Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leading to testicular atrophy||adjacent||High||Not Specified|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
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 Supporting this KER
Induced apoptosis during development of germ cells results in progressive depletion of spermatocyte [Brinkworth et al., 1995]. A HDAC inhibitor, MAA, induced apoptosis and spermatocyte depletion at stages IX-II [Brinkworth et al., 1995].
In the mouse spermatocyte, spermatogenesis is inhibited by knockdown of Sucla2, a beta subunit of succinyl coenzyme A synthase, which is located in mitochondria and catalyzes the reversible synthesis of succinate and adenosine triphosphate in the tricarboxylic acid cycle [Huang et al., 2016]. The knockdown of Sucla2 induces apoptosis of mouse spermatocytes [Huang et al., 2016]. The prolonged cryptorchidism leads to germs cell apoptosis and testicular sperm count decrease [Barqawi et al., 2004]. CD147 was reported to regulate apoptosis in mouse testis and spermatocyte cell line (GC-2 cells) via NFκB pathway [Wang et al., 2017]. MicroRNA-21 regulates the spermatogonial stem cell homeostasis, in which suppression of microRNA-21 with anti-miR-21 oligonucleotides led to apoptosis of spermatogonial stem cell-enriched germ cell cultures and the decrease in the number of spermatogonial stem cells [Niu et al., 2011].
Uncertainties and Inconsistencies
The process of apoptosis is necessary for the meitosis 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].
Quantitative Understanding of the Linkage
The apoptotic germ cells occurred in the Stra8-Cre KO tubules were approximately 68%, whereas 46% of the cells were germ cells in WT tubules, as determined by double staining for Tra98, a germ cell marker, and cleaved caspase 3 [Bose et al., 2018].
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.
- Spermatogenesis was inhibited by 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, a 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 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 epidydimis 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