API

Relationship: 1735

Title

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Apoptosis leads to Spermatocyte depletion

Upstream event

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Apoptosis

Downstream event

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Spermatocyte depletion

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Histone deacetylase inhibition leading to testicular atrophy adjacent High Not Specified

Taxonomic Applicability

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Term Scientific Term Evidence Link
Mus musculus Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Sex Applicability

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Sex Evidence
Male High

Life Stage Applicability

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Term Evidence
Adult, reproductively mature High

Key Event Relationship Description

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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

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Biological Plausibility

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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].

Empirical Evidence

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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

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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

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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].

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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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].

References

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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