API

Relationship: 2010

Title

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Histone deacetylase inhibition leads to Spermatocyte depletion

Upstream event

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Histone deacetylase inhibition

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 non-adjacent Moderate Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
rat 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 Moderate

Key Event Relationship Description

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Histone deacetylase inhibition trigerred by histone deacetylase inhibitors such as methoxyacetic acid (MAA) leads to spermatocyte death causing spermatocyte depletion [Wade et al., 2008]. Histone deacetylase inhibition leads to increase in histone acetylation, leading to spermatocyte apoptosis.

Evidence Supporting this KER

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MAA administration induces the spermatocyte deaths, which has been revealed by section staining of the germ cell death [Wade et al., 2008].

Biological Plausibility

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Histone deacetylase inhibition causes histone acetylation, which increases the gene expression of cell-cyle related protein, followed by spermatocyte apoptosis in testis.

Empirical Evidence

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Administration of MAA in rats, a histone deacetylase inhibitor, demonstrated the emergence of TUNEL-positive spermatocytes, which indicates the spermatocyte apoptosis [Wade et al., 2008]. Treatment of valproate (VPA) resulted in a decline in the sperm count [Yerby and McCoy, 1999; Kose-Ozlece et al., 2015].

Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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The administration of MAA in rats induced spermatocyte depletion which was confirmed with TUNEL-staining of the germ cells [Wade et al., 2008].

Response-response Relationship

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Time-scale

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TUNEL-positive germ cell were increased after 8, 12, and 24 hrs of MAA exposure (650 mg/kg i.p.) in the rats [Wade et al., 2008]. TUNEL-positive zygotene spermratocytes were emerged in after 12 hrs of MAA exposure in the rats, which was confirmed by the section staining [Wade et al., 2008].  

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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・Histone deacetylase inhibition by histone deacetylase inhibitors caused spermatocyte death in rats. MAA treatment induced spermatocyte death in Sprague-Dawley rats (Rattus norvegicus) [Wade et al., 2008].

・VPA exposure caused decrease in sperm count in human (Homo sapiens) [Yerby and McCoy, 1999; Kose-Ozlece et al., 2015].

 

References

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Kose-Ozlece, H. et al. (2015), "Alterations in semen parameters in men wıth epilepsy treated with valproate", Iran J Neurol 14:164-167

Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831

Yerby, M.S. and McCoy, G.B. (1999), "Male infertility: Possible association with valproate exposure", Epilepsia 40:520-521