Weight of evidence evaluation of the metabolism disrupting effects of triphenyl phosphate using an expert knowledge elicitation approach.

Identification of Endocrine-Disrupting Chemicals (EDCs) in a regulatory context requires a high level of evidence. However, lines of evidence (e.g. human, in vivo, in vitro or in silico) are heterogeneous and incomplete for quantifying evidence of the adverse effects and mechanisms involved. To date, for the regulatory appraisal of metabolism-disrupting chemicals (MDCs), no harmonised guidance to assess the weight of evidence has been developed at the EU or international level. To explore how to develop this, we applied a formal Expert Knowledge Elicitation (EKE) approach within the European GOLIATH project. EKE captures expert judgment in a quantitative manner and provides an estimate of uncertainty of the final opinion. As a proof of principle, we selected one suspected MDC -triphenyl phosphate (TPP) - based on its related adverse endpoints (obesity/adipogenicity) relevant to metabolic disruption and a putative Molecular Initiating Event (MIE): activation of peroxisome proliferator activated receptor gamma (PPARγ). We conducted a systematic literature review and assessed the quality of the lines of evidence with two independent groups of experts within GOLIATH, with the objective of categorising the metabolic disruption properties of TPP, by applying an EKE approach. Having followed the entire process separately, both groups arrived at the same conclusion, designating TPP as a "suspected MDC" with an overall quantitative agreement exceeding 85%, indicating robust reproducibility. The EKE method provides to be an important way to bring together scientists with diverse expertise and is recommended for future work in this area.

Ethnic and socioeconomic inequalities in air pollution exposure: a cross-sectional analysis of nationwide individual-level data from the Netherlands.

BACKGROUND: Air pollution contributes to a large disease burden and some populations are disproportionately exposed. We aimed to evaluate ethnic and socioeconomic differences in exposure to air pollution in the Netherlands. METHODS: We did a nationwide, cross-sectional analysis of all residents of the Netherlands on Jan 1, 2019. Sociodemographic information was centralised by Statistics Netherlands and mainly originated from the National Population Register, the tax register, and education registers. Concentrations of NO2, PM2·5, PM10, and elemental carbon, modelled by the National Institute for Public Health and the Environment, were linked to the individual-level demographic data. We assessed differences in air pollution exposures across the 40 largest minority ethnic groups. Evaluation of how ethnicity intersected with socioeconomic position in relation to exposures was done for the ten largest ethnic groups, plus Chinese and Indian groups, in both urban and rural areas using multivariable linear regression analyses. FINDINGS: The total study population consisted of 17 251 511 individuals. Minority ethnic groups were consistently exposed to higher levels of air pollution than the ethnic Dutch population. The magnitude of inequalities varied between the minority ethnic groups, with 3-44% higher exposures to NO2 and 1-9% higher exposures to PM2·5 compared with the ethnic Dutch group. Average exposures were highest for the lowest socioeconomic group. Ethnic inequalities in exposure remained after adjustment for socioeconomic position and were of similar magnitude in urban and rural areas. INTERPRETATION: The variability in air pollution exposure across ethnic and socioeconomic subgroups in the Netherlands indicates environmental injustice at the intersection of social characteristics. The health consequences of the observed inequalities and the underlying processes driving them warrant further investigation. FUNDING: The Gravitation programme of the Dutch Ministry of Education, Culture, and Science, the Netherlands Organization for Scientific Research, the Netherlands Organisation for Health Research and Development, and Amsterdam University Medical Center.

Exposure to a Mixture of Endocrine-Disrupting Chemicals and Metabolic Outcomes in Belgian Adolescents.

Childhood exposure to endocrine-disrupting chemicals (EDCs), either alone or in mixtures, may affect metabolic outcomes, yet existing evidence remains inconclusive. In our study of 372 adolescents from the Flemish Environment and Health Study (FLEHS IV, 2017-2018), we measured 40 known and suspected EDCs and assessed metabolic outcomes, including body mass index z-score (zBMI), abdominal obesity (AO), total cholesterol (TC), and triglycerides (TG). We applied Bayesian kernel machine regression (BKMR) and Bayesian penalized horseshoe regression for variable selection and then built multivariate generalized propensity score (mvGPS) models to provide an overview of the effects of selected EDCs on metabolic outcomes. As a result, BKMR and horseshoe together identified five EDCs associated with zBMI, three with AO, three with TC, and five with TG. Through mvGPS analysis, monoiso-butyl phthalate (MIBP), polychlorinated biphenyl (PCB-170), and hexachlorobenzene (HCB) each showed an inverse association with zBMI, as did PCB-170 with AO. Copper (Cu) was associated with higher TC and TG, except in boys where it was linked to lower TG. Additionally, monoethyl phthalate (MEP) and monobenzyl phthalate (MBzP) were associated with higher TG. To conclude, our findings support the association between certain chemicals (Cu, MEP, and MBzP) and elevated lipid levels, aligning with prior studies. Further investigation is needed for sex-specific effects.

Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies.

BACKGROUND: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs). OBJECTIVE: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae. METHOD: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect. RESULTS: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. ß-Hexachlorocyclohexane (ß-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of ß-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 % CI: 1.20, 2.77 for an interquartile range increase in ln-transformed ß-HCH concentration). The median concentration of ß-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 µg/kg of body weight. The neurodevelopmental and social behavioral effects of ß-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with ß-HCH. CONCLUSIONS: Prenatal exposure to ß-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm ß-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.

Impact of occupational pesticide exposure on the human gut microbiome.

The rising use of pesticides in modern agriculture has led to a shift in disease burden in which exposure to these chemicals plays an increasingly important role. The human gut microbiome, which is partially responsible for the biotransformation of xenobiotics, is also known to promote biotransformation of environmental pollutants. Understanding the effects of occupational pesticide exposure on the gut microbiome can thus provide valuable insights into the mechanisms underlying the impact of pesticide exposure on health. Here we investigate the impact of occupational pesticide exposure on human gut microbiome composition in 7198 participants from the Dutch Microbiome Project of the Lifelines Study. We used job-exposure matrices in combination with occupational codes to retrieve categorical and cumulative estimates of occupational exposures to general pesticides, herbicides, insecticides and fungicides. Approximately 4% of our cohort was occupationally exposed to at least one class of pesticides, with predominant exposure to multiple pesticide classes. Most participants reported long-term employment, suggesting a cumulative profile of exposure. We demonstrate that contact with insecticides, fungicides and a general "all pesticides" class was consistently associated with changes in the gut microbiome, showing significant associations with decreased alpha diversity and a differing beta diversity. We also report changes in the abundance of 39 different bacterial taxa upon exposure to the different pesticide classes included in this study. Together, the extent of statistically relevant associations between gut microbial changes and pesticide exposure in our findings highlights the impact of these compounds on the human gut microbiome.

Associations between lifestyle factors and levels of per- and polyfluoroalkyl substances (PFASs), phthalates and parabens in follicular fluid in women undergoing fertility treatment.

BACKGROUND: Concerns have been raised whether exposure to endocrine-disrupting chemicals (EDCs) can alter reproductive functions and play a role in the aetiology of infertility in women. With increasing evidence of adverse effects, information on factors associated with exposure is necessary to form firm recommendations aiming at reducing exposure. OBJECTIVE: Our aim was to identify associations between lifestyle factors including the home environment, use of personal care products (PCP), and dietary habits and concentrations of EDCs in ovarian follicular fluid. METHODS: April-June 2016, 185 women undergoing ovum pick-up for in vitro fertilisation in Sweden were recruited. Correlation analyses were performed between self-reported lifestyle factors and concentration of EDCs analysed in follicular fluid. Habits related to cleaning, PCPs, and diet were assessed together with concentration of six per- and polyfluoroalkyl substances (PFASs) [PFHxS, PFOA, PFOS, PFNA, PFDA and PFUnDA], methyl paraben and eight phthalate metabolites [MECPP, MEHPP, MEOHP, MEHP, cxMinCH, cxMiNP, ohMiNP, MEP, MOHiBP]. Spearman's partial correlations were adjusted for age, parity and BMI. RESULTS: Significant associations were discovered between multiple lifestyle factors and concentrations of EDCs in ovarian follicular fluid. After correcting p values for multiple testing, frequent use of perfume was associated with MEP (correlation ρ = 0.41 (confidence interval 0.21-0.47), p < 0.001); hens' egg consumption was positively associated with PFOS (ρ = 0.30 (0.15-0.43), p = 0.007) and PFUnDA (ρ = 0.27 (0.12-0.40), p = 0.036). White fish consumption was positively associated with PFUnDA (ρ = 0.34 (0.20-0.47), p < 0.001) and PFDA (ρ = 0.27 (0.13-0.41), p = 0.028). More correlations were discovered when considering the raw uncorrected p values. Altogether, our results suggest that multiple lifestyle variables affect chemical contamination of follicular fluid. IMPACT STATEMENT: This study shows how lifestyle factors correlate with the level of contamination in the ovary by both persistent and semi-persistent chemicals in women of reproductive age. Subsequently, these data can be used to form recommendations regarding lifestyle to mitigate possible negative health outcomes and fertility problems associated with chemical exposure, and to inform chemical policy decision making. Our study can also help form the basis for the design of larger observational and intervention studies to examine possible effects of lifestyle changes on exposure levels, and to unravel the complex interactions between biological factors, lifestyle and chemical exposures in more detail.

Defining and Measuring Resilience in Children with a Chronic Disease: a Scoping Review.

More than 25% of all children grow up with a chronic disease. They are at higher risk for developmental and psychosocial problems. However, children who function resiliently manage to adapt positively to these challenges. We aim to systematically review how resilience is defined and measured in children with a chronic disease. A search of PubMed, Cochrane, Embase, and PsycINFO was performed on December 9, 2022, using resilience, disease, and child/adolescent as search terms. Two reviewers independently screened articles for inclusion according to predefined criteria. Extraction domains included study characteristics, definition, and instruments assessing resilience outcomes, and resilience factors. Fifty-five out of 8766 articles were identified as relevant. In general, resilience was characterized as positive adaptation to adversity. The included studies assessed resilience by the outcomes of positive adaptation, or by resilience factors, or both. We categorized the assessed resilience outcomes into three groups: personal traits, psychosocial functioning, and disease-related outcomes. Moreover, myriad of resilience factors were measured, which were grouped into internal resilience factors (cognitive, social, and emotional competence factors), disease-related factors, and external factors (caregiver factors, social factors, and contextual factors). Our scoping review provides insight into the definitions and instruments used to measure resilience in children with a chronic disease. More knowledge is needed on which resilience factors are related to positive adaptation in specific illness-related challenges, which underlying mechanisms are responsible for this positive adaptation, and how these underlying mechanisms interact with one another. Supplementary Information: The online version contains supplementary material available at 10.1007/s42844-023-00092-2.

Prenatal Exposure to Metabolism-Disrupting Chemicals, Cord Blood Transcriptome Perturbations, and Birth Weight in a Belgian Birth Cohort.

Prenatal exposure to metabolism-disrupting chemicals (MDCs) has been linked to birth weight, but the molecular mechanisms remain largely unknown. In this study, we investigated gene expressions and biological pathways underlying the associations between MDCs and birth weight, using microarray transcriptomics, in a Belgian birth cohort. Whole cord blood measurements of dichlorodiphenyldichloroethylene (p,p'-DDE), polychlorinated biphenyls 153 (PCB-153), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and transcriptome profiling were conducted in 192 mother-child pairs. A workflow including a transcriptome-wide association study, pathway enrichment analysis with a meet-in-the-middle approach, and mediation analysis was performed to characterize the biological pathways and intermediate gene expressions of the MDC-birth weight relationship. Among 26,170 transcriptomic features, we successfully annotated five overlapping metabolism-related gene expressions associated with both an MDC and birth weight, comprising BCAT2, IVD, SLC25a16, HAS3, and MBOAT2. We found 11 overlapping pathways, and they are mostly related to genetic information processing. We found no evidence of any significant mediating effect. In conclusion, this exploratory study provides insights into transcriptome perturbations that may be involved in MDC-induced altered birth weight.

Multi-source data approach for personalized outcome prediction in lung cancer screening: update from the NELSON trial.

Trials show that low-dose computed tomography (CT) lung cancer screening in long-term (ex-)smokers reduces lung cancer mortality. However, many individuals were exposed to unnecessary diagnostic procedures. This project aims to improve the efficiency of lung cancer screening by identifying high-risk participants, and improving risk discrimination for nodules. This study is an extension of the Dutch-Belgian Randomized Lung Cancer Screening Trial, with a focus on personalized outcome prediction (NELSON-POP). New data will be added on genetics, air pollution, malignancy risk for lung nodules, and CT biomarkers beyond lung nodules (emphysema, coronary calcification, bone density, vertebral height and body composition). The roles of polygenic risk scores and air pollution in screen-detected lung cancer diagnosis and survival will be established. The association between the AI-based nodule malignancy score and lung cancer will be evaluated at baseline and incident screening rounds. The association of chest CT imaging biomarkers with outcomes will be established. Based on these results, multisource prediction models for pre-screening and post-baseline-screening participant selection and nodule management will be developed. The new models will be externally validated. We hypothesize that we can identify 15-20% participants with low-risk of lung cancer or short life expectancy and thus prevent ~140,000 Dutch individuals from being screened unnecessarily. We hypothesize that our models will improve the specificity of nodule management by 10% without loss of sensitivity as compared to assessment of nodule size/growth alone, and reduce unnecessary work-up by 40-50%.

Prenatal exposure to persistent organic pollutants and changes in infant growth and childhood growth trajectories.

BACKGROUND: Children are born with a burden of persistent organic pollutants (POPs) which may have endocrine disrupting properties and have been postulated to contribute to the rise in childhood obesity. The current evidence is equivocal, which may partly because many studies investigate the effects at one time point during childhood. We assessed associations between prenatal exposure to POPs and growth during infancy and childhood. METHODS: We used data from two Belgian cohorts with cord blood measurements of five organochlorines [(dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), polychlorinated biphenyls (PCB-138, -150, -180)] (N = 1418) and two perfluoroalkyl substances [perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS)] (N = 346). We assessed infant growth, defined as body mass index (BMI) z-score change between birth and 2 years, and childhood growth, characterized as BMI trajectory from birth to 8 years. To evaluate associations between POP exposures and infant growth, we applied a multi-pollutant approach, using penalized elastic net regression with stability selection, controlling for covariates. To evaluate associations with childhood growth, we used single-pollutant linear mixed models with random effects for child individual, parametrized using a natural cubic spline formulation. RESULTS: PCB-153 was associated with increased and p,p'-DDE with decreased infant growth, although these results were imprecise. No clear association between any of the exposures and longer-term childhood growth trajectories was observed. We did not find evidence of effect modification by child sex. CONCLUSION: Our results suggest that prenatal exposure to PCB-153 and p,p'-DDE may affect infant growth in the first two years, with no evidence of more persistent effects.

Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia.

OBJECTIVE: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per- and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics. METHODS: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in >90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Machine Regression. RESULTS: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, ß = -0.21, 95% CI: -0.38, -0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, ß = -0.22, 95% CI: -0.44, -0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1, ß = -0.16, 95% CI -0.31, -0.02) and the Estonian population (Q2 vs. Q1, ß = -0.27, 95% CI -0.45, -0.08), and for PFOA in the Estonian population (Q4 vs. Q1, ß = -0.31, 95% CI -0.61, -0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals. CONCLUSIONS: Within a large chemical mixture, we observed significant inverse associations levels of DEHP metabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.

Predictors of Human Milk Fatty Acids and Associations with Infant Growth in a Norwegian Birth Cohort.

Triglyceride-bound fatty acids constitute the majority of lipids in human milk and may affect infant growth. We describe the composition of fatty acids in human milk, identify predictors, and investigate associations between fatty acids and infant growth using data from the Norwegian Human Milk Study birth cohort. In a subset of participants (n = 789, 30% of cohort), oversampled for overweight and obesity, we analyzed milk concentrations of detectable fatty acids. We modelled percent composition of fatty acids in relation to maternal body mass index, pregnancy weight gain, parity, smoking, delivery mode, gestational age, fish intake, and cod liver oil intake. We assessed the relation between fatty acids and infant growth from 0 to 6 months. Of the factors tested, excess pregnancy weight gain was positively associated with monounsaturated fatty acids and inversely associated with stearic acid. Multiparity was negatively associated with monounsaturated fatty acids and n-3 fatty acids while positively associated with stearic acid. Gestational age was inversely associated with myristic acid. Medium-chain saturated fatty acids were inversely associated with infant growth, and mono-unsaturated fatty acids, particularly oleic acid, were associated with an increased odds of rapid growth. Notably, excessive maternal weight gain was associated with cis-vaccenic acid, which was further associated with a threefold increased risk of rapid infant growth (OR = 2.9, 95% CI 1.2-6.6), suggesting that monounsaturated fatty acids in milk may play a role in the intergenerational transmission of obesity.

Tracking Mental Wellbeing of Dutch Adolescents During the First Year of the COVID-19 Lockdown: A Longitudinal Study.

PURPOSE: Adolescents might be susceptible to the effects of the COVID-19 lockdown. We assessed changes in mental wellbeing throughout the first year of the pandemic and compared these with prepandemic levels. METHODS: This five-wave prospective study among Dutch adolescents aged 12-17 years used data collected before the pandemic (n = 224) (T0), in May (T1), July (T2), and October 2020 (T3), and in February 2021 (T4). Generalized estimating equations were used to assess the association between stringency of the lockdown with mental wellbeing. RESULTS: Adolescents had a lower life satisfaction during the first full lockdown (T1) [adjusted ß: -0.36, 95% confidence interval (CI): -0.58 to -0.13], during the partial lockdown (T3) (adjusted ß: -0.37, 95% CI: -0.63 to -0.12), and during the second full lockdown (T4) (adjusted ß: -0.79, 95% CI: -1.07 to -0.52) compared to before the pandemic (T0). Adolescents reported more internalizing symptoms during only the second full lockdown (T4) (adjusted ß: 2.58, 95% CI: 0.41-4.75). During the pandemic [at T1 (adjusted ß: 0.29, 95% CI: 0.20-0.38), T2 (adjusted ß: 0.36, 95% CI: 0.26-0.46), T3 (adjusted ß: 0.33, 95% CI: 0.22-0.45), and T4 (adjusted ß: 0.20, 95% CI: 0.07-0.34)], adolescents reported a better psychosomatic health, partly attributable to less trouble falling asleep (p < .01). DISCUSSION: The COVID-19 lockdown measures have had both a negative and positive impact on mental wellbeing of Dutch adolescents. However, mental wellbeing was most impacted during the second full lockdown compared to before the pandemic.

Gender-Specific Changes in Life Satisfaction After the COVID-19-Related Lockdown in Dutch Adolescents: A Longitudinal Study.

PURPOSE: The purposes of this study were to assess whether mental well-being has changed after introduction of the lockdown measures compared with that before, whether this change differs between boys and girls, and whether this change is associated with COVID-19-related concerns. METHODS: This is a two-wave prospective study among Dutch adolescents using data collected up to one year before the COVID-19 pandemic (n = 224) and 5-8 weeks after the first introduction of lockdown measures (n = 158). Mental well-being was assessed by three indicators: life satisfaction, internalizing symptoms, and psychosomatic health. General linear model repeated-measures analysis of variance was used to assess whether mental well-being has changed and if this differed by sex. Univariate linear regressions were used to assess associations between COVID-19-related concerns and a change in mental well-being. RESULTS: Life satisfaction decreased (η2p = .079, p < .001), but no change in internalizing symptoms was observed (η2p = .014, p = .14), and psychosomatic health increased (η2p = .194, p < .001) after the introduction of lockdown measures. Boys scored significantly better on all mental health indicators compared with girls at baseline and follow-up. However, boys' life satisfaction significantly decreased at the follow-up (η2p = .038, p = .015), whereas girls' life satisfaction did not change. Concerns about COVID-19 were significantly associated with a lower life satisfaction and more internalizing symptoms. CONCLUSIONS: Adolescents', especially boys', life satisfaction decreased during the lockdown. They reported no change in internalizing symptoms and an improved psychosomatic health. Adolescents' mental well-being is expected to vary during the COVID-19 pandemic and should continue to be monitored.

Environmental toxicants in breast milk of Norwegian mothers and gut bacteria composition and metabolites in their infants at 1 month.

BACKGROUND: Early disruption of the microbial community may influence life-long health. Environmental toxicants can contaminate breast milk and the developing infant gut microbiome is directly exposed. We investigated whether environmental toxicants in breastmilk affect the composition and function of the infant gut microbiome at 1 month. We measured environmental toxicants in breastmilk, fecal short-chain fatty acids (SCFAs), and gut microbial composition from 16S rRNA gene amplicon sequencing using samples from 267 mother-child pairs in the Norwegian Microbiota Cohort (NoMIC). We tested 28 chemical exposures: polychlorinated biphenyls (PCBs), polybrominated flame retardants (PBDEs), per- and polyfluoroalkyl substances (PFASs), and organochlorine pesticides. We assessed chemical exposure and alpha diversity/SCFAs using elastic net regression modeling and generalized linear models, adjusting for confounders, and variation in beta diversity (UniFrac), taxa abundance (ANCOM), and predicted metagenomes (PiCRUSt) in low, medium, and high exposed groups. RESULTS: PBDE-28 and the surfactant perfluorooctanesulfonic acid (PFOS) were associated with less microbiome diversity. Some sub-OTUs of Lactobacillus, an important genus in early life, were lower in abundance in samples from infants with relative "high" (> 80th percentile) vs. "low" (< 20th percentile) toxicant exposure in this cohort. Moreover, breast milk toxicants were associated with microbiome functionality, explaining up to 34% of variance in acetic and propionic SCFAs, essential signaling molecules. Per one standard deviation of exposure, PBDE-28 was associated with less propionic acid (- 24% [95% CI - 35% to - 14%] relative to the mean), and PCB-209 with less acetic acid (- 15% [95% CI - 29% to - 0.4%]). Conversely, PFOA and dioxin-like PCB-167 were associated with 61% (95% CI 35% to 87%) and 22% (95% CI 8% to 35%) more propionic and acetic acid, respectively. CONCLUSIONS: Environmental toxicant exposure may influence infant gut microbial function during a critical developmental window. Future studies are needed to replicate these novel findings and investigate whether this has any impact on child health.

Early-life exposure to persistent organic pollutants (OCPs, PBDEs, PCBs, PFASs) and attention-deficit/hyperactivity disorder: A multi-pollutant analysis of a Norwegian birth cohort.

BACKGROUND: Numerous ubiquitous environmental chemicals are established or suspected neurotoxicants, and infants are exposed to a mixture of these during the critical period of brain maturation. However, evidence for associations with the risk of attention-deficit/hyperactivity disorder (ADHD) is sparse. We investigated early-life chemical exposures in relation to ADHD. METHODS: We used a birth cohort of 2606 Norwegian mother-child pairs enrolled 2002-2009 (HUMIS), and studied a subset of 1199 pairs oversampled for child neurodevelopmental outcomes. Concentrations of 27 persistent organic pollutants (14 polychlorinated biphenyls, 5 organochlorine pesticides, 6 brominated flame retardants, and 2 perfluoroalkyl substances) were measured in breast milk, reflecting the child's early-life exposures. We estimated postnatal exposures in the first 2 years of life using a pharmacokinetic model. Fifty-five children had a clinical diagnosis of ADHD (hyperkinetic disorder) by 2016, at a median age of 13 years. We used elastic net penalized logistic regression models to identify associations while adjusting for co-exposure confounding, and subsequently used multivariable logistic regression models to obtain effect estimates for the selected exposures. RESULTS: Breast milk concentrations of perfluorooctane sulfonate (PFOS) and ß­hexachlorocyclohexane (ß-HCH) were associated with increased odds of ADHD: odds ratio (OR) = 1.77, 95% confidence interval (CI): 1.16, 2.72 and OR = 1.75, 95% CI: 1.22, 2.53, per interquartile range increase in ln-transformed concentrations, respectively. Stronger associations were observed among girls than boys for PFOS (pinteraction = 0.025). p,p'­Dichlorodiphenyltrichloroethane (p,p'-DDT) levels were associated with lower odds of ADHD (OR = 0.64, 95% CI: 0.42, 0.97). Hexachlorobenzene (HCB) had a non-linear association with ADHD, with increasing risk in the low-level exposure range that switched to a decreasing risk at concentrations above 8 ng/g lipid. Postnatal exposures showed similar results, whereas effect estimates for other chemicals were weaker and imprecise. CONCLUSIONS: In a multi-pollutant analysis of four classes of chemicals, early-life exposure to ß-HCH and PFOS was associated with increased risk of ADHD, with suggestion of sex-specific effects for PFOS. The unexpected inverse associations between p,p'-DDT and higher HCB levels and ADHD could be due to live birth bias; alternatively, results may be due to chance findings.

Modeled and perceived RF-EMF, noise and air pollution and symptoms in a population cohort. Is perception key in predicting symptoms?

BACKGROUND: Psychosocial research has shown that perceived exposure can influence symptom reporting, regardless of actual exposure. The impact of this phenomenon on the interpretation of results from epidemiological research on environmental determinants of symptoms is unclear. OBJECTIVE: Our aim was to compare associations between modeled exposures, the perceived level of these exposures and reported symptoms (non-specific symptoms, sleep disturbances, and respiratory symptoms) for three different environmental exposures (radiofrequency electromagnetic fields (RF-EMF), noise, and air pollution). These environmental exposures vary in the degree to which they can be sensorially observed. METHODS: Participant characteristics, perceived exposures, and self-reported health were assessed with a baseline (n = 14,829, 2011/2012) and follow-up (n = 7905, 2015) questionnaire in the Dutch population-based Occupational and Environmental Health Cohort (AMIGO). Environmental exposures were estimated at the home address using spatial models. Cross-sectional and longitudinal regression models were used to examine the associations between modeled and perceived exposures, and reported symptoms. RESULTS: The extent to which exposure sources could be observed by participants likely influenced correlations between modeled and perceived exposure as correlations were moderate for air pollution (rSp = 0.34) and noise (rSp = 0.40), but less so for RF-EMF (rSp = 0.11). Perceived exposures were consistently associated with increased symptom scores (respiratory, sleep, non-specific). Modeled exposures, except RF-EMF, were associated with increased symptom scores, but these associations disappeared or strongly diminished when accounted for perceived exposure in the analyses. DISCUSSION: Perceived exposure has an important role in symptom reporting. When environmental determinants of symptoms are studied without acknowledging the potential role of both modeled and perceived exposures, there is a risk of bias in health risk assessment. However, the etiological role of exposure perceptions in relation to symptom reporting requires further research.

Preterm infants have distinct microbiomes not explained by mode of delivery, breastfeeding duration or antibiotic exposure.

Background: Preterm infants have low gut microbial diversity and few anaerobes. It is unclear whether the low diversity pertains to prematurity itself or is due to differences in delivery mode, feeding mode or exposure to antibiotics. Methods: The Norwegian Microbiota Study (NoMIC) was established to examine the colonization of the infant gut and health outcomes. 16S rRNA gene Illumina amplicon-sequenced samples from 519 children (160 preterms), collected at 10 days, 4 months and 1 year postnatally, were used to calculate alpha diversity. Short-chain fatty acids (SCFA) were analysed with gas chromatography and quantified using flame ionization detection. We regressed alpha diversity on gestational age, taking into account possible confounding and mediating factors, such as breastfeeding and antibiotics. Taxonomic differences were tested using Analysis of Composition of Microbiomes (ANCOM) and SCFA profile (as a functional indicator of the microbiota) was tested by Wilcoxon rank-sum. Results: Preterm infants had 0.45 Shannon units lower bacterial diversity at 10 days postnatally compared with infants born at term (95% confidence interval: -0.60, -0.32). Breastfeeding status and antibiotic exposure were not significant mediators of the gestational age-diversity association, although time spent in the neonatal intensive care unit was. Vaginally born, exclusively breastfed preterm infantss not exposed to antibiotics at 10 days postnatally had fewer Firmicutes and more Proteobacteria than children born at term and an SCFA profile indicating lower saccharolytic fermentation. Conclusions: Preterm infants had distinct gut microbiome composition and function in the early postnatal period, not explained by factors more common in preterms, such as shorter breastfeeding duration, more antibiotics or caesarean delivery.

Impact of Di-2-Ethylhexyl Phthalate Metabolites on Male Reproductive Function: a Systematic Review of Human Evidence.

PURPOSE OF REVIEW: The purpose of this review is to systematically review the literature linking di-2-ethylhexyl phthalate (DEHP) exposure with effects on reproductive health in adult males. RECENT FINDINGS: Thirty-three papers were included of which 28 were cross-sectional. Twenty-one papers investigated semen samples, 18 investigated reproductive hormones, and three studies investigated time to pregnancy. Studies revealed some but inconsistent indications that higher urinary DEHP metabolite levels are associated with an increase in the proportion of spermatozoa with damaged DNA and to a decrease in sperm concentration and motility. A negative association between DEHP metabolites and testosterone levels was more consistent. DEHP metabolites do not seem to be associated with a delay in time to pregnancy, but data are sparse. The studies on DEHP exposure and reproductive biomarkers in men converge to support the hypothesis that DEHP exposure is related to impaired male reproductive function. Longitudinal studies are needed to establish if the observed associations are causal.

Cohort profile: LIFEWORK, a prospective cohort study on occupational and environmental risk factors and health in the Netherlands.

PURPOSE: LIFEWORK is a large federated prospective cohort established in the Netherlands to quantify the health effects of occupational and environmental exposures. This cohort is also the Dutch contribution to the international Cohort Study of Mobile Phone Use and Health (COSMOS). In this paper, we describe the study design, ongoing data collection, baseline characteristics of participants and the repeatability of key questionnaire items. PARTICIPANTS: 88 466 participants were enrolled in three cohort studies in 2011-2012. Exposure information was collected by a harmonised core questionnaire, or modelled based on occupational and residential histories; domains include air pollution (eg, nitrogen dioxide (NO2), particulate matter with diameter ≤2.5 µm (PM2.5)), noise, electromagnetic fields (EMF), mobile phone use, shift work and occupational chemical exposures. Chronic and subacute health outcomes are assessed by self-report and through linkage with health registries. FINDINGS TO DATE: Participants had a median age of 51 years at baseline (range 19-87), and the majority are female (90%), with nurses being over-represented. Median exposure levels of NO2, PM2.5, EMF from base stations and noise at the participants' home addresses at baseline were 22.9 µg/m3, 16.6 µg/m3, 0.003 mWm2 and 53.1 dB, respectively. Twenty-two per cent of participants reported to have started using a mobile phone more than 10 years prior to baseline. Repeatability for self-reported exposures was moderate to high (weighted kappa range: 0.69-1) for a subset of participants (n=237) who completed the questionnaire twice. FUTURE PLANS: We are actively and passively observing participants; we plan to administer a follow-up questionnaire every 4-5 years-the first follow-up will be completed in 2018-and linkage to cause-of-death and cancer registries occurs on a (bi)annual basis. This prospective cohort offers a unique, large and rich resource for research on contemporary occupational and environmental health risks and will contribute to the large international COSMOS study on mobile phone use and health.