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Relationship: 1735


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

Apoptosis leads to Spermatocyte depletion

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 Brendan Ferreri-Hanberry (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

Apoptosis results in spermatocyte depletion via cell death. Apoptosis and spermatocyte depletion is correlated, where spermatocyte depletion via apoptosis is a general mechanism [Brinkworth et al., 1995].

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

Induced apoptosis during the development of germ cells results in the progressive depletion of spermatocytes [Brinkworth et al., 1995]. An HDAC inhibitor, MAA, induced apoptosis and spermatocyte depletion at stages IX-II [Brinkworth et al., 1995].

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

The process of apoptosis is necessary for the meiosis of the stem cell differentiation in the testis, which remains in question for the regulation of spermatocyte deletion and testis atrophy/weight loss [Dym, 1994].

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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
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 apoptosis of the cells leads to spermatocyte depletion. The relationship between apoptosis and spermatocyte depletion is likely well conserved between species. The examples are only given for mammals:

  • Spermatogenesis was inhibited by the knockdown of Sucla2, a β subunit of succinyl coenzyme A synthase, via apoptosis in the mouse spermatocyte (Mus musculus) [Huang et al., 2016].
  • The suppression of microRNA-21 led to apoptosis of spermatogonial stem cell-enriched germ cell cultures and the decrease in the number of spermatogonial stem cells in mice (Mus musculus) [Niu et al., 2011].
  • MAA induced apoptosis and depletion of spermatocytes in adult rats (Rattus norvegicus) [Brinkworth et al., 1995].
  • The apoptosis and proliferation inhibition induced by MAA, an HDAC inhibitor,  was measured in human prostate cancer cell lines (Homo sapiens) [Parajuli et al., 2014].

  • The cell viability inhibition induced by SAHA or TSA, which are HDAC inhibitors, was observed in NHDFs (Homo sapiens) [Glaser et al., 2003].

  • The proliferation of the HDAC-/- ES cells was inhibited compared to HDAC+/+ ES cells (Homo sapiens) [Zupkovitz et al., 2010].

  • It has been reported that the mice lacking both Ink4c and Ink4d, cyclin D-dependent kinase inhibitors, produced few mature sperm, and the residual spermatozoa had reduced motility and decreased viability (Mus musculus) [Zindy et al., 2001].

  • The sperm counts in the cauda epididymis of rats exposed to butylparaben were significantly decreased (Rattus norvegicus) [Oishi, 2001].

  • MAA treatment-induced spermatocyte death in Sprague-Dawley rats (Rattus norvegicus) [Wade et al., 2008].


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

Barqawi, A. et al. (2004), "Effect of prolonged cryptorchidism on germ cell apoptosis and testicular sperm count", Asian J Androl 6:47-51

Bose, R. et al. (2017), "Ubiquitin ligase Huwe1 modulates spermatogenesis by regulating spermatogonial differentiation and entry into meiosis", Sci Rep 7:17759

Brinkworth, M. et al. (1995), "Identification of male germ cells undergoing apoptosis in adult rats", J Reprod Fertil 105:25-33

Dym, M. (1994), "Spermatogonial stem cells of the testis", Proc Natl Acad Sci USA 91:11287-11289

Glaser, K.B. et al. (2003), "Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines", Mol Cancer Ther 2:151-163

Huang, S. et al. (2016), "Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells", Folia Histochem Cytobiol 54:134-142

Niu, Z. et al. (2011), "microRNA-21 regulates the self-renewal of mouse spermatogonial stem cells", Proc Natl Acad Sci 108:12740-12745

Oishi, S. (2001), "Effects of butylparaben on the male reproductive system in rats", Toxicol Indust Health 17:31-39

Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313

Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831

Wang, C. et al. (2017), "CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFkB signaling pathways", Oncotarget 8:3132-3143

Zindy, F. et al. (2001), "Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18Ink4c and p19Ink4d", Mol Cell Biol 21:3244-3255

Zupkovitz, G. et al. (2010), "The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation", Mol Cell Biol 30:1171-1181