Upstream eventHistone deacetylase inhibition
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leading to testicular atrophy||non-adjacent||Moderate||Moderate|
Life Stage Applicability
|Adult, reproductively mature||Moderate|
Key Event Relationship Description
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
MAA administration induces the spermatocyte deaths, which has been revealed by section staining of the germ cell death [Wade et al., 2008].
Histone deacetylase inhibition causes histone acetylation, which increases the gene expression of cell-cyle related protein, followed by spermatocyte apoptosis in testis.
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
Quantitative Understanding of the Linkage
The administration of MAA in rats induced spermatocyte depletion which was confirmed with TUNEL-staining of the germ cells [Wade et al., 2008].
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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
・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].
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