Relationship: 1717



Histone deacetylase inhibition leads to Testicular atrophy

Upstream event


Histone deacetylase inhibition

Downstream event


Testicular atrophy

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

Taxonomic Applicability


Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Sex Applicability


Sex Evidence
Male High

Life Stage Applicability


Term Evidence
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


Biological Plausibility


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


  • 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


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


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




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