Can proteomic analysis help us understand the molecular events in men with idiopathic germ cell aplasia?

Abstract

Nonobstructive azoospermia (NOA) is a condition in which no sperm is found in the ejaculate due to failure of spermatogenesis. Studies have identified specific biomarkers in men with NOA; however, few markers, such as karyotype and Y chromosome microdeletion, have been successfully translated to the clinic (1Behre H.M. Bergmann M. Simoni M. et al.Primary Testicular Failure. [Updated 2015 Aug 30].in: Feingold K.R. Anawalt B. Boyce A. Endotext [Internet]. MDText.com, Inc., South Dartmouth (MA)2000https://www.ncbi.nlm.nih.gov/books/NBK279076/Google Scholar). In adult mammalian testes, Sertoli and germ cells are in close contact with the basement membrane, a modified form of extracellular matrix (ECM). The ECM plays a significant role in regulating spermatogenesis (2Siu M.K. Cheng C.Y. Extracellular matrix and its role in spermatogenesis.Adv Exp Med Biol. 2008; 636: 74-91Crossref PubMed Scopus (55) Google Scholar). Vitamin A is known to affect the ECM and regulates germ cell differentiation, and spermatogenesis (3Hogarth C.A. Griswold M.D. The key role of vitamin A in spermatogenesis.J Clin Invest. 2010; 120: 956-962Crossref PubMed Scopus (171) Google Scholar). These factors suggest the significance of exploring ECM for NOA. The article by Alfano et al. (4Alfano M. Pederzoli F. Locatelli I. Ippolito S. Longhi E. Zerbi P. et al.Impaired testicular signaling of vitamin A and vitamin K contributes to the aberrant composition of the extracellular matrix in idiopathic germ cell aplasia.Fertil Steril. 2019; 111: 687-698Abstract Full Text Full Text PDF Scopus (12) Google Scholar) used proteomic analysis to investigate the ECM as a potential source of biomarker detection in men with idiopathic germ cell aplasia. For this, the investigators used 5 control biopsies from testes of men with seminoma and 5 biopsies from a group of 20 men with idiopathic NOA. Among the 20 men with NOA, 10 had sperm identified on micro-testicular sperm extraction (TESE) and 10 did not. Proteomic analysis of 5 controls and 10 men with NOA showed deregulation of 11 ECM proteins in men with NOA, including components of the basement membrane. Among the 11 ECM proteins, 5 were involved with vitamin A (retinoic acid) and vitamin K signaling. In men with NOA compared to controls, the investigators demonstrated that decreased vitamin K signaling in Leydig cells and increased vitamin A signaling in Sertoli cells was associated with NOA. Although the investigators discussed the importance of ECM composition on testicular environment and role of retinoic acid and vitamin K signaling on germ cell aplasia, they did not explain the rationale behind exclusion of miR-663 and p53 from the five upstream regulators they selected for the validation. In addition, validation of more ECM markers from proteomic study could have strengthened the argument of their potential use as a biomarker to understand the pathogenesis of NOA. In summary, this critical study reports findings similar to a previous study (5Clavijo R.I. Arora H. Gibbs E. Cohen S. Griswold A. Bakircioglu E. et al.Whole exome sequencing of a consanguineous Turkish family identifies a mutation in GTF2H3 in brothers with spermatogenic failure.Urology. 2018; 120: 86-89Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar) that demonstrated the importance of retinoic acid signaling in a consanguineous Turkish family with NOA. Furthermore, this study highlights the importance of vitamin A and vitamin K signaling to identify the biomarkers that could be clinically translated to understand the pathophysiology of NOA. Impaired testicular signaling of vitamin A and vitamin K contributes to the aberrant composition of the extracellular matrix in idiopathic germ cell aplasiaFertility and SterilityVol. 111Issue 4PreviewTo study pathogenic features of the somatic testicular microenvironment associated with idiopathic germ cell aplasia. Full-Text PDF Open Access