Pyrethroid insecticide exposure and cognitive developmental disabilities in children: The PELAGIE mother–child cohort

International audiencePyrethroid insecticides are widely used in agriculture and in homes. Despite the neurotoxicity of these insecticides at high doses, few studies have examined whether lower-level exposures could adversely affect children's neurodevelopment. The PELAGIE cohort included 3421 pregnant women from Brittany, France between 2002 and 2006. When their children reached their sixth birthday, 428 mothers from the cohort were randomly selected, successfully contacted and found eligible. A total of 287 (67%) mothers agreed to participate with their children in the neuropsychological follow-up. Two cognitive domains were assessed by the Wechsler Intelligence Scale for Children: verbal comprehension and working memory. Five pyrethroid and two organophosphate insecticide metabolites were measured in maternal and child first-void urine samples collected between 6 and 19 gestational weeks and at 6 years of age, respectively. Linear regression models were used to estimate associations between cognitive scores and urinary pyrethroid metabolite concentrations, adjusting for organophosphate metabolite concentrations and potential confounders. Maternal prenatal pyrethroid metabolite concentrations were not consistently associated with any children's cognitive scores. By contrast, childhood 3-PBA and cis-DBCA concentrations were both negatively associated with verbal comprehension scores (P-trend = 0.04 and P-trend < 0.01, respectively) and with working memory scores (P-trend = 0.05 and P-trend < 0.01, respectively). No associations were observed for the three other childhood pyrethroid metabolite concentrations (4-F-3-PBA, cis-DCCA, and trans-DCCA). Low-level childhood exposures to deltamethrin (as cis-DBCA is its principal and selective metabolite), in particular, and to pyrethroid insecticides, in general (as reflected in levels of the 3-PBA metabolite) may negatively affect neurocognitive development by 6 years of age. Whatever their etiology, these cognitive deficits may be of importance educationally, because cognitive impairments in children interfere with learning and social development. Potential causes that can be prevented are of paramount public health importanc

State-of-the-art methods for exposure-health studies: Results from the exposome data challenge event

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

The LifeCycle Project-EU Child Cohort Network : a federated analysis infrastructure and harmonized data of more than 250,000 children and parents

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.Peer reviewe

Endocrine disruption during pregnancy and early reproductive anomalies : analyses from birth cohort studies

Depuis plusieurs décennies, le rôle des expositions environnementales dans l’apparition des anomalies de la reproduction suscite l’intérêt de la communauté scientifique. La période prénatale est une phase critique du développement et l’exposition à des substances chimiques au cours de la grossesse pourrait avoir des conséquences sur la santé de l’enfant et de l’adulte. De nombreuses études chez l’animal ont mis en évidence que diverses molécules chimiques étaient toxiques pour la reproduction et le développement et que certaines d’entre elles étaient capables d’interférer avec le système endocrinien. Chez l’Homme, les effets de l’exposition prénatale à des substances susceptibles d’altérer l’équilibre hormonal du fœtus restent mal documentés. L’objectif de ce travail de thèse est d’étudier l’effet de l’exposition prénatale à certains polluants chimiques en s’intéressant à deux indicateurs d’anomalie du développement du système reproducteur à la naissance : les niveaux d’hormones sexuelles et les malformations congénitales de l’appareil génital du garçon. Ce travail s’appuie sur les données issues de cohortes mère-enfants françaises ayant recruté des femmes enceintes au cours de leur grossesse et pour lesquelles des prélèvements biologiques ont permis la mesure de l’exposition. Les classes chimiques plus spécifiquement étudiées dans cette thèse comprennent les polluants organiques persistants (polychlorobiphényles, pesticides organochlorés et retardateurs de flamme bromés) et les éthers de glycol, une classe de solvants oxygénés. Les études menées mettent en évidence des effets sur le développement du système reproducteur, potentiellement associés à des mécanismes de perturbation endocrinienne, en lien avec l’exposition prénatale aux deux familles de polluants étudiées. Des modifications des niveaux d’hormones sexuelles sont observées en association avec l’exposition prénatale à divers polluants organiques persistants. L’exposition prénatale à certains éthers de glycol est associée à une augmentation du risque d’hypospade ainsi qu’à des modifications des niveaux d’hormones sexuelles. Ces résultats mettent en évidence les effets d’expositions prénatales à des polluants chimiques ubiquitaires, sur le système endocrinien du fœtus.From last decades, researchers had increased interest about the impact of environmental exposure on reproductive impairments. The fetal life is a crucial period of development and exposure to chemical during gestation may lead to adverse health outcomes at birth or later in life. Several toxicological studies have reported that some chemicals are reproductive and developmental toxicants and that some of them are able to interact with the endocrine system. In humans, evidence about the endocrine effects of these molecules is limited. The aim of this thesis is to study the effect of prenatal exposure to chemicals on two endocrine-sensitive endpoints at birth: sex hormone levels and congenital anomalies of the genitalia. This work is based on data collected in two French mother-child cohorts that included pregnant women during pregnancy and collected biological samples to perform exposure assessment. Two chemicals classes are studies including persistent organic pollutants (polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers) and glycol ethers, a class of oxygenated solvent. The studies conducted show effects of prenatal exposure to both classes of chemicals on endocrine-sensitive endpoints related to reproductive health. Modifications of sex hormone levels are observed in association with exposure to various persistent organic pollutants. Prenatal exposure to some glycol ethers is associated with an increased risk of hypospadias and with modifications of sex hormone levels. These results highlight the effect of prenatal exposure to ubiquitous chemicals, on the endocrine system of the fetus

Concerning the plausibility of the findings reported in 'Prenatal exposure to glycol ethers and cryptorchidism and hypospadias a nested case-control study' by Smet and Kelsey authors' response

International audienceReply Letter to Smet and Kelsey: Concerning the plausibility of the findings reported in “Prenatal exposure to glycol ethers and cryptorchidism and hypospadias: a nested case–control study”, Warembourg et al, Occup Environ Med 2018;75:59–6

Reply II. Cord blood androgen measurements: the importance of assay validation

International audienceReply: We thank Keelan and colleagues for their letter questioning the accuracy of testosterone measurement in cord blood obtained by immunoassay methods..

Potential impact of pesticide exposures during pregnancy on the newborn’s metabolome

International audienc

Behavioural disorders in 6-year-old children and pyrethroid insecticide exposure: the PELAGIE mother-child cohort

International audienceObjective The potential impact of environmental exposure to pyrethroid insecticides on child neurodevelopment has only just started to receive attention despite their widespread use. We investigated the associations between prenatal and childhood exposure to pyrethroid insecticides and behavioural skills in 6-year-olds. Methods The PELAGIE cohort enrolled 3421 pregnant women from Brittany, France between 2002 and 2006. 428 mothers were randomly selected for the study when their children turned 6, and 287 (67%) agreed to participate. Children's behaviour was assessed using the Strengths and Difficulties Questionnaire (SDQ). Three subscales (prosocial behaviour, internalising disorders and externalising disorders) were considered. Five pyrethroid metabolites were measured in maternal and child urine samples collected between 6 and 19 gestational weeks and at 6 years of age, respectively. Logistic regression and reverse-scale Cox regression models were used to estimate the associations between SDQ scores and urinary pyrethroid metabolite concentrations, adjusting for organophosphate metabolite concentrations and potential confounders. Results Increased prenatal cis-3-(2,2-dichlorovinyl)-2,2dimethylcyclopropane carboxylic acid (DCCA) concentrations were associated with internalising difficulties (Cox p value=0.05). For childhood 3phenoxybenzoic acid (PBA) concentrations, a positive association was observed with externalising difficulties (Cox p value=0.04) and high ORs were found for abnormal or borderline social behaviour (OR 2.93, 95% CI 1.27 to 6.78, and OR 1.91, 95% CI 0.80 to 4.57, for the intermediate and highest metabolite categories, respectively). High childhood trans-DCCA concentrations were associated with reduced externalising disorders (Cox p value=0.03). Conclusions The present study suggests that exposure to certain pyrethroids, at environmental levels, may negatively affect neurobehavioral development by 6 years of age

Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy.

International audienceBACKGROUND: People in developed countries are widely exposed to low levels of organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). Seafood is a major contributor to PCB exposure. Toxicity of those various pollutants to reproductive and endocrine functions raises questions about possible effects on fertility. We explored whether serum levels of these pollutants and seafood consumption were associated with the fertility of couples enrolled in a French birth cohort (PELAGIE). METHODS: Time-to-pregnancy was investigated in 3,421 pregnant women by asking how many months they had taken to conceive. Levels of 14 organochlorine pesticides, 12 PCBs, and 10 PBDE compounds were measured in cord blood serum from a random subcohort (n = 394). Mercury concentrations measured in maternal hair were considered as a potential coexposure. Fecundability odds ratios (ORs) were estimated from multivariate discrete-time Cox proportional hazard models. RESULTS: Shellfish consumption was associated with longer time-to-pregnancy (fecundability OR ≥twice/week vs. 0.410 µg/L vs. <0.266 µg/L, fecundability OR = 0.46 [0.32-0.66]). In multiple sensitivity analyses, reduced fecundability was most consistently associated with shellfish consumption, p,p'-DDE, total PCBs, PCB153, and PCB187. Models that simultaneously included multiple coexposure factors led to similar conclusions. CONCLUSIONS: Our findings were robust in sensitivity analyses, including analysis restricted to primiparous women. These results suggest that PCBs, p,p'-DDE, and other shellfish contaminants may impair human fertility