Upstream eventSpermatocyte depletion
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leading to testicular atrophy||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 leads to testicular toxicity such as testicular atrophy with decrease in size. The spermatocyte depletion is involved in testicular atrophy and testicular toxicity [Chapin et al., 1984]. There are different insults that can induce spermatocyte depletion and consequently testicular toxicity.
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 et al., 1972].
2-methoxyethanol (ME) or its major metabolite, methoxyacetic acid (MAA), HDAC inhibitor, induced spermatocyte depletion and testicular atrophy [Beattie et al., 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 et al., 2015].
Quantitative Understanding of the Linkage
The sperm count as well as motility and morphology were decreased in mice [Abedi et al., 2017]. Exposures with hydroxyurea decreased the early pachtene spermatocytes on days 5 and 10, and induced testicular atrophy [Wiger et al., 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 et al., 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 et al., 1984].
- Ethylene glycol monomethyl ether induced depletion of late spermatocytes and testicular atrophy in F344 rat (Rattus norvegicus) [Chapin et al., 1984].
- The epididymal tubules of rats with testicular degeneration had low sperm density (Rattus norvegicus) [Lee et al., 1993].
- Hydroxyurea induced spermatocyte reduction and testicular atrophy (Mus musculus) [Wiger et al., 1995].
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
Beattie, P.J. 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
Chapin, R.E. et al. (1984), "The effects of ethylene glycol monomethyl ether on testicular histology in F344 rats", J Andro 5:369-380
Chen, S. and Liu, Y. (2015), "Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling", Reproduction 149:R159-R167
de Rooij, D.G. et al. (2001), "Proliferation and differentiation of spermatogonial stem cells", Reproduction 121:347-354
de Rooij, D.G. (1998), "Stem cells in the testis", Int J Exp Path 79:67-80
Kerr, J.F.R. et al. (1972), "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics", Br J Cancer 26:239-257
Lee, K.P. et al. (1993), "Testicular degeneration and spermatid retention in young male rats", Toxicol Pathol 21:292-302
Wiger, R. et al. (1995), "Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatin structure in laboratory mice", Reprod Toxicol 9:21-33