Current projects

Chemical pollutants

Project investigator: Claire Philippat and Valérie Siroux
Location of the projet: Inserm U1209
Funding sources: European Union Horizon research and innovation programme (ENDOMIX project, No. 101136566)

Using biomarkers of exposure to compounds from several chemical families, measured in the mother's urine or blood collected during pregnancy, the associations between the chemical exposome and markers of the immune system will be investigated. The chemical compounds studied belong to the families of PFAS (perfluorinated compounds), phthalates, phenols, and organophosphate flame retardants. On the other hand, the markers of the immune system are signaling proteins, called cytokines or chemokines, which have numerous immune activities such as defense against pathogens, but are also involved in allergies and autoimmunity.

Project investigator: Claire Philippat and Johanna Lepeule
Location of the projet: Inserm U 1209
Funding sources:

The placenta plays an important role in the developmental origins of health and disease (DOHaD) paradigm, a concept focused on the role of the prenatal environment in determining the development of diseases later in life. These effects could be partly explained by epigenetic mechanisms in the placenta that may be sensitive to environmental factors, such as chemicals. Our objective is to assess whether exposure to PFAS can affect placental DNA methylation, assessed in placental tissues collected at birth.

Project investigator: Claire Philippat 
Location of the projet: Inserm U 1209
Funding sources: Joint funding from Inserm and Inrae (Project THYREX)

Environmental contaminants are suspected to affect thyroid homeostasis during pregnancy as well as neurodevelopment. Most epidemiological studies have relied on a limited number of urine samples to assess exposure, leading to bias in effect estimates for contaminants with short half-lives. Thus, new studies relying on improved exposure assessments are needed. This project aims to: 1) study the associations between approximately 50 chemical substances (alone and in mixture) and thyroid hormone concentrations; 2) conduct a mediation analysis to explore whether effects observed on the thyroid could explain effects on neurodevelopment. To carry out the project, we will use data from two European cohorts (BISC and SEPAGES). These two cohorts have enhanced exposure assessment based on repeated urine samples throughout pregnancy.

Project investigator: Claire Philippat
Location of the projet: Inserm U1209
Funding sources: Fondation de France (ELEMENTUM project, n° FDF - 00124527)

Brain-derived neurotrophic factor (BDNF) constitutes a key regulator of brain development and neural plasticity, likley being involved in the pathophysiology of diverse psychiatric disorders. Toxicological evidence highlights altered BDNF signaling as a key central event disrupted by bisphenol A (BPA) and other endocrine disrupting chemicals (EDCs) such as phthalates. Our research objective inside SEPAGES is:

  • 1) to measure BDNF biomarkers (serum protein levels and blood methylation), together with a common functional BDNF polymorphism (Val66Met), in cord blood,
  • 2) to investigate whether they can explain part of the associations between prenatal exposure to phenols/phthalates and child neurodevelopment. We also measure BDNF protein and methylation levels in a subset of available serum/blood samples in 1-year infants and 3-year children (n≈100), to assess the variability of these biomarkers from birth to early childhood, which is currently unknown.

Project investigator: Annabelle Bédard
Location of the projet: Inserm UMRS1018
Funding sources: French Agency for Food, Environmental and Occupational Health & Safety (project PENDALIRE, n° Anses 22-EST-169)

The role of exposure to endocrine disruptors (EDs), to which pregnant women and infants (i.e. children aged < 1 year) are particularly vulnerable, has been suggested in the aetiology of respiratory and allergic diseases. Diet is an ubiquitous and potentially modifiable source of chronic EDs exposure, including phenols, phthalates and per- and polyfluoroalkyl substances (PFASs), which can bio-accumulate directly in foods (e.g. non organic fish/shellfish, fruits, dairy) or indirectly via food production, processing, packaging practices or food storage conditions (e.g. use of plastic or canned foods). The research objectives are:

  • 1) to characterize dietary sources of exposure to EDs in: a) pregnant women and b) infants;
  • 2) to investigate the associations of the dietary habits that are sources of exposure to EDs, a) during pregnancy and b) during infancy (identified in Aim 1), in relation with childhood respiratory health.

Project investigator: Claire Philippat and Marion Ouidir
Location of the projet: Inserm U1209
Funding sources: European Union's Horizon 2020 research and innovation program (No. OBERON Project), French National Agency for Research (MEMORI project N° ANR-21-CE34-0022)

Endocrine disruptors are chemical substances present in our environment that have the ability to disrupt the normal functioning of hormones in the human body. They can be found in many common products such as pesticides, plastics, personal care products, and even some foods. Children are particularly vulnerable to the adverse effects of endocrine disruptors as their hormonal system is still developing. Most studies investigating the cardio-metabolic health of young children (before 5 years old) have focused on associations with prenatal exposures to endocrine disruptors. Increasingly, cross-sectional research has highlighted an association between exposure to endocrine disruptors and cardio-metabolic diseases in children and adolescents, such as diabetes, obesity, high blood pressure, and cardiovascular diseases. However, research on young children (before 3 years old) remains very limited, underscoring the need to deepen our understanding of the effects of early exposure to endocrine disruptors on children's health. The objective of this project is to investigate the associations between chemical compounds (phenols, phthalates, DINCH, and PFAS) and cardio-metabolic health of children in the SEPAGES cohort.

Project investigator: Claire Philippat and Chantal Delon
Location of the projet: Inserm U1209 and U1216
Funding sources: French National Agency for Research (ORANDANI n°ANR-22-CE36-0018)

Organophosphate flame retardants (OPFRs) are emerging chemicals with high prevalence and controllable sources of exposure. Toxicological studies support their neurotoxicity, but epidemiological studies on their effects on child mental health are scarce We hypothesize that exposure to organophosphorus flame retardants (OPFRs) during pregnancy and early childhood has a negative impact on child brain development and mental health. Specific objectives are:

  • 1) to provide the first investigation of the effects of OPFRs on brain morphology, structures, on white matter microstructure and on cognitive functioning;
  • 2) to investigate the effects of early life exposure to OPFRs on child neurodevelopment (cognition, behavior and social aspects) between 2 and 8 years;
  • 3) to explore to which extent effects seen on child neurodevelopment are explained (i.e., mediated) by a direct effect on the brain.

Climate and air pollution

Project investigator: Johanna Lepeule
Location of the projet: Inserm U 1209, CNRS UMR7275
Funding sources: Agence Nationale de la Recherche (HEAT-4P Project, grant number ANR-22-CE28-00X)

Heat is one of the major public health challenges that France will rapidly face. Epidemiological studies have shown the adverse effects of heat stress on several perinatal health events, including decreased birth weight, increased preterm births, and stillbirths. However, there is limited knowledge on the significance of chronic temperature exposures compared to acute exposures, on the most impactful temperature exposure windows, on the causal mechanisms occurring during pregnancy, or on the impact of socio-economic factors on the vulnerability of pregnant women to ambient temperature. All these limitations hinder the translation of current knowledge into preventive public health policies. Through data including pre- and postnatal exposures from the mother-child cohorts Sepages, Eden, Pelagie, and Elfe, the Heat-4P project aims to:

  • identify the physiopathological and biological markers of heat stress in pregnant women;
  • assess the perinatal and long-term effects of heat exposure during pregnancy on child health and identify underlying biological pathways (cardiovascular, angiogenic, inflammatory, placental);
  • examine social factors that moderate/exacerbate the impact of heat exposure during pregnancy on maternal-child health.

Project investigator: Valérie Siroux and Gaëlle Uzu
Location of the projet: Inserm U1209; IRD Umr 252
Funding sources: PHD grant from ADEME-ANSES (ADEME); CDP IDEX UGA MOBILAIR (ANR-15-IDEX-02) ; ANR (GetOPstandOP ANR-19-CE34-0002) ; CDP CDTOOLS IDEX UGA ACME

The project addresses the general issue of the health impact associated with exposure to particulate matters, specifically focusing on the validation of the oxidative potential (OP) of particulate matter (PM) as a relevant indicator to quantify the health effects of exposure to PM. This thesis work is structured around the following specific objectives:

  • 1) Estimate the population's exposure to the oxidative potential of aerosols in a medium-sized city and characterize its spatiotemporal variability. This aspect relies in part on indoor and outdoor air samples collected between 2018-2019 from families in the SEPAGES cohort, funded by MobilAir;
  • 2) Characterize the associations between OP measurements and objective health measures and immune markers in the SEPAGES cohorte. These associations will be compared with those obtained for the current regulatory metric (mass concentration of particles).
  • 3) Characterize the associations between OP measurements and biomarkers of oxidative stress.

Project investigator: Johanna Lepeule
Location of the projet: Inserm U1209
Funding sources: No funding

Maternal air pollution exposure during pregnancy has been associated with adverse birth outcomes. Epigenetic modifications could be one of the gene-regulatory mechanisms underlying these associations. Little is known about the effect of maternal air pollution exposure on placental epigenetic aging. The objective of this project is to build a placental epigenetic clock and investigate the relationship of NO2, PM10 and PM2.5 exposure during pregnancy with placental epigenetic aging.

Project investigator: Johanna Lepeule
Location of the projet: Inserm U1209
Funding sources: ANR ETAPE (No. ANR-18-CE36-0005)

The project is based on two mother-child cohorts (SEPAGES and EDEN) with longitudinal data including prenatal and postnatal exposures, placental methylation, and repeated assessments of health events. "Poly-mediator" models will be developed to identify all mediators and characterize the direct and indirect roles of these mediators in the associations between exposure and health events. Latent variable methods will be used to specify causal factors and confounding factors, thus providing a better understanding of the relationship between exposure/event and high-dimensional mediators. The project objectives are as follows:

  • 1) To study the links between air pollution exposure and placental methylation in SEPAGES and EDEN cohorts;
  • 2) To study the links between placental methylation in SEPAGES and pulmonary function at 2 months and 3 years;
  • 3) To evaluate the effects of air pollutants on behavior and cognitive function mediated by placental methylation in SEPAGES and EDEN cohorts;
  • 4) To assess the effects of air pollutants on pulmonary function mediated by placental methylation in SEPAGES cohort.

Project investigator: Johanna Lepeule and Mathilde Pascal
Location of the projet: Inserm U1209, Santé Publique France
Funding sources: Santé Publique France

An increasing number of studies suggest an effect of heat on prematurity, low birth weight and stillbirth. There are possible modifying or mediating effects between temperatures and other environmental and socioeconomic risk factors. The presence of urban heat islands, exposure to air pollution, or low socioeconomic status may simultaneously exacerbate heat exposure, physiological susceptibility to heat, and individual adaptation capacity and thus influence the relationship between temperatures and perinatal health. The different degrees of exposure to these factors can hide social and territorial inequalities that cause ecological inequalities. Conversely, urban vegetation is a potentially protective factor, likely to limit exposure to other risk factors (heat, pollution), while promoting health-promoting behaviors (physical activity, social contacts, psychological well-being). The research objectives are to:

  • 1) identify temporal windows of heat sensitivity during pregnancy;
  • 2) quantify their effects on prematurity and birth weight in 4 mother-child cohorts, considering the modifying or mediating effect of environmental co-exposures and socioeconomic factors;
  • 3) study the association between high temperature exposures during pregnancy and accelerated epigenetic placental aging.

Project investigator: Johanna Lepeule and Claire Philippat
Location of the projet: Inserm U1209
Funding sources: Inserm recurring allocation

Maternal thyroxine (T4) and triiodothyronine (T3) have been demonstrated to be crucial for fetal growth, development, and maturation as well as embryogenesis. Uncontrolled maternal hypothyroidism can negatively affect fetal growth, birth outcomes, children's development, as well as other pregnancy-related issues. To promote proper fetal growth throughout pregnancy, maternal thyroid hormones pass through the placenta, amniotic fluid, and umbilical cord to the fetus. In early pregnancy the fetus is most dependent on the mother's thyroid hormones, making it crucial to maintain normal levels for the fetus' growth, metabolism, and development. To prevent unfavorable pregnancy and delivery outcomes caused by alterations in thyroid hormones, it is crucial to identify factors that can change maternal thyroid hormone levels throughout the early stages of pregnancy. The research objective is to study the influence of air pollution (NO2, PM2.5, benzene, toluene, ethylbenzene, and xylenes) on thyroid hormones (free and total T3, free and total T4, ratio of T3 and T4, TSH) during pregnancy.

Project investigator: Marion Ouidir
Location of the projet: Inserm U1209
Funding sources: National Research Agency (PEACH Project No. ANR-24-CE36-5914-01)

Previous studies have shown associations between birth weight and exposure to air pollutants during pregnancy. However, studies investigating the associations between these prenatal exposures and the future health of children are less common. Given the increasing prevalence of cardiovascular diseases in children and adolescents, identifying early and modifiable risk factors is a significant public health concern. So far, most studies examining the effects of air pollution on health have used ambient models based on residential address, without considering an individual's daily activities or indoor air quality. This approach can introduce biases in the dose-response relationship and compromise the precision of estimating this relationship. To further our understanding of environmental impacts and how the placenta can mediate the future health of children, some studies have focused on placental epigenetics as a potential candidate mechanism to explain the effects of the broader environment on fetal development and future child and adult health. The majority of molecular-scale studies on the placenta have explored epigenomics, particularly DNA methylation, as a proxy for gene expression to explain a phenotype. However, other mechanisms are involved in the reversible modification of gene expression (e.g., acetylation). Direct analysis of transcriptomic allows us to overcome the various mechanisms that modify gene expression by quantifying transcript expression levels. The objective of this project is to investigate the potential mediating role of placental gene expression (transcript expression levels) in the associations between prenatal exposure to air pollutants and the genesis of cardiovascular diseases in later life.

Health and biology

Project investigator: Johanna Lepeule
Location of the projet: Inserm U1209
Funding sources: Foundation for Medical Research (EPIMEX project) - European Union's Horizon 2020 research and innovation program (ATHLETE project, No. 874583)

The placenta plays an important role in the developmental origins of health and disease (DOHaD) paradigm, a concept focused on the role of the prenatal environment in determining the development of diseases later in life. These effects could be partly explained by epigenetic mechanisms in the placenta that may be sensitive to environmental factors.
Our objective is to assess whether DNA methylation, assessed in placental tissues collected at birth, is associated with i) exposure prenatal exposure to air pollutants or a mixture of ambient exposures (vegetation, heat, air pollutants), ii) diet and folic acid supplementation during pregnancy, iii) characteristics of birth weight and duration of pregnancy.

Project investigator: Peter D Sly AO
Location of the projet: Queensland Children’s Hospital, Australia
Funding sources: European Respiratory Society

The ERS CRC INCIRCLE was formed with the aim of improving assessment of lung function in young children, primarily through improving and validating intra-breath oscillometry for use in young children. A substantial amount of data has been collected in healthy young children and in those with various respiratory conditions, including in the SEPAGES cohort. We now propose to combine data collected in different parts of the world to create a normative data set for IB-OSC outcome variables. Most data have been collected with INCIRCLE wave-tube equipment and analysed using ad hoc software. A few data sets have been collected with TremoFlo or pneumotach-based equipment. The research objectives were:

  • 1) To develop normative equations for IB-OSC outcome variables in children, to create Z-scores, where appropriate, and to investigate factors influencing lung function in healthy children;
  • 2) To determine whether data collected with commercial or other pneumotach-based) equipment is equivalent to those collected with INCIRCLE equipment;
  • 3) To use the normative data to examine changes in children with various respiratory conditions;
  • 4) To make the normative data available in the GLI data set.

Project investigator: Marion Ouidir
Location of the projet: Inserm U1209
Funding sources: APMC (Project Dyscard)

Blood lipid levels, such as total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides, undergo significant changes during pregnancy to support its maintenance and ensure fetal development. Epidemiological studies have shown an association between abnormal blood lipid levels, known as dyslipidemia, during pregnancy and an increased risk of cardiovascular events in adulthood. Blood pressure, commonly measured in adults, is rarely assessed in children due to its high variability. Repeated blood pressure measurements throughout early childhood can provide a better characterization of children's cardiovascular health. Furthermore, direct examination of microcirculation would offer a more comprehensive insight into children's cardiovascular health. The eye's fundus is the only part of the body where microcirculation can be directly evaluated. Analysis of retinal vessels serves as a promising surrogate vascular biomarker for the long-term assessment of cardiovascular risk, including hypertension, coronary artery diseases, and cardiovascular mortality. Studying retinal microcirculation in pediatric studies could yield new insights into the origins of cardiovascular diseases in their very early stages. The primary objective of the project is to investigate whether maternal blood lipid concentrations are associated with the cardiovascular health of children, as assessed through repeated blood pressure measurements during childhood and changes in retinal microcirculation at the age of 8. Secondary objectives include:

  • 1) Identifying whether changes in child blood lipid concentrations explain part of the link between maternal dyslipidemia and the cardiovascular health of the child;
  • 2) Describing the children's blood pressure trajectories up to the age of 8;
  • 3) Investigating the direct link between children's blood pressure from early infancy to 8 years of age and the retinal microcirculation of the children at 8 years.

Project investigator: Sabine Plancoulaine
Location of the projet: Inserm U1153
Funding sources: Doctoral scholarship

The arrival of a child in a family disturbs the life habits and in particular the sleep of the parents. Studies on the sleep of new parents focus mainly on the mother's sleep, and on the first months of life, showing a decrease in the quality and quantity of sleep, in postpartum mothers, generally linked to symptoms of depression. The research objectives are:

  • 1) to describe the sleep characteristics (quality and quantity) of the new parents (father and mother) between birth and 3 years and their changes over time, based on questionnaires; to identify early associated factors with a focus on parents’ chronotypes and child’s birth rank; to study the interrelations between the new fathers and mothers sleep characteristics over time;
  • 2) to describe the child sleep characteristics between birth and 3 years and their changes over time, based on questionnaires and accelerometer data; to identify early associated factors with a focus on parents’ chronotypes;
  • 3) to study the interrelationships between both parents’ and their child sleep characteristics over time.

Project investigator: Liesbeth Duijts
Location of the projet: Erasmus Medical Center Rotterdam
Funding sources: European Union’s Horizon 2020 research and innovation program (ATHLETE Project N° 874583)

It is already known that several early-life risk factors play a role in the development of childhood diseases. However, the interplay between these factors is not fully understood. Therefore the aim of this project is to develop a prediction model on meta-analysis level based on novel risk factors and protective factors to predict a personalized risk on the development of respiratory outcomes in childhood. Potential risk factor groups include parental factors of atopy, maternal factors during pregnancy, birth characteristics, infant to pre-school anthropometrics and disease history.

Project investigator: Judith van der Waerden
Location of the projet: Department of Social Epidemiology (ERES) | Inserm U1136
Funding sources: Doctoral scholarship

Environmental stressors during childhood are established to influence certain aspects of psychological, behavioural, and socioemotional development. However, the impact of paternal mental illness remains understudied. Global data suggests that approximately 5-10% of fathers are susceptible to depression in the perinatal period (both pre- and post-partum), with rates of perinatal anxiety also ranging 3.4%-25.0% prenatally and 2.4%-51.0% postnatally. With changing family dynamics and increased paternity leave across Europe, fathers are arguably playing a more active role in child rearing now more than ever. Indeed, paternal mental illness has been shown to negatively impact child development from infancy to late adolescence, resulting in behavioural and emotional problems in children, as well as subsequent psychological problems such as depression, substance abuse, and suicidal behaviour. However, certain domains have not yet been investigated, particularly so in relation to neurodevelopmental disorders in a French context. Moreover, the effect of father’s mental health on their children has also been seen to act independently of mothers’ psychopathology, with the presence of paternal depression shown even to aggravate the negative effects of maternal depression on child development. Improved understanding of the relationship between fathers’ mental illness and their child’s development will enable social and health care services to better target, support and prevent developmental impairment in children most at risk. With the data from Sepages, the aim is to investigate the link between paternal mental illness and child psychological, behavioural, and socioemotional development. As the population of the SEPAGES cohort has been shown to be unrepresentative of the French national population, these associations will be further examined in relation to various environmental and socioeconomic factors.

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