API

Relationship: 1734

Title

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Spermatocyte depletion leads to Testicular atrophy

Upstream event

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Spermatocyte depletion

Downstream event

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Testicular atrophy

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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Spermatocyte depletion leads to testicular toxicity such as testicular atrophy with decrease in size. The spermatocyte depletion is involved in testicular atrophy and testicular toxicity [Chapin et al., 1984]. There are different insults that can induce spermatocyte depletion and consequently testicular toxicity.

Evidence Supporting this KER

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Biological Plausibility

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Spermatocyte depletion caused by apoptosis leads to the testicular toxicity. Apoptosis is a basic biological phenomenon in which the cells are controlled in the atrophy of various tissues and organs through the deletion and turnover, as well as in tumor regression [Kerr et al., 1972].

Empirical Evidence

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2-methoxyethanol (ME) or its major metabolite, methoxyacetic acid (MAA), HDAC inhibitor, induced spermatocyte depletion and testicular atrophy [Beattie et al., 1984].

Uncertainties and Inconsistencies

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Spermatogonial stem cell self-renewal and spermatocyte meiosis are regulated by Sertoli cell signaling, which suggests us that various pathways in spermatocytes or spermatogonia are involved in the spermatocyte deletion and testis atrophy/weight loss [Chen et al., 2015].

Quantitative Understanding of the Linkage

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The sperm count as well as motility and morphology were decreased in mice [Abedi et al., 2017]. Exposures with hydroxyurea decreased the early pachtene spermatocytes on days 5 and 10, and induced testicular atrophy [Wiger et al., 1995]. The ratio between self-renewal and differentiation of the spermatogonial stem cells is regulated by glial cell line-derived neurotrophic factor produced by Sertoli cells [de Rooij et al., 2001]. The development of the spermatogenic cell lineage is strictly regulated with 12 epithelial stages, in which G1 arrest is involved [de Rooij, 1998].

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 relationship between spermatocyte depletion and testicular toxicity is likely well conserved between species.

  • ME and MAA induced spermatocyte depletion and testicular atrophy in rat (Rattus norvegicus) [Beattie et al., 1984].
  • Ethylene glycol monomethyl ether induced depletion of late spermatocytes and testicular atrophy in F344 rat (Rattus norvegicus) [Chapin et al., 1984].
  • The epididymal tubules of rats with testicular degeneration had low sperm density (Rattus norvegicus) [Lee et al., 1993].
  • Hydroxyurea induced spermatocyte reduction and testicular atrophy (Mus musculus) [Wiger et al., 1995].

References

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Abedi, N. et al. (2017), "Short and long term effects of different doses of paracetamol on sperm parameters and DNA integrity in mice", Middle East Fertility Society Journal 22:323-328

Beattie, P.J. et al. (1984), "The effect of 2-methoxyethanol and methoxyacetic acid on Sertoli cell lactate production and protein synthesis in vitro", Toxicol Appl Pharmacol 76:56-61

Chapin, R.E. et al. (1984), "The effects of ethylene glycol monomethyl ether on testicular histology in F344 rats", J Andro 5:369-380

Chen, S. and Liu, Y. (2015), "Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling", Reproduction 149:R159-R167

de Rooij, D.G. et al. (2001), "Proliferation and differentiation of spermatogonial stem cells", Reproduction 121:347-354

de Rooij, D.G. (1998), "Stem cells in the testis", Int J Exp Path 79:67-80

Kerr, J.F.R. et al. (1972), "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics", Br J Cancer 26:239-257

Lee, K.P. et al. (1993), "Testicular degeneration and spermatid retention in young male rats", Toxicol Pathol 21:292-302

Wiger, R. et al. (1995), "Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatin structure in laboratory mice", Reprod Toxicol 9:21-33