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Human and animal fertility studies in cystinosis reveal signs for obstructive azoospermia, a disruptive blood-testis barrier and a subtherapeutic effect of cysteamine in testes

Reda, Ahmed, Veys, Koenraad, Kadam, Prashant, Taranta, Anna, Rega, Laura R, Goffredo, Bianca M, Camps, Chelsea, Besouw, Martine, Cyr, Daniel G. ORCID: https://orcid.org/0000-0002-6566-783X, Albersen, Maarten, Spiessens, Carl, de Wever, Liesbeth, Hamer, Robert, Janssen, Mirian C H, D'Hauwers, Kathleen, Wetzels, Alex, Monnens, Leo, Van den Heuvel, Lambertus, Goossens, Ellen et Levtchenko, Elena (2021). Human and animal fertility studies in cystinosis reveal signs for obstructive azoospermia, a disruptive blood-testis barrier and a subtherapeutic effect of cysteamine in testes Journal of Inherited Metabolic Disease , vol. 44 , nº 6. p. 1393-1408. DOI: 10.1002/jimd.12434.

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Résumé

Cystinosis is an inherited metabolic disorder caused by recessive mutations in the CTNS gene. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which is not improved by cysteamine treatment, the only available disease-modifying treatment. We aimed at unravelling the origin of azoospermia in cysteamine-treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns(-/-) mice model compared to wild-type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact either at testicular or epididymal level in cystinosis patients, an enlarged caput epididymis and reduced levels of seminal markers for obstruction Neutral α-Glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Transcriptomic analysis of CTNS KD in a fertile human caput epididymal cell line demonstrated upregulation of pathways related to inflammation and cell polarization. Interestingly, histopathological examination in human and mice revealed a disturbed blood-testis barrier (BTB) characterized by an altered zonula occludens-1 (ZO-1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, and showed that cystine in the testes is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism as an additional non-obstructive process. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testes. This article is protected by copyright. All rights reserved.

Type de document: Article
Mots-clés libres: Azoospermia; Cysteamine; Cystinosis; Epididymal Obstruction; Infertility
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 30 juin 2022 14:06
Dernière modification: 30 juin 2022 14:06
URI: https://espace.inrs.ca/id/eprint/12427

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