CE36 - Santé Publique

Prenatal Exposure to Tobacco smoking and Air Pollution and Effects on offspring respiratory and neurodevelopmental outcomes: role of placental DNA methylation – ETAPE

Prenatal Exposure to tobacco smoking and air pollution and effects on offspring respiratory and neurodevelopmental outcomes: role of placental DNA methylation

About 11% of children in France are affected by asthma and 10% by neurodevelopmental disorders. Several toxicological and epidemiological studies show that in utero exposure to tobacco smoking and air pollutants imply developmental pulmonary and neurological toxicity and thus contribute to the etiology of child’s respiratory and neurodevelopmental disorders.

Aims

Several Mechanisms are suspected to explain these effects and epigenetics is likely one of them. DNA methylation has been associated with a range of exposures and health outcomes, including maternal exposure to tobacco smoking and air pollution as well as respiratory health and neurodevelopmental phenotypes. Yet, most studies investigating prenatal exposures and developmental outcomes have relied on cord blood DNA methylation marks. Very few studies have explored placenta, which may be both a relevant exposure biomarker, as placenta is considered as an accurate ‘record’ of children’s in-utero exposures, and a relevant health biomarker due to its master regulator function of the fetal hormonal and endocrine milieu. In humans, despite a growing number of DNA methylation association studies, evidence of epigenetic mediation of exposure-outcome relationships is sparse and usually focused on the mediated effect for each of the mediator. The ETAPE project aims at identifying placental DNA methylation biomarkers of 1) pre-natal exposure to tobacco smoking and air pollution and 2) children respiratory health and neurodevelopment and 3) characterizing the contribution of placental methylation in the associations of maternal exposure to tobacco smoking and air pollution children respiratory health and neurodevelopment.

We will take advantage of the EDEN and SEPAGES mother-child cohorts providing life-course data with high quality data on pre- and post-natal exposures, placental methylation measurements, and offspring repeated measurements of health outcomes. Epigenome-Wide Association Studies will be conducted to answer aims 1 and 2. Mediation-EWAS models (i.e. polymediator models) will be developed and investigated in order to provide accurate identification of multiple mediators and estimation of direct and indirect effects. We will apply latent variable methods to characterize causal and confounding factors and better understand the relationship between a high-dimensional set of mediators and an exposure / outcome for the ETAPE data.

ETAPE will provide innovative results on the pulmonary and neurological toxicity of in utero exposure to tobacco smoking and air pollutants. The prevalence of exposure of these two contaminants make it a major public health issue especially in vulnerable populations such as pregnant women and children.

ETAPE will provide innovative results on the pulmonary and neurological toxicity of in utero exposure to tobacco smoking and air pollutants. The prevalence of exposure of these two contaminants make it a major public health issue especially in vulnerable populations such as pregnant women and children.

1. Rousseaux S, Seyve E, Chuffart F, Bourova Flin E, Benmerad M, Charles MA, Forhan A, Heude B, Siroux V, Slama R, Tost J, Vaiman D, Khochbin S, Lepeule J. Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinting gene-containing regions. In revision. Also published in Biorxiv doi: 10.1101/852186.

2. Blum MGB, Valeri L, François O, Cadiou S, Siroux V, Lepeule J, Slama R. Challenges Raised by Mediation Analysis in a High-Dimension Setting. Environ Health Perspect. 2020 doi: 10.1289/EHP6240.

3. Caye K, Jumentier B, Lepeule J, François O. LFMM 2: Fast and Accurate Inference of Gene-Environment Associations in Genome-Wide Studies. Mol Biol Evol. 2019. doi: 10.1093/molbev/msz008.

4. Jumentier B, Caye K, …, Lepeule J, François O. Sparse latent factor regression models for genome-wide and epigenome-wide association studies. 2020. BioRxiv. doi: 10.1101/2020.02.07.938381

5. Everson T*, Vives-Usano M*, Seyve E*, …, Marsit C*, Lepeule J*, Hivert MF*, Bustamante M*. Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth. In revision. Also published in Biorxiv doi: 10.1101/663567 (* co-first and co-last authors)

About 11% of children in France are affected by asthma and 10% by neurodevelopmental disorders. Several toxicological and epidemiological studies show that in utero exposure to tobacco smoking and air pollutants imply developmental pulmonary and neurological toxicity and thus contribute to the etiology of child’s respiratory and neurodevelopmental disorders. Several Mechanisms are suspected to explain these effects and epigenetics is likely one of them. DNA methylation has been associated with a range of exposures and health outcomes, including maternal exposure to tobacco smoking and air pollution as well as respiratory health and neurodevelopmental phenotypes. Yet, most studies investigating prenatal exposures and developmental outcomes have relied on cord blood DNA methylation marks. Very few studies have explored placenta, which may be both a relevant exposure biomarker, as placenta is considered as an accurate ‘record’ of children’s in-utero exposures, and a relevant health biomarker due to its master regulator function of the fetal hormonal and endocrine milieu. In humans, despite a growing number of DNA methylation association studies, evidence of epigenetic mediation of exposure-outcome relationships is sparse and usually focused on the mediated effect for each of the mediator. The ETAPE project aims at identifying placental DNA methylation biomarkers of 1) pre-natal exposure to tobacco smoking and air pollution and 2) children respiratory health and neurodevelopment and 3) characterizing the contribution of placental methylation in the associations of maternal exposure to tobacco smoking and air pollution children respiratory health and neurodevelopment. We will take advantage of the EDEN and SEPAGES mother-child cohorts providing life-course data with high quality data on pre- and post-natal exposures, placental methylation measurements, and offspring repeated measurements of health outcomes. Epigenome-Wide Association Studies will be conducted to answer aims 1 and 2. Mediation-EWAS models (i.e. polymediator models) will be developed and investigated in order to provide accurate identification of multiple mediators and estimation of direct and indirect effects. We will apply latent variable methods to characterize causal and confounding factors and better understand the relationship between a high-dimensional set of mediators and an exposure / outcome for the ETAPE data. ETAPE will provide innovative results on the pulmonary and neurological toxicity of in utero exposure to tobacco smoking and air pollutants. The prevalence of exposure of these two contaminants make it a major public health issue especially in vulnerable populations such as pregnant women and children.

Project coordinator

Madame Johanna Lepeule (Institut pour l'Avancée des Biosciences)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

TIMC-IMAG Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble
iPLESP Institut Pierre Louis d'épidémiologie et de santé publique
IAB Institut pour l'Avancée des Biosciences
CRESS Centre de Recherche Epidémiologiques et Bio Statistiques de Sorbonne Paris Cité

Help of the ANR 431,708 euros
Beginning and duration of the scientific project: September 2018 - 48 Months

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