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Spermatocyte depletion leads to Testicular atrophy
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Histone deacetylase inhibition leading to testicular atrophy||adjacent||High||Not Specified||Shihori Tanabe (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
Spermatocyte depletion leads to testicular atrophy with a 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 atrophy.
Evidence Collection Strategy
Evidence Supporting this KER
Spermatocyte depletion caused by apoptosis leads to testicular atrophy. Apoptosis is a basic biological phenomenon in which the cells are controlled through the deletion and turnover in the atrophy of various tissues and organs as well as in tumor regression [Kerr et al., 1972].
2-methoxyethanol (ME) or its major metabolite, methoxyacetic acid (MAA), an 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 that various pathways in spermatocytes or spermatogonia are involved in the spermatocyte deletion and testis atrophy/weight loss [Chen et al., 2015].
Known modulating factors
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 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 rats (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