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, 1982]. HDAC inhibition in cell culture resulted in the testicular toxicity including germ cell apoptosis and cell morphology change [Li, 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, 1996]. The HDAC inhibitor treatment resulted in degeneration in spermatocytes in rat seminiferous tubules [Li, 1996]. The HDAC inhibition induced the germ cell apoptosis in human testicular tissues [Li, 1996].

Empirical Evidence


  • HDAC inhibitor, methoxyacetic acid (MAA), (300 mg/kg) induced testicular toxicity measured with testis weight loss [Miller, 1982].
  • MAA induced apoptosis and degeneration in spermatocytes in human testicular tissue and 25-day rat seminiferous tubule cultures [Li, 1996].
  • MAA-induced spermatocyte death with an association of histone acetylation increase [Wade, 2008].
  • Doxorubicin, which has a testicular toxicity, induced caspase 3 activation and g-H2AX induction, apoptosis markers, in human lung cancer A549 cells [El-Awady, 2015, Yamazoe, 2015].
  • Doxorubicin-resistant A549 cells showed reduced expression of HDAC1, 3 and 4 compared to A549 cells [El-Awady, 2015].
  • MAA-induced apoptosis in male germ cells was modulated by Sertoli cells via P/Q type voltage-operated calcium channels [Barone, 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, 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, 1985].
  • The exposure of MAA induced morphological changes on embryonic forelimbs [Dayan, 2014].

Uncertainties and Inconsistencies


Methyl and ethyl esters of p-hydroxybenzoic acid did not show spermatotoxic effects in rats (Rattus norvegicus) [Oishi, 2004]. 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, 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, 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, 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, 1984]. The treatment of 5 mM MAA for 5 hrs induced the pachytene spermatocyte death in early stage tubules in 19 hrs [Li, 1996]. The degeneration in late spermatocytes was observed in late-stage tubules in 19 hrs after 5 mM MAA treatment for 5 hrs [Li, 1996].

Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability


The administration of di(2-ethylhexyl)-phthalate induced testis atrophy in rats (Rattus norvegicus) [Oishi, 1994]. The administration of butylparaben resulted in decrease in sperm counts in rats (Rattus norvegicus) [Oishi, 2001]. MAA induced spermatocyte apoptosis in human testes (Homo sapiens) [Li, 1996].



Miller RR et al. (1982) Toxicity of methoxyacetic acid in rats. Fundam Appl Toxicol 2: 158-160

Li LH et al. (1996) 2-Methoxyacetic acid (MAA)-induced spermatocyte apoptosis in human and rat testes: an in vitro comparison. J Androl 17: 538-549

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

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

El-Awady RA et al. (2015) Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy. Cancer Biol Ther 16: 1056-1070

Yamazoe Y. et al. (2015) Embryo- and testicular-toxicities of methoxyacetate and the related: a review on possible roles of one-carbon transfer and histone modification. Food Safety 3:92-107

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 PM et al. (1983) Testicular toxicity of ethylene glycol monomethyl and monoethyl ethers in the rat. Toxicol Appl Pharmacol 69:385-399

Moss EJ et al. (1985) The role of metabolism in 2-methoxyethanol-induced testicular toxicity. Toxicol Appl Pharmacol 79:480-489

Dayan C and Hales BF. (2014) Effects of ethylene glycol monomethyl ether and its metabolite, 2-methoxyacetic acid, on organogenesis stage mouse limbs in vitro. Birth Defects Res (Part B) 101:254-261

Oishi S. (2004) Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food Chem Tox 42: 1845-1849

Menegola E et al. (2006) Inhibition of histone deacetylase as a new mechanism of teratogensis. Birth Defects Res 78: 345-353

Wise LD et al. (2008) Assessment of female and male fertileity in Sprague-Dawley rats administered vorinostat, a histone deacetylase inhibitor. Birth Defects Res B Dev Reprod Toxicol 83: 19-26

Foster PM et al. (1984) Testicular toxicity produced by ethylene glycol monomethyl and monoethyl esters in the rat. Environ Health Perspect 57: 207-217

Oishi S. (1994) Prevention of Di(2-ethylhexyl)phthalate-induced testicular atrophy in rats by co-administration of the vitamin B12 derivative denosylcobalamin. Arch Environ Contam Toxicol 26: 497-503

Oishi S. (2001) Effects of butylparaben on the male reproductive system in rats. Tox Industr Health 17: 31-39