Environnement et fertilité féminine : étude du rôle des perturbateurs endocriniens sur la réserve ovarienne

Endocrine disrupting chemicals (EDCs) are suspected to affect the female reproductive system. However, little attention has been given to their potential impact on the ovarian reserve, a key component of female fertility. The overarching aim of this thesis was to study the impact of EDCs on the ovarian reserve. Specifically, we looked at the effects of four families of EDCs (53 persistent organic pollutants (POPs), 4 heavy metals, 4 phenols, and 8 phthalates), as single-exposure analysis and as mixtures, on different indicators of the ovarian reserve including anti-Müllerian hormones (AMH), antral follicle count (AFC), follicle-stimulating hormones (FSH) and diminished ovarian reserve (DOR). In addition, we explored whether in utero exposure to POPs were associated with AMH in teenage girls. We conducted our research among two populations of women seeking reproductive assistance at fertility centres in two countries (France and the United States) and in the French mother-child PELAGIE cohort. Overall, we found limited evidence that EDCs were associated with markers of the ovarian reserve or with DOR, both individually and as mixtures. In the French AROPE case-control study, p,p’-DDE was significantly associated with an increased risk of DOR, whereas β-HCH was significantly associated with a decreased risk of DOR. Furthermore, we observed non-significant increased risks of DOR for cadmium and chromium with a close to significant association for the second tercile of cadmium. We also observed that increased PCB 180 measured in cord blood significantly increased AMH levels in teenage girls in the PELAGIE cohort. In the American EARTH cohort, phenols and phthalates were not associated with various ovarian reserve markers (AFC, FSH or DOR). This work includes the first studies on the associations between POPs and heavy metals, and DOR. Further studies are necessary to validate our results and explore the influence of EDCs during various susceptibility windows on the ovarian reserve at different life stages.Les perturbateurs endocriniens (PEs) sont soupçonnés d’affecter le système reproducteur féminin. Cependant, peu d'attention a été accordée à leur impact potentiel sur la réserve ovarienne, un élément clé de la fertilité féminine. L'objectif principal de cette thèse était d'étudier l'impact des PEs sur la réserve ovarienne. Plus précisément, nous avons examiné les effets de quatre familles de PEs (53 polluants organiques persistants (POPs), 4 métaux lourds, 4 phénols et 8 phtalates), en tant qu'expositions individuelles et en mélange, sur différents indicateurs de la réserve ovarienne, dont les hormones anti-Müllériennes (AMH), le nombre de follicules antraux (AFC), les hormones folliculostimulantes (FSH) et la diminution de la réserve ovarienne (DOR). De plus, nous avons exploré si l'exposition in utero aux POPs était associée aux niveaux d'AMH chez les adolescentes. Nous avons mené notre recherche auprès de deux populations de femmes en recherche d'aide à la procréation dans deux pays (France et États-Unis) et dans la cohorte mère-enfant française PELAGIE. Dans l'ensemble, nous avons trouvé peu d’associations entre PEs et les marqueurs de la réserve ovarienne ou la DOR, individuellement ou en mélange. Dans l'étude cas-témoins française AROPE, le p,p'-DDE était significativement associé à un risque accru de DOR, tandis que le β-HCH était significativement associé à un risque réduit de DOR. De plus, nous avons observé des risques non significativement accrus de DOR pour le cadmium et le chrome, avec une association proche de la significativité pour le deuxième tercile de cadmium. Nous avons également observé que des niveaux accrus de PCB 180 mesurés dans le sang du cordon augmentaient significativement les niveaux d'AMH chez les adolescentes de la cohorte PELAGIE. Dans la cohorte américaine EARTH, les phénols et les phtalates n'ont pas été associés à divers indicateurs de réserve ovarienne (AFC, FSH ou DOR). Ce travail comprend les premières études sur les associations entre les POP et les métaux lourds, et la DOR. D'autres études sont nécessaires pour valider nos résultats et explorer l'influence des PEs pendant différentes fenêtres de susceptibilité sur la réserve ovarienne à différentes étapes de la vie

Mixtures of phenol and phthalate urinary biomarkers in relation to the ovarian reserve among women attending a fertility clinic

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Mixtures of urinary concentrations of phenols and phthalate biomarkers in relation to the ovarian reserve among women attending a fertility clinic

International audienceAlthough prior studies have found associations of the ovarian reserve with urinary concentrations of some individual phenols and phthalate metabolites, little is known about the potential associations of these chemicals as a mixture with the ovarian reserve. We investigated whether mixtures of four urinary phenols (bisphenol A, butylparaben, methylparaben, propylparaben) and eight metabolites of five phthalate diesters including di(2-ethylhexyl) phthalate were associated with markers of the ovarian reserve among 271 women attending a fertility center who enrolled in the Environment and Reproductive Health study (2004-2017). The analysis was restricted to one outcome per study participant using the earliest outcome after the last exposure assessment. Ovarian reserve markers included lower antral follicle count (AFC) defined as AFC < 7, circulating serum levels of day 3 follicle stimulating hormone (FSH) assessed by immunoassays, and diminished ovarian reserve (DOR) defined as either AFC < 7, FSH > 10 UI/L or primary infertility diagnosis of DOR. We applied Bayesian Kernel Machine Regression (BKMR) and quantile g-computation to estimate the joint associations and assess the interactions between chemical exposure biomarkers on the markers of the ovarian reserve while adjusting for confounders. Among all 271 women, 738 urine samples were collected. In quantile g-computation models, a quartile increase in the exposure biomarkers mixture was not significantly associated with lower AFC (OR = 1.10, 95 % CI = 0.52, 2.30), day 3 FSH levels (Beta = 0.30, 95 % CI = -0.32, 0.93) or DOR (OR = 1.02, 95 % CI = 0.52, 2.05). Similarly, BKMR did not show any evidence of associations between the mixture and any of the studied outcomes, or interactions between chemicals. Despite the lack of associations, these results need to be explored among women in other study cohorts

Mixtures of phenol and phthalate exposure biomarkers in relation to semen parameters among men from a fertility clinic

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Heavy metals and diminished ovarian reserve: single-exposure and mixture analyses amongst women consulting in French fertility centres

International audienceRESEARCH QUESTION: Do heavy metals affect the risk of diminished ovarian reserve (DOR) in women of reproductive age? DESIGN: A total of 139 cases and 153 controls were included between 2016 and 2020. The participants were aged between 18 and 40 years and attended consultations for couple infertility in one of four fertility centres in western France. Cases of DOR were defined as women with an antral follicle count less than 7, anti-Müllerian hormone levels 1.1 ng/ml or less, or both. Controls were frequency matched on age groups and centres, and were women with normal ovarian reserve evaluations, no malformations and menstrual cycles between 26 and 35 days. Heavy metals (lead, mercury, cadmium and chromium) were measured in whole blood at inclusion. Single-exposure associations were examined with multivariable logistic regressions adjusted on potential confounders. Mixture effects were investigated with quantile g-computation and Bayesian kernel machine regression (BKMR). RESULTS: Chromium as a continuous exposure was significantly associated with DOR in unadjusted models (OR 2.07, 95% CI 1.04 to 4.13) but the association was no longer significant when confounders were controlled for (adjusted OR 2.75, 95% CI 0.88 to 8.60). Similarly, a statistically significant association was observed for the unadjusted second tercile of cadmium exposure (OR 1.87, 95% CI 1.06 to 3.30); however, this association was no longer statistically significant after adjustment. None of the other associations tested were statistically significant. Quantile g-computation and BKMR both yielded no significant change of risk of DOR for the mixture of metals, with no evidence of interaction. CONCLUSIONS: Weak signals that some heavy metals could be associated with DOR were detected. These findings should be replicated in other studies

Associations of Maternal Urinary Concentrations of Phenols, Individually and as a Mixture, with Serum Biomarkers of Thyroid Function and Autoimmunity: Results from the EARTH Study

The associations between urinary phenol concentrations and markers of thyroid function and autoimmunity among potentially susceptible subgroups, such as subfertile women, have been understudied, especially when considering chemical mixtures. We evaluated cross-sectional associations of urinary phenol concentrations, individually and as a mixture, with serum markers of thyroid function and autoimmunity. We included 339 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2009–2015). We quantified four phenols in urine using isotope dilution high-performance liquid chromatography–tandem mass spectrometry, and biomarkers of thyroid function (thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4), and triiodothyronine (fT3, TT3)), and autoimmunity (thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies (Ab)) in serum using electrochemoluminescence assays. We fit linear and additive models to investigate the association between urinary phenols—both individually and as a mixture—and serum thyroid function and autoimmunity, adjusted for confounders. As a sensitivity analysis, we also applied Bayesian Kernel Machine Regression (BKMR) to investigate non-linear and non-additive interactions. Urinary bisphenol A was associated with thyroid function, in particular, fT3 (mean difference for a 1 log unit increase in concentration: −0.088; 95% CI [−0.151, −0.025]) and TT3 (−0.066; 95% CI [−0.112, −0.020]). Urinary methylparaben and triclosan were also associated with several thyroid hormones. The overall mixture was negatively associated with serum fT3 concentrations (mean difference comparing all four mixture components at their 75th vs. 25th percentiles: −0.19, 95% CI [−0.35, −0.03]). We found no evidence of non-linearity or interactions. These results add to the current literature on phenol exposures and thyroid function in women, suggesting that some phenols may alter the thyroid system