L’endométriose est une maladie gynécologique pour laquelle l’exposition à certains contaminants chimiques environnementaux est évoquée parmi les facteurs de risque associés. Les conclusions des études épidémiologiques existantes restent toutefois non convergentes. Leur hétérogénéité en termes de lésions décrites, de méthodologie et d’effectifs contribuent à ce constat, de même que l’étendue limitée des marqueurs d’exposition considérés dans ces études. Nous avons réalisé une étude cas-témoins appariés à partir d’une bio-collection de 113 patientes réunissant68 cas de patientes opérées d’endométriose profonde et 45 patientes témoins. Un ensemble unique de 78 polluants organiques persistants a été recherché, incluant dioxines, polychlorobiphényles, retardateurs de flamme polybromés, et pesticides organochlorés. Les niveaux d’exposition interne des sujets ont été mesurés à la fois dans les tissus adipeux pariétal et épiploïque ainsi que dans le sérum. La distribution de ces différents polluants au sein de ces trois compartiments a tout d’abord été caractérisée. Celle-ci a permis la prise en compte encore très rare de l’équilibre entre compartiments de stockage et compartiment circulant, ce rapport de concentration apparaissant comme un potentiel indicateur additionnel permettant d’affiner d’éventuels liens de causalité entre exposition chronique à des dangers chimiques et pathologie chez l’homme. Certains des contaminants ciblés sont ensuite apparus significativement associés à l’endométriose profonde, la stratification plus fine de notre population de cas indiquant un lien d’autant plus significatif en présence d’endométriome. Les mécanismes sous-jacents de cette association restent toutefois à élucider. / Endometriosis is a gynecological disease for whichexposure to some environmental chemicals is evocatedamong the associated risk factors. Epidemiological studies are however globally non convergent and finally fairly conclusive. Their heterogeneity in terms of lesion localization and sub-phenotype, methodology, size and nature of the populations studied, as well as the limited number of monitored markers of exposure contribute to this situation. We realized a matched case-control study based on a biocollection of 113 patients including 68 patients suffering of deep endometriosis and 45 controls. We characterized the internal exposure levels of an extended range of around 78 persistent organic pollutants (including dioxins, polychlorobiphenyls, brominated flame retardants and organochlorine pesticides). Internal level exposures were measured in three biological compartments (omental fat, subcutaneous fat and serum). First, the distribution of these chemicals was characterized within these compartments. These extended exposure data from deep infiltrating endometriosis patients are the first ones available for France and give a new insight about the equilibrium of chemicals between storage and circulating compartments that should be further considered as a potential indicator permitting to establish a possible association between a chronic exposure to chemical hazards and human pathology. Afterwards, some of the targeted chemicals appeared significantly associated with deep endometriosis. A sub-stratification of our case population indicated a more significant relationship with the presence of endometrioma. Underlying mechanisms remain to be determined.

Os mecanismos da infertilidade relacionada à endometriose ainda não foram esclarecidos, embora diversos estudos proponham um efeito deletério desta doença sobre a qualidade oocitária (QO). No entanto, a análise de oócitos em pacientes com endometriose não é rotineiramente exequível, uma vez que os oócitos humanos raramente são doados para pesquisa e sua aplicação em técnicas invasivas impede sua utilização em procedimentos de reprodução assistida. Neste contexto, as evidências sugerem que as células cumulus (CC) podem ser utilizadas como biomarcadores indiretos capazes de prever a QO. Desta forma, através de um estudo inédito, objetivamos determinar o perfil diferencial de transcritos em CC de mulheres inférteis, com e sem endometriose avançada, submetidas à estimulação ovariana controlada para injeção intracitoplasmática de espermatozoides. Para tanto, realizamos um estudo caso-controle, que analisou via sequenciamento de nova geração de RNA (RNA-Seq), 3 grupos (controle, endometriose III/IV sem endometrioma e endometriose III/IV com endometrioma), com 3 pools de 3 pacientes cada. Dentre os principais genes desregulados identificados nas comparações entre os grupos com endometriose avançada e mulheres sem a doença foram evidenciados transcritos com expressão alterada envolvidos na via de fosforilação oxidativa, genes relacionados aos processos da acetilação e conjugação de ubiquitina, além de genes associados a via de biossíntese do colesterol e do estradiol. Esses resultados demonstram que as CC de mulheres inférteis com endometriose avançada apresentam alterações moleculares possivelmente relacionadas ao desenvolvimento folicular e oocitário. Através do enriquecimento dos principais genes desregulados, nossos dados indicam as potenciais vias alteradas nesse processo que podem interferir na aquisição da competência gamética e por sua vez, mediar o comprometimento da fertilidade dessas pacientes. / The endometriosis related infertility mechanisms still remain to be elucidated, although several studies propose a deleterious effect of this disease on oocyte quality. However, the oocyte analysis in patients with endometriosis is not routinely feasible, since human oocytes are rarely donated to researches and their application in invasive techniques precludes their use in reproduction procedures. In this context, evidences suggest that cumulus cells (CC) could be used as indirect biomarkers capable of predicting oocyte quality. Thus, through an unprecedented study, we aimed to determine the differential transcripts profile in CC of infertile women with and without advanced endometriosis and its different stages, undergoing controlled ovarian stimulation for intracytoplasmic sperm injection. Therefore, we performed a case-control study, which analyzed by RNA next generation sequencing (RNA-Seq), 3 groups (control, endometriosis III/IV without endometrioma and endometriosis III/IV with endometrioma), with 3 pools of 3 patients each. The comparison of top deregulated genes among groups of advanced endometriosis and control patients show us altered genes associated with oxidative pathways, acetylation and ubiquitination process, aside from genes related to cholesterol and estradiol regulation. These data elucidated that CC of infertile woman with advanced endometriosis carried essential molecular alteration linked with follicular and gametic development. Through enrichment of the top deregulated genes, we can point out the potential pathways altered in this process toward oocyte commitment and infertility in these patients.

Os mecanismos da infertilidade relacionada à endometriose ainda não foram esclarecidos, embora diversos estudos proponham um efeito deletério desta doença sobre a qualidade oocitária (QO). No entanto, a análise de oócitos em pacientes com endometriose não é rotineiramente exequível, uma vez que os oócitos humanos raramente são doados para pesquisa e sua aplicação em técnicas invasivas impede sua utilização em procedimentos de reprodução assistida. Neste contexto, as evidências sugerem que as células cumulus (CC) podem ser utilizadas como biomarcadores indiretos capazes de prever a QO. Desta forma, através de um estudo inédito, objetivamos determinar o perfil diferencial de transcritos em CC de mulheres inférteis, com e sem endometriose avançada, submetidas à estimulação ovariana controlada para injeção intracitoplasmática de espermatozoides. Para tanto, realizamos um estudo caso-controle, que analisou via sequenciamento de nova geração de RNA (RNA-Seq), 3 grupos (controle, endometriose III/IV sem endometrioma e endometriose III/IV com endometrioma), com 3 pools de 3 pacientes cada. Dentre os principais genes desregulados identificados nas comparações entre os grupos com endometriose avançada e mulheres sem a doença foram evidenciados transcritos com expressão alterada envolvidos na via de fosforilação oxidativa, genes relacionados aos processos da acetilação e conjugação de ubiquitina, além de genes associados a via de biossíntese do colesterol e do estradiol. Esses resultados demonstram que as CC de mulheres inférteis com endometriose avançada apresentam alterações moleculares possivelmente relacionadas ao desenvolvimento folicular e oocitário. Através do enriquecimento dos principais genes desregulados, nossos dados indicam as potenciais vias alteradas nesse processo que podem interferir na aquisição da competência gamética e por sua vez, mediar o comprometimento da fertilidade dessas pacientes. / The endometriosis related infertility mechanisms still remain to be elucidated, although several studies propose a deleterious effect of this disease on oocyte quality. However, the oocyte analysis in patients with endometriosis is not routinely feasible, since human oocytes are rarely donated to researches and their application in invasive techniques precludes their use in reproduction procedures. In this context, evidences suggest that cumulus cells (CC) could be used as indirect biomarkers capable of predicting oocyte quality. Thus, through an unprecedented study, we aimed to determine the differential transcripts profile in CC of infertile women with and without advanced endometriosis and its different stages, undergoing controlled ovarian stimulation for intracytoplasmic sperm injection. Therefore, we performed a case-control study, which analyzed by RNA next generation sequencing (RNA-Seq), 3 groups (control, endometriosis III/IV without endometrioma and endometriosis III/IV with endometrioma), with 3 pools of 3 patients each. The comparison of top deregulated genes among groups of advanced endometriosis and control patients show us altered genes associated with oxidative pathways, acetylation and ubiquitination process, aside from genes related to cholesterol and estradiol regulation. These data elucidated that CC of infertile woman with advanced endometriosis carried essential molecular alteration linked with follicular and gametic development. Through enrichment of the top deregulated genes, we can point out the potential pathways altered in this process toward oocyte commitment and infertility in these patients.