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Histone deacetylase inhibition leads to Testicular atrophy
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Histone deacetylase inhibition leading to testicular atrophy||non-adjacent||Moderate||Moderate||Brendan Ferreri-Hanberry (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
HDAC inhibition induced testicular toxicity including testis atrophy such as the decrease in size [Miller et al., 1982]. HDAC inhibition in cell culture resulted in the testicular toxicity including germ cell apoptosis and cell morphology change [Li et al., 1996]. Valproic acid, a HDAC inhibitor, caused a reduced testicular weight in the offspring in rats [Kallen, 2004].
Evidence Supporting this KER
The HDAC inhibition induced cell death in spermatocytes in both rat and human seminiferous tubules [Li et al., 1996]. The HDAC inhibitor treatment resulted in degeneration in spermatocytes in rat seminiferous tubules [Li et al., 1996]. The HDAC inhibition induced the germ cell apoptosis in human testicular tissues [Li et al., 1996].
Uncertainties and Inconsistencies
It is reported that HDAC inhibition leads to teratogenic toxicity, whereas the correlation with testicular toxicity and teratogenic toxicity by HDAC inhibition is not fully understood [Menegola et al., 2006]. The oral administration of vorinostat (SAHA), a HDAC inhibitor, in Sprague-Dawley rats showed no indication of reproductive toxicity in drug-treated male rats, which suggested the involvement of some compensation mechanisms or digestion [Wise et al., 2008]. Some studies have demonstrated that the decrease in histone acetylation in spermatids is associated with impaired spermatogenesis corresponding with the well-known reduction of protamine expression in the cells [Sonnack et al., 2002; Li et al., 2014]. It has also been reported that the histological examination of sections revealed no difference between wild-type and HDAC6-deficient testes [Zhang et al., 2008].
The relative testicular weight was decreased at day 2 after the treatment of 500 mg/kg/day treatment of ethylene glycol monomethyl ether [Foster et al., 1984]. The treatment of 5 mM MAA for 5 hrs induced the pachytene spermatocyte death in early stage tubules in 19 hrs [Li et al., 1996]. The degeneration in late spermatocytes was observed in late-stage tubules in 19 hrs after 5 mM MAA treatment for 5 hrs [Li et al., 1996].
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
MAA induced spermatocyte apoptosis and cell morphogy change in human testes (Homo sapiens) [Li et al., 1996].
Valproic acid caused the decrease in rat testicular weight (Rattus norvegicus) [Kallen, 2004].
Barone, F. et al. (2005), "Modulation of MAA-induced apoptosis in male germ cells: role of Sertoli cell P/Q-type calcium channels", Reprod Biol Endocrinol 3:13
Foster, P.M. et al. (1983), "Testicular toxicity of ethylene glycol monomethyl and monoethyl ethers in the rat", Toxicol Appl Pharmacol 69:385-399
Foster, P.M. et al. (1984), "Testicular toxicity produced by ethylene glycol monomethyl and monoethyl esters in the rat", Environ Health Perspect 57:207-217
Kallen, B. (2004), "Valproic acid is known to cause hypospadias in man but does not reduce anogenital distance or causes hypospadias in rats", Basic Clin Pharmacol Toxicol 94:51-54
Li, L.H. et al. (1996), "2-Methoxyacetic acid (MAA)-induced spermatocyte apoptosis in human and rat testes: an in vitro comparison", J Androl 17:538-549
Li, W. et al. (2014), "Chd5 orchestrates chromatin remodeling during sperm development", Nat Commun 5:3812
Menegola, E. et al. (2006), "Inhibition of histone deacetylase as a new mechanism of teratogensis", Birth Defects Res 78:345-353
Miller, R.R. et al. (1982), "Toxicity of methoxyacetic acid in rats", Fundam Appl Toxicol 2:158-160
Moss, E.J. et al. (1985), "The role of metabolism in 2-methoxyethanol-induced testicular toxicity", Toxicol Appl Pharmacol 79:480-489
Sonnack, V. et al. (2002), "Expression of hyperacetylated histone H4 during normal and impaired human spermatogenesis", Andrologia. 34:384-390
Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831
Wise, L.D. et al. (2008), "Assessment of female and male fertility in Sprague-Dawley rats administered vorinostat, a histone deacetylase inhibitor", Birth Defects Res B Dev Reprod Toxicol 83:19-26
Zhang, Y. et al. (2008), "Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally", Mol Cel Biol 28:1688-1701