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Apoptosis leads to Spermatocyte depletion
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Histone deacetylase inhibition leading to testicular atrophy||adjacent||High||Not Specified||Brendan Ferreri-Hanberry (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
Apoptosis results in spermatocyte depletion via cell death. Apoptosis and spermatocyte depletion is correlated, where spermatocyte depletion via apoptosis is a general mechanism [Brinkworth et al., 1995].
Evidence Collection Strategy
Evidence Supporting this KER
Induced apoptosis during the development of germ cells results in the progressive depletion of spermatocytes [Brinkworth et al., 1995]. An HDAC inhibitor, MAA, induced apoptosis and spermatocyte depletion at stages IX-II [Brinkworth et al., 1995].
Uncertainties and Inconsistencies
The process of apoptosis is necessary for the meiosis of the stem cell differentiation in the testis, which remains in question for the regulation of spermatocyte deletion and testis atrophy/weight loss [Dym, 1994].
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The apoptosis of the cells leads to spermatocyte depletion. The relationship between apoptosis and spermatocyte depletion is likely well conserved between species. The examples are only given for mammals:
- Spermatogenesis was inhibited by the knockdown of Sucla2, a β subunit of succinyl coenzyme A synthase, via apoptosis in the mouse spermatocyte (Mus musculus) [Huang et al., 2016].
- The suppression of microRNA-21 led to apoptosis of spermatogonial stem cell-enriched germ cell cultures and the decrease in the number of spermatogonial stem cells in mice (Mus musculus) [Niu et al., 2011].
- MAA induced apoptosis and depletion of spermatocytes in adult rats (Rattus norvegicus) [Brinkworth et al., 1995].
The apoptosis and proliferation inhibition induced by MAA, an HDAC inhibitor, was measured in human prostate cancer cell lines (Homo sapiens) [Parajuli et al., 2014].
The cell viability inhibition induced by SAHA or TSA, which are HDAC inhibitors, was observed in NHDFs (Homo sapiens) [Glaser et al., 2003].
The proliferation of the HDAC-/- ES cells was inhibited compared to HDAC+/+ ES cells (Homo sapiens) [Zupkovitz et al., 2010].
It has been reported that the mice lacking both Ink4c and Ink4d, cyclin D-dependent kinase inhibitors, produced few mature sperm, and the residual spermatozoa had reduced motility and decreased viability (Mus musculus) [Zindy et al., 2001].
The sperm counts in the cauda epididymis of rats exposed to butylparaben were significantly decreased (Rattus norvegicus) [Oishi, 2001].
MAA treatment-induced spermatocyte death in Sprague-Dawley rats (Rattus norvegicus) [Wade et al., 2008].
Barqawi, A. et al. (2004), "Effect of prolonged cryptorchidism on germ cell apoptosis and testicular sperm count", Asian J Androl 6:47-51
Bose, R. et al. (2017), "Ubiquitin ligase Huwe1 modulates spermatogenesis by regulating spermatogonial differentiation and entry into meiosis", Sci Rep 7:17759
Brinkworth, M. et al. (1995), "Identification of male germ cells undergoing apoptosis in adult rats", J Reprod Fertil 105:25-33
Dym, M. (1994), "Spermatogonial stem cells of the testis", Proc Natl Acad Sci USA 91:11287-11289
Glaser, K.B. et al. (2003), "Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines", Mol Cancer Ther 2:151-163
Huang, S. et al. (2016), "Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells", Folia Histochem Cytobiol 54:134-142
Niu, Z. et al. (2011), "microRNA-21 regulates the self-renewal of mouse spermatogonial stem cells", Proc Natl Acad Sci 108:12740-12745
Oishi, S. (2001), "Effects of butylparaben on the male reproductive system in rats", Toxicol Indust Health 17:31-39
Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313
Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831
Wang, C. et al. (2017), "CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFkB signaling pathways", Oncotarget 8:3132-3143
Zindy, F. et al. (2001), "Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18Ink4c and p19Ink4d", Mol Cell Biol 21:3244-3255
Zupkovitz, G. et al. (2010), "The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation", Mol Cell Biol 30:1171-1181