The exposome recognizes that individuals are exposed simultaneously to a multitude of different environmental factors and takes a holistic approach to the discovery of etiological factors for disease. However, challenges arise when trying to quantify the health effects of complex exposure mixtures. Analytical challenges include dealing with high dimensionality, studying the combined effects of these exposures and their interactions, integrating causal pathways, and integrating high-throughput omics layers. To tackle these challenges, the Barcelona Institute for Global Health (ISGlobal) held a data challenge event open to researchers from all over the world and from all expertises. Analysts had a chance to compete and apply state-of-the-art methods on a common partially simulated exposome dataset (based on real case data from the HELIX project) with multiple correlated exposure variables (P > 100 exposure variables) arising from general and personal environments at different time points, biological molecular data (multi-omics: DNA methylation, gene expression, proteins, metabolomics) and multiple clinical phenotypes in 1301 mother-child pairs. Most of the methods presented included feature selection or feature reduction to deal with the high dimensionality of the exposome dataset. Several approaches explicitly searched for combined effects of exposures and/or their interactions using linear index models or response surface methods, including Bayesian methods. Other methods dealt with the multi-omics dataset in mediation analyses using multiple-step approaches. Here we discuss features of the statistical models used and provide the data and codes used, so that analysts have examples of implementation and can learn how to use these methods. Overall, the exposome data challenge presented a unique opportunity for researchers from different disciplines to create and share state-of-the-art analytical methods, setting a new standard for open science in the exposome and environmental health field.

Prenatal exposure to persistent organic pollutants (POPs) has been linked to cardiometabolic (CM) risk factors in childhood, but there are no studies evaluating the persistence of these associations into adolescence, a period of relevant changes in endocrine-dependent organ systems and rapid increases in lean and fat mass. We examined the associations of prenatal POP exposures with body mass index (BMI) from age 4 to 18 years, and with other CM risk markers in adolescence. We analysed 379 children from the Spanish INMA-Menorca birth cohort study with measured cord blood POP concentrations. We calculated BMI z-scores at ages 4, 6, 11, 14 and 18 years using the WHO growth reference. Body fat % was measured at 11 and 18 years and waist-to-height ratio (WHtR) and blood pressure (BP) at 11, 14 and 18 years. We measured CM biomarkers in fasting blood collected at age 14 years and calculated a CM-risk score as the sum of the sex-, and age-specific z-scores for waist circumference, mean arterial BP, homeostatic model assessment of insulin resistance, fasting blood triglycerides, and high-density lipoprotein cholesterol (HDL-C) (n = 217). Generalised estimating equations and multivariate linear regression models assessed the associations with repeated and single time-point measures, respectively. Hexachlorobenzene (HCB) exposure in the third tertile, compared to the first tertile, was associated with higher BMI (β = 0.24; 95% CI: 0.01, 0.47) and WHtR z-score (β = 0.27; 95% CI: 0.04, 0.51). A continuous increase in HCB was associated with an elevated body fat % (β per 10-fold increase = 4.21; 95% CI: 0.51, 7.92), systolic BP (β = 0.32; 95% CI: 0.02, 0.64) and diastolic BP z-score (β = 0.32; 95% CI: 0.02, 0.62) across all ages, and with higher CM-risk score (β = 1.59; 95% CI: 0.02, 3.18) and lipid biomarkers (total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C)) at 14 years. Dichlorodiphenyltrichloroethane (p,p'-DDT) exposure was non-monotonically associated with BMI and systolic BP. p,p'-DDE and Σ-polychlorinated biphenyls (PCBs) (sum of congeners 118, 138, 153, 180) were not associated with adiposity or BP. p,p'-DDT exposure was associated with an increased CM-risk score, and ΣPCBs concentrations with LDL-C in all adolescents and with total cholesterol only in girls (p-sex interaction = 0.05). This first longitudinal study from 4 to 18 years suggests that the previously reported POP associations with child BMI persist later in adolescence and that prenatal POP exposures are associated with major risk factors for adult CM syndrome.

The impact of legacy per- and polyfluoroalkyl substances (PFAS) on fetal growth has been well studied, but assessments of next-generation PFAS and PFAS mixtures are sparse and the potential role of fetoplacental hemodynamics has not been studied. We aimed to evaluate associations between prenatal PFAS exposure and fetal growth and fetoplacental hemodynamics. We included 747 pregnant women from the BiSC birth cohort (Barcelona, Spain (2018-2021)). Twenty-three PFAS were measured at 32 weeks of pregnancy in maternal plasma, of which 13 were present above detectable levels. Fetal growth was measured by ultrasound, as estimated fetal weight at 32 and 37 weeks of gestation, and weight at birth. Doppler ultrasound measurements for uterine (UtA), umbilical (UmA), and middle cerebral artery (MCA) pulsatility indices (PI), as well as the cerebroplacental ratio (CPR - ratio MCA to UmA), were obtained at 32 weeks to assess fetoplacental hemodynamics. We applied linear mixed effects models to assess the association between singular PFAS and longitudinal fetal growth and PI, and Bayesian Weighted Quantile Sum models to evaluate associations between the PFAS mixture and the aforementioned outcomes, controlled for the relevant covariates. Single PFAS and the mixture tended to be associated with reduced fetal growth and CPR PI, but few associations reached statistical significance. Legacy PFAS PFOS, PFHpA, and PFDoDa were associated with statistically significant decreases in fetal weight z-score of 0.13 (95%CI (-0.22, -0.04), 0.06 (-0.10, 0.01), and 0.05 (-0.10, 0.00), respectively, per doubling of concentration. The PFAS mixture was associated with a non-statistically significant 0.09 decrease in birth weight z-score (95%CI -0.22, 0.04) per quartile increase. This study suggests that legacy PFAS may be associated with reduced fetal growth, but associations for next generation PFAS and for the PFAS mixture were less conclusive. Associations between PFAS and fetoplacental hemodynamics warrant further investigation.

Exposure to non-persistent endocrine disrupting chemicals (EDCs) is widespread, causing various adverse health effects, especially during pregnancy. Diet is a major source of EDCs and the identification of dietary patterns that give rise to higher exposure levels is crucial. We aimed to explore the relationship between dietary patterns during pregnancy and exposure to non-persistent EDCs. We included 640 pregnant women from the Barcelona Life Study Cohort (BiSC), Spain. Using food frequency questionnaires (2nd trimester), we estimated ultraprocessed food (UPF) consumption and Mediterranean diet adherence, and derived data-driven dietary patterns. Metabolites of phthalates, 1,2-cyclohexane dicarboxylic acid di(isononyl) ester (DINCH), chlorpyrifos and pyrethroid, polycyclic aromatic hydrocarbons (PAHs, including phenanthrenes), and organophosphates, and parent compounds of phenols and parabens were measured in weekly urine pools (3rd trimester). Associations between dietary patterns and EDCs were evaluated through multivariable linear regressions. Higher compliance with a "Vegetarian" pattern or the Mediterranean diet was associated with lower levels of some of the phthalate metabolites (e.g., di-iso-nonyl phthalates [Geometric mean ratio (GMR) per unit increases in the "Vegetarian" score = 0.97, 95 %CI 0.95, 1.00]). Conversely, "Western" and "Animal protein" patterns, and UPF intake were associated with higher PAHs (e.g., "Western" and 2-Hydroxynaphthalene [GMR(95 %CI) 1.07(1.01, 1.13)]), pesticides (e.g., "Animal protein" and 3-Phenoxybenzoic acid [1.15(1.01, 1.32]), and phthalates metabolites levels (e.g., UPF and Monoethyl phthalate [1.05(1.01, 1.09)]). No association remained significant after correcting for multiple testing. Following a plant-based diet may help reduce the exposure to certain phthalate and organophosphate metabolites, whereas higher consumption of foods from animal origin and high in fat/sugar/salt may increase exposure to PAHs, pesticides, and phthalates metabolites in pregnancy.

Type 2 Diabetes (T2D) is a major health concern in Sweden, where prevalence rates have been increasing in socioeconomically disadvantaged areas. Self-Determination Theory (SDT) is posited as an optimal framework to build interventions targeted to improve and maintain long-term healthy habits preventing and delaying the onset of T2D. However, research on SDT, T2D and diet has been widely overlooked in socio-economically disadvantaged populations. This study aims to identify the main dietary patterns of adults at risk of and with T2D from two socio-economically disadvantaged Stockholm areas and to determine the association between those patterns and selected SDT constructs (relatedness, autonomy motivation and competence). Cross-sectional data of 147 participants was collected via questionnaires. Exploratory Factor Analysis was used to identify participants’ main dietary patterns. Multiple linear regressions were conducted to assess associations between the SDT and diet behaviours, and path analysis was used to explore mediations. Two dietary patterns (healthy and unhealthy) were identified. Competence construct was most strongly associated with healthy diet. Autonomous motivation and competence mediated the effect of relatedness on diet behaviour. In conclusion, social surroundings can promote adults at high risk of or with T2D to sustain healthy diets by supporting their autonomous motivation and competence.

Exposure to endocrine-disrupting chemicals (EDCs) during pregnancy may influence the placenta and fetal growth; however, evidence is scarce regarding EDC mixtures, newer chemicals, and the role of angiogenic biomarkers and fetoplacental hemodynamics. We aimed to examine the associations between nonpersistent EDC mixtures and fetal growth, fetoplacental hemodynamics, and angiogenic biomarkers. We included 734 pregnant participants from the Barcelona Life Study Cohort (BiSC), Spain (2018-2021). Metabolites of phthalates, DINCH, insecticides, polycyclic aromatic hydrocarbons, pesticides, flame retardants, and parent compounds of phenols and parabens were measured in pools of week-long maternal urine samples at 18 and 34 weeks' gestation. Penalized LASSO-type multigroup Bayesian Weighted Quantile Sum Regression estimated associations with fetal growth, fetoplacental hemodynamics, and angiogenic biomarkers. Birthweight z-score decreased with low-molecular-weight phthalate (LMWP) (β = -0.119; CrI -0.224, -0.008) mixtures and increased with organophosphate mixtures (β = 0.143; CrI 0.042, 0.245). LMWP exposure was also associated with altered hemodynamics and angiogenic biomarkers; angiogenic biomarkers mediated the relationship with birthweight z-score (ACME = -0.032; 95% CI -0.062, -0.009; p = 0.002). This comprehensive study suggests that mixtures of low-molecular-weight phthalates and organophosphate compounds may alter fetal growth and that angiogenic biomarkers may play a role as mediator.