Upstream eventspermatocyte depletion
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leading to testicular toxicity||adjacent||High||Not Specified|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
Spermatocyte depletion includes and is included in testicular toxicity such as testicular atrophy. The treatment of ethylene glycol monomethyl ether induces spermatocyte depletion and testicular atrophy [Chapin, 1984].
Evidence Supporting this KER
Spermatocyte depletion caused by apoptosis leads to the testicular toxicity. Apoptosis is a basic biological phenomenon in which the cells are controlled in the atrophy of various tissues and organs through the deletion and turnover, as well as in tumor regression [Kerr, 1972].
2-methoxyethanol (ME) or its major metabolite, methoxyacetic acid (MAA), HDAC inhibitor, induced spermatocyte depletion and testicular atrophy [Beattie, 1984].
Uncertainties and Inconsistencies
Spermatogonial stem cell self-renewal and spermatocyte meiosis are regulated by Sertoli cell signaling, which suggests us that various pathways in spermatocytes or spermatogonia are involved in the spermatocyte deletion and testis atrophy/weight loss [Chen, 2015].
Quantitative Understanding of the Linkage
The sperm count as well as motility and morphology were decreased in mice [Abedi, 2017]. Exposures with hydroxyurea decreased the early pachtene spermatocytes on days 5 and 10, and induced testicular atrophy [Wiger, 1995]. The ratio between self-renewal and differentiation of the spermatogonial stem cells is regulated by glial cell line-derived neurotrophic factor produced by Sertoli cells [de Rooij, 2001]. The development of the spermatogenic cell lineage is strictly regulated with 12 epithelial stages, in which G1 arrest is involved [de Rooij, 1998].
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship between spermatocyte depletion and testicular toxicity is likely well conserved between species.
- ME and MAA induced spermatocyte depletion and testicular atrophy in rat (Rattus norvegicus) [Beattie, 1984].
- Ethylene glycol monomethyl ether induced depletion of late spermatocytes and testicular atrophy in F344 rat (Rattus norvegicus) [Chapin, 1984].
- The epididymal tubules of rats with testicular degeneration had low sperm density (Rattus norvegicus) [Lee, 1993].
- Hydroxyurea induced spermatocyte reduction and testicular atrophy (Mus musculus) [Wiger, 1995].
Chapin RE et al. (1984) The effects of ethylene glycol monomethyl ether on testicular histology in F344 rats. J Andro 5: 369-380
Kerr JFR et al. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239-257
Beattie PJ, et al. (1984) The effect of 2-methoxyethanol and methoxyacetic acid on Sertoli cell lactate production and protein synthesis in vitro. Toxicol Appl Pharmacol 76: 56-61
Chen S and Liu Y. (2015) Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. Reproduction 149: R159-R167
Abedi N et al. (2017) Short and long term effects of different doses of paracetamol on sperm parameters and DNA integrity in mice. Middle East Fertility Society Journal 22: 323-328
Wiger R et al. (1995) Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatin structure in laboratory mice. Reprod Toxicol 9: 21-33
De Rooij DG et al. (2001) Proliferation and differentiation of spermatogonial stem cells. Reproduction 121: 347-354
De Rooij DG. (1998) Stem cells in the testis. Int J Exp Path 79: 67-80
Lee KP et al. (1993) Testicular degeneration and spermatid retention in young male rats. Toxicol Pathol 21: 292-302