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Event: 1506

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Testicular atrophy

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Testicular atrophy
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Biological Context

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Level of Biological Organization
Organ

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
testis

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
Testicular atrophy Testis increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Histone deacetylase inhibition leading to testicular atrophy AdverseOutcome 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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Rattus norvegicus Rattus norvegicus Moderate NCBI
Mus musculus Mus musculus Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult, reproductively mature Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Male High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

It is hypothesized that the testicular effects of 1,6-dimethoxyhexane (DMH) are caused by its metabolism to methoxyacetic acid (MAA) [Wade et al., 2006; Poon et al., 2004]. MAA produces testicular and thymic atrophy such as the decrease in size [Miller et al., 1982; Moss et al., 1985]. The spermatogenic stages in which the toxicity of MAA is induced are on the patchytene spermatocytes immediately before and during meiotic division, which are Stages XII-XIV of the cycle in the rat and the early pachytene spermatocytes at stages I-IV of the cycle. Dead germ cells can be seen as soon as 12 hours after the treatment of MAA [Casarett & Doull’s, 7th edition].

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help
  • Testicular atrophy can be assessed by testicular volume measurement using an orchidometer, rulers, calipers, and ultrasonography or by testis weighing and histopathologic examination.
  • The testis weight is measured to detect testicular atrophy [Foster et al., 1983].
  • The urinary zinc excretion and testicular zinc content are examined since zinc concentration has been shown to play an important role in the production of testicular injury  [Foster et al., 1983].
  • The testicular tissue structure is observed whether there are normal germinal epithelial cells and Leydig cells [Mercantepe et al., 2018]. The testis is fixed for observations by light microscopy or transmission electron microscopy [McDowell and Trump, 1976; Mercantepe et al., 2018].
  • Changes in sperm are measured by computer-assisted sperm analysis [Foote et al., 1995].
  • For the assessment of sperm morphology, eosin-stained sperm collected from the cauda epididymis is observed. At least 200 sperm on each slide were examined for the proportion of sperm with abnormal head (overhooked, blunt hook, banana-shaped, amorphous, or extremely oversized) or tail (twisted, bent, corkscrew, double/multiple) [Wade et al., 2006].
  • For the measurement of the total number of condensed spermatids per testis, a weighed portion of the parenchyma from the left testis was homogenized [Wade et al., 2006]. Sperm or homogenization-resistant spermatid nuclei densities were calculated from the average number of nuclei and were expressed as total or as per gram of epididymis or testis weight [Wade et al., 2006].
  • For the determination of total LDH and LDH-X in the supernatant of the homogenized testis fragment, enzyme activity was measured by monitoring the extinction of NAD absorbance [Wade et al., 2006].

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help
  • The decrease in testis weight associated with testicular cell damage was induced by ethylene glycol monomethyl ether (EGME) or MAA treatment in rats (Rattus norvegicus) [Foster et al., 1983].
  • The number of spermatocytes, principally pachytene cells, is decreased by EGME treatment in CD-1 mice (Mus musculus) and CD rats (Rattus norvegicus) [Anderson et al., 1987].
  • The testicular lesions induced by 2-methoxyethanol (or EGME) were observed in rats (Rattus norvegicus) and guinea pigs (Cavia porcellus), which are different in onset, characteristics, and severity [Ku et al., 1984].
  • Spermatogenesis was disrupted by EGME treatment in rabbits (Oryctolagus cuniculus) [Foote et al., 1995].
  • Testicular toxicity such as spermatocyte death in seminiferous tubule stages I-IV and stages XII-XIV was induced by dimethoxyhexane (DMH) treatment in Sprague-Dawley rats (Rattus norvegicus) [Wade et al., 2006].

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

The testicular atrophy assessment is important for assessing the side effects of the medicines such as anti-cancer drugs, as well as the hazard and risk of chemicals. The testicular atrophy including a decrease in testis weight and sperm count, fertility, decrease in morphology and function of the sperm, can become one of the main endpoints as the adverse effects of the therapeutics. The unexpected effects of the therapeutics may be predicted with this Adverse Outcome (AO). In terms of chemical risk assessment, the AO may be related to the health effects caused by the usage of pesticides or biocides.

References

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

Anderson, D. et al. (1987), "Effect of ethylene glycol monomethyl ether on spermatogenesis, dominant lethality, and F1 abnormalities in the rat and the mouse after treatment of F0 males", Teratog Carcinog Mutagen 7:141-158

Casarett & Doull’s Toxicology, the Basic Science of Poisons, 7th Edition, Edited by Curtis D. Klaassen, Chapter 20 Toxic responses of the reproductive system

Foote, R.H. et al. (1995), "Ethylene glycol monomethyl ether effects on health and reproduction in male rabbits", Reprod Toxicol 9:527-539

Foster, P.M. et al. (1983), "Testicular toxicity of ethylene glycol monomethyl and monoethyl ethers in the rats", Toxicol Appl Pharmacol 69:385-399

Ku, W.W. et al. (1994), "Comparison of the testicular effects of 2-methoxyethanol (ME) in rats and guinea pigs", Exp Mol Pathol 61:119-133

McDowell, E.M. and Trump, B.F. (1976), "Histologic fixatives suitable for diagnostic light and electron microscopy", Arch Pathol Lab Med 100:405-414

Mercantepe, T. et al. (2018), "Protective effects of amifostine, curcumin and caffeic acid phenethyl ester against cisplatin-induced testis tissue damage in rats", Exp Ther Med 15:3404-3412

Miller, R. et al. (1982), "Toxicity of methoxyacetic acid in rats", Fundam Appl Toxicol 2:158-160

Moss, E.J. et al. (1985), "The role of metabolism in 2-methoxyethanol-induced testicular toxicity", Toxicol Appl Pharmacol 79:480-489

Poon, R. et al. (2004), "Short-term oral toxicity of pentyl ether, 1,4-diethoxybutane, and 1,6-dimethoxyhexane in male rats", Toxicol Sci 77:142-150

Wade, M.G. et al. (2006), "Testicular toxicity of candidate fuel additive 1,6-dimethoxyhexane: comparison with several similar aliphatic ethers", Toxicol Sci 89:304-313