API

Relationship: 1717

Title

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Histone deacetylase inhibition leads to Testicular atrophy

Upstream event

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Histone deacetylase inhibition

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 non-adjacent Moderate Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens 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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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

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Biological Plausibility

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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].

Empirical Evidence

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  • HDAC inhibitor, methoxyacetic acid (MAA), (300 mg/kg) induced testicular toxicity measured with testis weight loss [Miller et al., 1982].
  • MAA induced apoptosis and degeneration in spermatocytes in human testicular tissue and 25-day rat seminiferous tubule cultures [Li et al., 1996].
  • MAA-induced spermatocyte death with an association of histone acetylation increase [Wade et al., 2008].
  • MAA-induced apoptosis in male germ cells was modulated by Sertoli cells via P/Q type voltage-operated calcium channels [Barone et al., 2005].
  • The p.o. administration of ethylene glycol monomethyl (500 mg/kg/day) in rats induced the testis or liver organ weight loss on 2, 4, 7 and 11 days or 24 hrs and 2, 4 and 7 days after treatment, respectively [Foster et al., 1983].
  • The investigation of 2-methoxyethanol (2-ME)-induced testicular toxicity has revealed that the conversion of 2-ME to MAA is required in 2-ME-induced testicular toxicity [Moss et al., 1985].

Uncertainties and Inconsistencies

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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].

Quantitative Understanding of the Linkage

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MAA administration (592 mg/kg/day) for 4 days showed testis weight loss in which the relative organ weights were 0.773 ± 0.022 g/100 g body weight, compared to 0.985 ± 0.028 g/100g body weight in control treated with water [Foster et al., 1984].

Response-response Relationship

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Time-scale

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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

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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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].

 

References

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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