-cause mortality in large administrative and traditional adult cohorts in Europe. Data from six administrative cohorts (Catalonia, Greece, Rome, Sweden, Switzerland and the Netherlands, totaling 27,913,545 subjects) and three traditional adult cohorts (CEANS-Sweden, EPIC-NL-the Netherlands, KORA-Germany, totaling 57,653 participants) were included. Multiple exposures were assigned at the residential addresses, and were divided into three a priori defined domains: (1) air pollution [fine particulate matter (PM2.5), nitrogen dioxide (NO₂), black carbon (BC) and warm-season Ozone (warm-O3)]; (2) land/built environment (Normalized Difference Vegetation Index-NDVI, impervious surfaces, and distance to water); (3) air temperature (cold- and warm-season mean and standard deviation). Each domain was synthesized through Principal Component Analysis (PCA), with the aim of explaining at least 80% of its variability. Cox proportional-hazards regression models were applied and the total risk of the external exposome was estimated through the Cumulative Risk Index (CRI). The estimates were adjusted for individual- and area-level covariates. More than 205 million person-years at risk and more than 3.2 million deaths were analyzed. In single-component models, IQR increases of the first principal component of the air pollution domain were associated with higher mortality [HRs ranging from 1.011 (95% CI: 1.005-1.018) for the Rome cohort to 1.076 (1.071-1.081) for the Swedish cohort]. In contrast, lower levels of the first principal component of the land/built environment domain, pointing to reduced vegetation and higher percentage of impervious surfaces, were associated with higher risks. Finally, the CRI of external exposome increased mortality for almost all cohorts. The associations found in the traditional adult cohorts were generally consistent with the results from the administrative ones, albeit without reaching statistical significance. Various components of the external exposome, analyzed individually or in combination, were associated with increased mortality across European cohorts. This sets the stage for future research on the connections between various exposure patterns and human health, aiding in the planning of healthier cities.

3D Airway Epithelial-Fibroblast Biomimetic Microfluidic Platform to Unravel Engineered Nanoparticle-Induced Acute Stress Responses as Exposome Determinants.

Insights into how biological systems respond to high- and low-dose acute environmental stressors are a fundamental aspect of exposome research. However, studying the impact of low-level environmental exposure in conventional in vitro settings is challenging. This study employed a three-dimensional (3D) biomimetic microfluidic lung-on-chip (μLOC) platform and RNA-sequencing to examine the effects of two model anthropogenic engineered nanoparticles (NPs): zinc oxide nanoparticles (Nano-ZnO) and copier center nanoparticles (Nano-CCP). The airway epithelium exposed to these NPs exhibited dose-dependent increases in cytotoxicity and barrier dysregulation (dominance of the external exposome). Interestingly, even nontoxic and low-level exposure (10 μg/mL) of the epithelium compartment to Nano-ZnO triggered chemotaxis of lung fibroblasts toward the epithelium. An increase in α smooth muscle actin (α-SMA) expression and contractile activity was also observed in these cells, indicating a bystander-like adaptive response (dominance of internal exposome). Further bioinformatics and network analysis showed that a low-dose Nano-ZnO significantly induced a robust transcriptomic response and upregulated several hub genes associated with the development of lung fibrosis. We propose that Nano-ZnO, even at a no observable effect level (NOEL) dose according to conventional standards, can function as a potent nanostressor to disrupt airway epithelium homeostasis. This leads to a cascade of profibrotic events in a cross-tissue compartment fashion. Our findings offer new insights into the early acute events of respiratory harm associated with environmental NPs exposure, paving the way for better exposomic understanding of this emerging class of anthropogenic nanopollutants.

Geographic uncertainties in external exposome studies: A multi-scale approach to reduce exposure misclassification

BackgroundMany studies on environment-health associations have emphasized that the selected buffer size (i.e., the scale of the geographic context when exposures are assigned at people's address location) may affect estimated effect sizes. However, there is limited methodological progress in addressing these buffer size-related uncertainties. AimWe aimed to 1) develop a statistical multi-scale approach to address buffer-related scale effects in cohort studies, and 2) investigate how environment-health associations differ between our multi-scale approach and ad hoc selected buffer sizes. MethodsWe used lacunarity analyses to determine the largest meaningful buffer size for multiple high-resolution exposure surfaces (i.e., fine particulate matter [PM2.5], noise, and the normalized difference vegetation index [NDVI]). Exposures were linked to 7.7 million Dutch adults at their home addresses. We assigned exposure estimates based on buffers with fine-grained distance increments until the lacunarity-based upper limit was reached. Bayesian Cox model averaging addressed geographic uncertainties in the estimated exposure effect sizes within the exposure-specific upper buffer limits on mortality. Z-tests assessed statistical differences between averaged effect sizes and those obtained through pre-selected 100, 300, 1200, and 1500 m buffers. ResultsThe estimated lacunarity curves suggested exposure-specific upper buffer size limits; the largest was for NDVI (960 m), followed by noise (910 m) and PM2.5 (450 m). We recorded 845,229 deaths over eight years of follow-up. Our multi-scale approach indicated that higher values of NDVI were health-protectively associated with mortality risk (hazard ratio [HR]: 0.917, 95 % confidence interval [CI]: 0.886–0.948). Increased noise exposure was associated with an increased risk of mortality (HR: 1.003, 95 % CI: 1.002–1.003), while PM2.5 showed null associations (HR:0.998, 95 % CI: 0.997–1.000). Effect sizes of NDVI and noise differed significantly across the averaged and prespecified buffers (p < 0.05). ConclusionsGeographic uncertainties in residential-based exposure assessments may obscure environment-health associations or risk spurious ones. Our multi-scale approach produced more consistent effect estimates and mitigated contextual uncertainties.

Identification of key predictors of severe annoyance caused by railway induced vibrations using machine learning: an external exposome study

Identification of key predictors of severe annoyance caused by railway induced vibrations using machine learning: an external exposome study

Molecular Mapping of Allergen Exposome among Different Atopic Phenotypes.

Climate change and exposure to environmental pollutants play a key role in the onset and aggravation of allergic diseases. As different climate-dependent patterns of molecular immunoglobulin E (IgE) reactivity have been regionally described, we sought to investigate the evolving allergen exposome in distinctive allergic phenotypes and subtropical weather conditions through a Precision Allergy Molecular Diagnosis (PAMD@) model. Concurrent sensitization to several house dust mites (HDM) and storage mite molecules were broadly dominant in the investigated cohort, followed by the major cat allergen Fel d 1, and regardless of the basal allergic disease. Although a complex repertoire of allergens was recognized, a steadily increasing number of IgE binding molecules was associated with the complexity of the underlying atopic disease. Besides the highly prevalent IgE responses to major HDM allergens, Der p 21, Der p 5, and Der p 7 also showed up as serodominant molecules, especially in subjects bothered by asthma and atopic dermatitis. The accurate characterization of the external exposome at the molecular level and their putative role as clinically relevant allergens is essential to elucidate the phenotypic diversity of atopic disease in terms of personalized diagnosis and therapy.

Exposome: from definition to future challenges.

The exposome concept arises from the need to integrate different disciplines of public health and environmental sciences, mainly including environmental epidemiology, exposure science, and toxicology. The role of the exposome is to understand how the totality of an individual's exposures throughout the lifetime can impact human health. The etiology of a health condition is rarely explained by a single exposure. Therefore, examining the human exposome as a whole becomes relevant to simultaneously consider multiple risk factors and more accurately estimate concurrent causes of different health outcomes. Generally, the exposome is explained through three domains: general external exposome, specific external exposome, and internal exposome. The general external exposome includes measurable population-level exposures such as air pollution or meteorological factors. The specific external exposome includes information on individual exposures, such as lifestyle factors, typically obtained from questionnaires. Meanwhile, the internal exposome encompasses multiple biological responses to external factors, detected through molecular and omics analyses. Additionally, in recent decades, the socio-exposome theory has emerged, where all exposures are studied as a phenomenon dependent on the interaction between socioeconomic factors that vary depending on the context, allowing the identification of mechanisms that lead to health inequalities. The considerable production of data in exposome studies has led researchers to face new methodological and statistical challenges, introducing various approaches to estimate the effect of the exposome on health. Among the most common are regression models (Exposome-Wide Association Study - ExWAS), dimensionality reduction and exposure grouping techniques, and machine learning methods. The significant conceptual and methodological innovation of the exposome for a more holistic evaluation of the risks associated with human health is continuously expanding and will require further investigations related to the application of information obtained from studies into prevention and public health policies.

Predicting self-perceived general health status using machine learning: an external exposome study

BackgroundSelf-perceived general health (SPGH) is a general health indicator commonly used in epidemiological research and is associated with a wide range of exposures from different domains. However, most studies on SPGH only investigated a limited set of exposures and did not take the entire external exposome into account. We aimed to develop predictive models for SPGH based on exposome datasets using machine learning techniques and identify the most important predictors of poor SPGH status.MethodsRandom forest (RF) was used on two datasets based on personal characteristics from the 2012 and 2016 editions of the Dutch national health survey, enriched with environmental and neighborhood characteristics. Model performance was determined using the area under the curve (AUC) score. The most important predictors were identified using a variable importance procedure and individual effects of exposures using partial dependence and accumulated local effect plots. The final 2012 dataset contained information on 199,840 individuals and 81 variables, whereas the final 2016 dataset had 244,557 individuals with 91 variables.ResultsOur RF models had overall good predictive performance (2012: AUC = 0.864 (CI: 0.852–0.876); 2016: AUC = 0.890 (CI: 0.883–0.896)) and the most important predictors were “Control of own life”, “Physical activity”, “Loneliness” and “Making ends meet”. Subjects who felt insufficiently in control of their own life, scored high on the De Jong-Gierveld loneliness scale or had difficulty in making ends meet were more likely to have poor SPGH status, whereas increased physical activity per week reduced the probability of poor SPGH. We observed associations between some neighborhood and environmental characteristics, but these variables did not contribute to the overall predictive strength of the models.ConclusionsThis study identified that within an external exposome dataset, the most important predictors for SPGH status are related to mental wellbeing, physical exercise, loneliness, and financial status.

The Imprint of Exposome on the Development of Atopic Dermatitis across the Lifespan: A Narrative Review.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that affects more than 200 million people worldwide, including up to 20% of children and 10% of the adult population. Although AD appears frequently in childhood and often continues into adulthood, about 1 in 4 adults develop the adult-onset disease. The prenatal period, early childhood, and adolescence are considered critical timepoints for the development of AD when the exposome results in long-lasting effects on the immune system. The exposome can be defined as the measure of all the exposures of an individual during their lifetime and how these exposures relate to well-being. While genetic factors could partially explain AD onset, multiple external environmental exposures (external exposome) in early life are implicated and are equally important for understanding AD manifestation. In this review, we describe the conceptual framework of the exposome and its relevance to AD from conception and across the lifespan. Through a spatiotemporal lens that focuses on the multi-level phenotyping of the environment, we highlight a framework that embraces the dynamic complex nature of exposome and recognizes the influence of additive and interactive environmental exposures. Moreover, we highlight the need to understand the developmental origins of AD from an age-related perspective when studying the effects of the exposome on AD, shifting the research paradigm away from the per se categorized exposome factors and beyond clinical contexts to explore the trajectory of age-related exposome risks and hence future preventive interventions.

Characterization of the external exposome and its contribution to the clinical respiratory and early biological effects in children: The PROMESA cohort study protocol.

Air pollution contains a mixture of different pollutants from multiple sources. However, the interaction of these pollutants with other environmental exposures, as well as their harmful effects on children under five in tropical countries, is not well known. This study aims to characterize the external exposome (ambient and indoor exposures) and its contribution to clinical respiratory and early biological effects in children. A cohort study will be conducted on children under five (n = 500) with a one-year follow-up. Enrolled children will be followed monthly (phone call) and at months 6 and 12 (in person) post-enrolment with upper and lower Acute Respiratory Infections (ARI) examinations, asthma development, asthma control, and genotoxic damage. The asthma diagnosis will be pediatric pulmonologist-based and a standardized protocol will be used. Exposure, effect, and susceptibility biomarkers will be measured on buccal cells samples. For environmental exposures PM2.5 will be sampled, and questionnaires, geographic information, dispersion models and Land Use Regression models for PM2.5 and NO2 will be used. Different statistical methods that include Bayesian and machine learning techniques will be used for the ambient and indoor exposures-and outcomes. This study was approved by the ethics committee at Universidad Pontificia Bolivariana. To estimate i) The toxic effect of particulate matter transcending the approach based on pollutant concentration levels; ii) The risk of developing an upper and lower ARI, based on different exposure windows; iii) A baseline of early biological damage in children under five, and describe its progression after a one-year follow-up; and iv) How physical and chemical PM2.5 characteristics influence toxicity and children's health.