Marion Ouidir

Le concept de DOHaD (Developmental Origins of Health and Disease) postule que les expositions environnementales subies durant la phase de développement (vie fœtale et premières années de la vie) ont des conséquences majeures sur la santé ultérieure. La diminution du poids de naissance est considérée à la fois comme un marqueur de ces agressions subies par le fœtus au cours de la grossesse et comme un indicateur de la santé future de l’enfant. La recherche en épidémiologie sur les effets de la pollution atmosphérique doit faire face au défi de l’évaluation de l’exposition aux polluants atmosphériques.L’objectif général de cette thèse était de caractériser l’effet des polluants atmosphériques sur la croissance fœtale, en améliorant la caractérisation des expositions et le contrôle des biais de confusion potentiels par rapport aux études antérieures.Dans une première partie, nous avons étudié les déterminants socio-économiques de l'exposition à la pollution de l’air ambiant dans l’étude nationale Française ELFE, incluant 18 000 couples mères-enfants. L'exposition maternelle aux particules fines (PM2,5), PM10 et au NO2 a été estimée à l'adresse du domicile à partir de modèles de dispersion avec des résolutions spatiale (1x1 km) et temporelle (données journalières) fines. En France, dans les zones urbaines, les femmes enceintes des quartiers les plus défavorisés étaient les plus exposées à la pollution atmosphérique.La deuxième partie de ce travail a porté sur la caractérisation de l'association entre les niveaux pollution atmosphérique dans l’air extérieur durant la grossesse et le poids de naissance de l’enfant, toujours dans la cohorte ELFE. Une fois les facteurs de confusion pris en compte à l’aide d’un score de propension, nous avons mis en évidence un effet délétère de l’exposition aux particules en suspension dans l’air au cours du troisième trimestre de grossesse sur le poids de naissance.Dans une troisième partie, nous avons comparé différentes approches pour évaluer l'exposition à la pollution atmosphérique chez la femme enceinte, incluant des mesures personnelles, chez 40 femmes de la cohorte SEPAGES-faisabilité. La considération du budget espace-temps ne modifiait que très légèrement les niveaux d’exposition estimés dans l’air extérieur à l’adresse du domicile. En revanche, l’exposition estimée était fortement modifiée par la prise en compte des niveaux de pollution atmosphérique à l’intérieur du domicile, ou quand l’exposition était l’estimée à l’aide de dosimètres personnels.Ceci a justifié, dans une quatrième partie, d’étudier l'association entre l’exposition à la pollution atmosphérique estimée à l'aide de mesures personnelles et le développement du fœtus dans la cohorte grenobloise SEPAGES, incluant 471 triades couples-enfant. L’exposition personnelle aux PM2,5 (n=174, plus nettement au 1er trimestre) et au NO2 (n=327, plus nettement au 3ème trimestre) étaient associées à une diminution du poids de naissance. L’estimation ponctuelle de l’association avec les PM2,5 était bien plus forte que dans la cohorte ELFE.En conclusion, ce travail vient renforcer la littérature sur l’effet délétère de la pollution atmosphérique sur le poids de naissance. Cette thèse, basée sur deux cohortes complémentaires, a également permis d’illustrer le compromis entre biais et variance entre les études s’appuyant sur des modèles d’exposition extérieurs (pouvant être réalisées sur de vastes zones géographiques permettant des effectifs et contrastes d’exposition larges et avec potentiellement des biais de confusion et d’erreur de mesure sur l’exposition importants) et les cohortes s’appuyant sur des dosimètres personnels (généralement conduites sur des zones plus limitées, dans une population plus homogène, avec moins de biais de confusion potentiels et une meilleure estimation de l’exposition).

The true impact of endocrine disrupting chemicals (EDCs) on human health is far from being understood. Humans are exposed to mixtures of chemicals throughout their lives, yet regulations and most studies focus on individual chemicals. ENDOMIX takes a novel approach to identifying associations and causality between EDCs and adverse health outcomes by focusing on exposure to mixtures of EDCs over the life course, including windows of susceptibility, using human biomonitoring data from several European cohorts. We will model and measure how real-life EDC mixtures act together and target the immune system to initiate, trigger or maintain disease. Health effects will be investigated using pioneering methodologies ranging from high-throughput in vitro bioassays, sophisticated organoid and co-culture systems, to in vivo models. In combination, they will provide valuable information on mechanistic pathways and transgenerational effects of EDC exposure. We aim to identify biomarkers and patterns of chemical exposures that are easy to measure, available for large cohorts and indicative for adverse health outcomes. We will use in vitro, in silico and in vivo data to strengthen causal inference using a weight-of-evidence approach. Moreover, using novel text mining methods, we will create knowledge graphs to capture and summarize the complexity of biomechanistic information, which aids rapid risk assessments and the creation of network models. The knowledge generated by ENDOMIX will provide an evidence base for policy-making and also reach people of all ages to raise awareness of the risks of EDC exposure and encourage health-promoting behaviors.

To investigate the association between placental methylation and placenta weight (PW) and placental-fetal weight ratio (PFR), which are markers of placental function linked to adverse pregnancy outcomes and risk for diseases in later life. We examined the association between placental epigenome-wide methylation and PW and PFR at birth (n = 301). Further tests assessed whether methylation levels of the cytosine-guanine sites (CpGs) linked to PW and PFR are associated with placental expression of nearby genes. At a 5% false discovery rate (FDR), methylation at 27 CpGs was associated with PW, of which two CpGs were also associated with PFR. Methylation at four of the 27 CpGs was associated with placental expression of nearby genes including LEPR, RPS6KA1, and COX5A which have known roles in early development, cellular growth, and oxidative stress. The identified CpGs overlap with previously reported methylation sites associated with perinatal and adult health outcomes such as preeclampsia, preterm delivery, obesity, and type 2 diabetes. The findings reveal epigenetic underpinnings of placental development and functional efficiency, and suggest their potential roles in mediating fetal development and late-onset diseases.

Sex differences in physiological and disease traits are pervasive and begin during early development, but the genetic architecture of these differences is largely unknown. Here, we leverage the human placenta, a transient organ during pregnancy critical to fetal development, to investigate the impact of sex in the regulatory landscape of placental autosomal methylome and transcriptome, and its relevance to health and disease. We find that placental methylation and its genetic regulation are extensively impacted by fetal sex, whereas sex differences in placental gene expression and its genetic regulation are limited. We identify molecular processes and regulatory targets that are enriched in a sex-specific manner, and find enrichment of imprinted genes in sex-differentiated placental methylation, including female-biased methylation within the well-known KCNQ1OT1/CDKN1C imprinting cluster of genes expressed in a parent-of-origin dependent manner. We establish that several sex-differentiated genetic effects on placental methylation and gene expression colocalize with birthweight and adult disease genetic associations, facilitating mechanistic insights on early life origins of health and disease outcomes shaped by sex.

The true impact of endocrine disrupting chemicals (EDCs) on human health is far from being understood. Humans are exposed to mixtures of chemicals throughout their lives, yet regulations and most studies focus on individual chemicals. ENDOMIX takes a novel approach to identifying associations and causality between EDCs and adverse health outcomes by focusing on exposure to mixtures of EDCs over the life course, including windows of susceptibility, using human biomonitoring data from several European cohorts. We will model and measure how real-life EDC mixtures act together and target the immune system to initiate, trigger or maintain disease. Health effects will be investigated using pioneering methodologies ranging from high-throughput in vitro bioassays, sophisticated organoid and co-culture systems, to in vivo models. In combination, they will provide valuable information on mechanistic pathways and transgenerational effects of EDC exposure. We aim to identify biomarkers and patterns of chemical exposures that are easy to measure, available for large cohorts and indicative for adverse health outcomes. We will use in vitro, in silico and in vivo data to strengthen causal inference using a weight-of-evidence approach. Moreover, using novel text mining methods, we will create knowledge graphs to capture and summarize the complexity of biomechanistic information, which aids rapid risk assessments and the creation of network models. The knowledge generated by ENDOMIX will provide an evidence base for policy-making and also reach people of all ages to raise awareness of the risks of EDC exposure and encourage health-promoting behaviors.

Introduction: Racial and ethnic differences in fetal growth and birth size in the USA have not been adequately explained by individual-level socioeconomic status (SES) factors. We explored whether differences may be partially explained by county-level indicators of SES. Methods: We linked participant zip codes from the National Institute of Child Health and Human Development Fetal Growth Studies (2009–2013; n=1614) to county-level US census data to calculate a neighbourhood deprivation index, education isolation index and two indices of segregation: racial isolation and evenness. Using causal mediation methods, we evaluated the extent to which racial/ethnic differences in neonatal anthropometrics could be eliminated in a hypothetical setting where everyone lived in counties with high resource availability and racial/ethnic integration. Results: Setting racial evenness to levels consistent with the highest diversity eliminated 79.9% of the difference in birth weight between non-Hispanic White and non-Hispanic Black and all the difference (106.3%) in birth weight between Hispanic and non-Hispanic White individuals. Setting racial evenness, racial isolation and education isolation to levels consistent with higher diversity and education was also associated with similar reductions in differences for other anthropometric measures. Conclusions: Our findings suggest that, in a hypothetical scenario where everyone lived in counties with low deprivation or segregation, race/ethnic differences in neonatal anthropometry may substantially decrease or be eliminated. Our results also highlight the importance of considering community-level and structural factors in analyses of race/ethnic health disparities.

Phenols, parabens, and phthalates (PPPs) are suspected or known endocrine disruptors. They are used in consumer products that pregnant women and their progeny are exposed to daily through the placenta, which could affect offspring health. This review aims to compile data from cohort studies and in vitro and in vivo models to provide a summary regarding placental transfer, fetoplacental development, and the predisposition to adult diseases resulting from maternal exposure to PPPs during the gestational period. In humans, using the concentration of pollutants in maternal urine, and taking the offspring sex into account, positive or negative associations have been observed concerning placental or newborn weight, children’s BMI, blood pressure, gonadal function, or age at puberty. In animal models, without taking sex into account, alterations of placental structure and gene expression linked to hormones or DNA methylation were related to phenol exposure. At the postnatal stage, pollutants affect the bodyweight, the carbohydrate metabolism, the cardiovascular system, gonadal development, the age of puberty, sex/thyroid hormones, and gamete quality, but these effects depend on the age and sex. Future challenges will be to explore the effects of pollutants in mixtures using models and to identify the early signatures of in utero exposure capable of predicting the health trajectory of the offspring.