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|
|Homo sapiens||Homo sapiens||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
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, 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
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].
- 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].
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