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Prenatal programming by testosterone of follicular theca cell functions in ovary

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Abstract

In mammalian ovaries, the theca layers of growing follicles are critical for maintaining their structural integrity and supporting androgen synthesis. Through combining the postnatal monitoring of ovaries by abdominal magnetic resonance imaging, endocrine profiling, hormonal analysis of the follicular fluid of growing follicles, and transcriptomic analysis of follicular theca cells, we provide evidence that the exposure of ovine fetuses to testosterone excess activates postnatal follicular growth and strongly affects the functions of follicular theca in adulthood. Prenatal exposure to testosterone impaired androgen synthesis in the small antral follicles of adults and affected the expression in their theca cells of a wide array of genes encoding extracellular matrix components, their membrane receptors, and signaling pathways. Most expression changes were uncorrelated with the concentrations of gonadotropins, steroids, and anti-Müllerian hormone in the recent hormonal environment of theca cells, suggesting that these changes rather result from the long-term developmental effects of testosterone on theca cell precursors in fetal ovaries. Disruptions of the extracellular matrix structure and signaling in the follicular theca and ovarian cortex can explain the acceleration of follicle growth through altering the stiffness of ovarian tissue. We propose that these mechanisms participate in the etiology of the polycystic ovarian syndrome, a major reproductive pathology in woman.

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Data availability

Raw Fastq files have been deposited in the NCBI sequenced Read archive under accession numbers SRR8776922-SRR8776937.

Abbreviations

AMH:

Anti-Müllerian hormone

DEGs:

Differentially expressed genes

ECM:

Extracellular matrix

ELISA:

Enzyme-linked immunosorbent assay

FSH:

Follicle stimulating hormone

GO:

Gene ontology

GnRH:

Gonadotropin-releasing hormone

IPA:

Ingenuity pathway analysis

LH:

Luteinizing hormone

MRI:

Magnetic resonance imaging

PCOS:

Polycystic ovarian syndrome

RT-qPCR:

Real-time quantitative PCR

sPLS:

Sparse partial least squares

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Acknowledgements

The authors acknowledge Damien Capo, Olivier Lasserre and the “ruminant” team of the “Unité Expérimentale de Physiologie Animale de l’Orfrasière” (UEPAO) for animal management and participation in the experimental design, Ramon Rubio (SIO ADM) for the gift of sesame oil used to dilute testosterone propionate before injections to ewes, Jean-Luc Touzé for ultrasonography scanning of lamb ovaries and Dominique Gennetay for her technical participation in hormonal assays. We acknowledge also the team of the “Chirurgie et Imagerie pour la Recherche et l’Enseignement” (CIRE) platform, particularly Gilles Gomot, Dominique Girardeau, Emilie Bled for abdominal magnetic resonance imaging analysis of sheep, and Jean-Philippe Dubois for animal slaughtering. The authors thank Julien Sarry for technical assistance in RNA library preparation, the staff of the GeT-Genotoul genomic platform (https//get/genotoul.fr/) for RNA sequencing, and Sarah Maman of the INRA Sigenae bioinformatics team for Galaxy support. We address special thanks to Kim-Anh le Cao and Sebastien Dejean for mixOmics training. We are also very grateful to Frédérique Robin and Frédérique Clément for their help in statistical analyses of endocrine data and their invaluable inputs in writing the manuscript.

Funding

This work was supported by Grants from France via the “Agence Nationale pour la Recherche” (https://anr.fr/) (ANR-12-BSV1-0034-02, AMHAROC). Anthony Estienne was supported by a French Fellowship from the Région Centre and INRA.

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Authors and Affiliations

  1. UMR Physiologie de la Reproduction et des Comportements, INRA, CNRS, IFCE, Université de Tours, 37380, Nouzilly, France

    Danielle Monniaux, Virginie Maillard, Peggy Jarrier, Hans Adriaensen, Anne-Lyse Lainé, Corinne Laclie, Pascal Papillier, Anthony Estienne, Juliette Cognié & Rozenn Dalbies-Tran

  2. GenPhySE, Université de Toulouse, INRA, INPT, ENVT, 31320, Castanet Tolosan, France

    Carine Genêt, Florence Plisson-Petit & Stéphane Fabre

  3. BOA, INRA, Université de Tours, 37380, Nouzilly, France

    Christelle Hennequet-Antier

  4. Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), 75012, Paris, France

    Nathalie di Clemente

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Ethical approval

All experimental procedures were approved by the French Agricultural and Scientific Research Government Committee (Approval number E37-175-2) and the Val de Loire ethics committee for animal experimentation (Referral 2012-12-21, n°19), in accordance with the guidelines for Care and Use of Agricultural Animals in Agricultural Research and Teaching.

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Monniaux, D., Genêt, C., Maillard, V. et al. Prenatal programming by testosterone of follicular theca cell functions in ovary. Cell. Mol. Life Sci. 77, 1177–1196 (2020). https://doi.org/10.1007/s00018-019-03230-1

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