API

Relationship: 1734

Title

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spermatocyte depletion leads to testicular toxicity

Upstream event

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spermatocyte depletion

Downstream event

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testicular toxicity

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 toxicity 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 includes and is included in testicular toxicity such as testicular atrophy. The treatment of ethylene glycol monomethyl ether induces spermatocyte depletion and testicular atrophy [Chapin, 1984].

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, 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, 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, 2015].

Quantitative Understanding of the Linkage

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The sperm count as well as motility and morphology were decreased in mice [Abedi, 2017]. Exposures with hydroxyurea decreased the early pachtene spermatocytes on days 5 and 10, and induced testicular atrophy [Wiger, 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, 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, 1984].
  • Ethylene glycol monomethyl ether induced depletion of late spermatocytes and testicular atrophy in F344 rat (Rattus norvegicus) [Chapin, 1984].
  • The epididymal tubules of rats with testicular degeneration had low sperm density (Rattus norvegicus) [Lee, 1993].
  • Hydroxyurea induced spermatocyte reduction and testicular atrophy (Mus musculus) [Wiger, 1995].

References

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

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

Beattie PJ, 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

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

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

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

De Rooij DG et al. (2001) Proliferation and differentiation of spermatogonial stem cells. Reproduction 121: 347-354

De Rooij DG. (1998) Stem cells in the testis. Int J Exp Path 79: 67-80

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