The mammalian ovary : Concerns about evaluation of prenatal environmental exposures

This work was supported by the European Union’s Horizon 2020 FREIA project (grant 277 agreement No. 825100). The authors declare no conflicts of interest regarding this study.Peer reviewedPostprin

Six Decades of Research on Human Fetal Gonadal Steroids

Acknowledgments: All authors wish to dedicate this review to Bernard Jégou who enabled their meeting, and who was a perpetual source of inspiration for their research on human fetal gonads and in particular on their steroidogenic capacities with testes as ovaries. Funding: This work was funded by the European Union’s Horizon 2020 FREIA (grant agreement No. 825100) and the Marie Skłodowska‐Curie PROTECTED projects (grant agreement No. 722634 to P.A.F.). P.A.F., S.C.P., P.L., and L.L. are FREIA project recipients. T.L. was a recipient of funding from the French agency for food and safety (Anses).Peer reviewedPublisher PD

Conserved Usage of Alternative 5′ Untranslated Exons of the GATA4 Gene

BACKGROUND:GATA4 is an essential transcription factor required for the development and function of multiple organs. Despite this important role, our knowledge of how the GATA4 gene is regulated remains limited. To better understand this regulation, we characterized the 5' region of the mouse, rat, and human GATA4 genes. METHODOLOGY/PRINCIPAL FINDINGS:Using 5' RACE, we identified novel transcription start sites in all three species. GATA4 is expressed as multiple transcripts with varying 5' ends encoded by alternative untranslated first exons. Two of these non-coding first exons are conserved between species: exon 1a located 3.5 kb upstream of the GATA4 ATG site in exon 2, and a second first exon (exon 1b) located 28 kb further upstream. Expression of both mRNA variants was found in all GATA4-expressing organs but with a preference for the exon 1a-containing transcript. The exception was the testis where exon 1a- and 1b-containing transcripts were similarly expressed. In some tissues such as the intestine, alternative transcript expression appears to be regionally regulated. Polysome analysis suggests that both mRNA variants contribute to GATA4 protein synthesis. CONCLUSIONS/SIGNIFICANCE:Taken together, our results indicate that the GATA4 gene closely resembles the other GATA family members in terms of gene structure where alternative first exon usage appears to be an important mechanism for regulating its tissue- and cell-specific expression

Dynamics of the transcriptional landscape during human fetal testis and ovary development

Acknowledgements We thank all members of the SEQanswers forums for helpful advice; Steven Salzberg and Cole Trapnell for continuous support with the ‘Tuxedo’ suite; and the UCSC Genome team members. Sequencing was performed by the GenomEast platform, a member of the ‘France Génomique’ consortium (ANR-10-INBS-0009). We thank Ms Linda Robertson, Ms Margaret Fraser, Ms Samantha Flannigan (University of Aberdeen) and the staff at Grampian NHS Pregnancy Counselling Service and all the staff of the Department of Obstetrics and Gynecology of the Rennes Sud Hospital for their expert assistance and help, and the participating women, without whom this study would not have been possible. The authors are grateful for Ms Gersende Lacombe and Mr Laurent Deleurme from the Biosit CytomeTri cytometry core facility of Rennes 1 University. Funding French National Institute of Health and Medical Research (Inserm); University of Rennes 1; French School of Public Health (EHESP); Swiss National Science Foundation [SNF n° CRS115_171007 to B.J.]; the French National Research Agency [ANR n° 16-CE14-0017-02 and n°18-CE14-0038-02 to F.C]; Medical Research Council [MR/L010011/1 to PAF]; European Community’s Seventh Framework Programme (FP7/2007–2013) [under grant agreement no 212885 to PAF]; European Union’s Horizon 2020 Research and Innovation Programme [under grant agreement no 825100 to P.A.F. and S.M.G.].Peer reviewedPostprin

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism

correction de l'article correspondant à la notice https://prodinra.inra.fr/record/425677International audienceConcern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition named "compensated hypogonadism," a condition prevalent among elderly men and associated with reproductive and physical disorders. In the men, luteinizing hormone (LH) and ibuprofen plasma levels were positively correlated, and the testosterone/LH ratio decreased. Using adult testis explants exposed or not exposed to ibuprofen, we demonstrate that the endocrine capabilities from testicular Leydig and Sertoli cells, including testosterone production, were suppressed through transcriptional repression. This effect was also observed in a human steroidogenic cell line. Our data demonstrate that ibuprofen alters the endocrine system via selective transcriptional repression in the human testes, thereby inducing compensated hypogonadism

Safeguarding Female Reproductive Health against Endocrine Disrupting Chemicals : The FREIA Project

Funding: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 825100.Peer reviewedPublisher PD

Origine et fonction endocrine des cellules de Leydig fœtales – mythes et modes.

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Dissecting the phthalate-induced Sertoli cell injury: the fragile balance of proteases and their inhibitors.

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Effets des antalgiques in utero: de nouvelles pistes en recherche fondamentale.

National audienceEffets des antalgiques in utero : de nouvelles pistes en recherche fondamentaleMAZAUD-GUITTOT SéverineUniv Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, FrancePendant la grossesse, seul le paracétamol est recommandé pour le traitement de la douleur et de la fièvre. Cependant, les recommandations pour l'utilisation de la famille des anti-inflammatoires non stéroïdiens (AINS) pour le traitement de ces symptômes pendant le premier trimestre de la grossesse sont plus flexibles, bien que l'organogenèse commence. Le pourcentage de femmes utilisant des AINS reste important pendant cette période, parfois justifié par le fait que la grossesse n'a pas encore été découverte. En outre, la consommation de paracétamol par la population à risque des femmes enceintes a atteint des sommets ces dernières décennies, atteignant 72% dans certains pays occidentaux (États-Unis). Cette consommation toujours croissante d’antalgiques au cours de cette période fragile est très préoccupante.De nombreuses études récentes plaident en faveur d'une origine développementale fœtale des troubles de la reproduction observés à l'âge adulte. Ces troubles, regroupés sous les termes de «syndrome de dysgénésie testiculaire» et de «syndrome de dysgénésie ovarienne», comprennent des malformations congénitales de l'appareil génital masculin telles que la cryptorchidie et l'hypospadias, une incidence accrue de stérilité, et une incidence accrue d'infertilité, d'endométriose, de troubles de l'utérus et de l'ovaire, tels que l'insuffisance ovarienne prématurée et le syndrome des ovaires polykystiques chez la femme.Les antalgiques ont récemment été identifiés comme une nouvelle famille de perturbateurs endocriniens pour le testicule chez les rongeurs comme chez l'Homme1. Nous avons montré les effets importants de l’ibuprofène pour le développement du testicule fœtal humain ex vivo, que ce soit sur sa fonction endocrine ou sur la lignée germinale2, et les effets sur la fonction endocrine du paracétamol, de l’aspirine et de l’indométacine3. En utilisant des cultures organotypiques d'ovaires fœtaux humains issus d’interruption volontaires de grossesse, nous avons montré que l'ibuprofène est hautement nocif pour le développement de l'ovaire fœtal humain, la lignée germinale étant une cible préférentielle4. Nous caractérisons les effets plus subtils du paracétamol et comparons les effets de quatre AINS, à savoir l'aspirine, le naproxène, le diclofénac et l'acide méfénamique. Nous montrons que, comme pour le testicule fœtal humain, chacun de ces antalgiques a un impact sur l'ovaire fœtal humain avec une signature spécifique au niveau cellulaire.1Kristensen D.M. et al. Nat Rev Endocrinol. 12(7):381-93 (2016); 2Ben Maamar M. et al. Sci. Rep. ;7:44184 (2017) ; 3Mazaud-Guittot S. et al. J Clin Endocrinol Metab 98: E1757–E1767 (2013); 4Leverrier-Penna S. et al. Human Reproduction, 33(3): 482–493 (2018)

Current methods to assess chemical contaminant mixture effects – Ex vivo organ culture.

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