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Relationship: 1734

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Spermatocyte depletion leads to Testicular atrophy

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Spermatocyte depletion

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Testicular atrophy

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Mus musculus	Mus musculus	High	NCBI
Rattus norvegicus	Rattus norvegicus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult, reproductively mature	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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].

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

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

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

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].

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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].

References

List of the literature that was cited for this KER description. More help

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