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Relationship: 3170

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

Epididymal agenesis leads to Impaired, Spermatogenesis

Upstream event

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

Epididymal agenesis

Downstream event

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

Impaired, Spermatogenesis

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
Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) leads to Impaired, Spermatogenesis	adjacent	High	Not Specified	John Frisch (send email)	Under development: Not open for comment. Do not cite

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
Vertebrates	Vertebrates	Moderate	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
During development and at adulthood	Moderate

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

In this key event relationship we are focused on epididymal agenesis and malformation of epididymis, and resulting impairment of spermatogenesis. During development issues arise with organ formation, with resulting impairment observed in mature individuals. The epididymus is a tube that is connected to each testes which stores sperm during maturation, as well as where sperm develop motility and fertilization capability (James et al. 2020). Impaired spermatogenesis results in a number of issues, including decreased sperm count, increased number of abnormal sperm, and limited regions in which sperm are able to develop.

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

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Palermo et al. (2021) focused on identifying Adverse Outcome Pathways associated with adverse male reproductive outcomes from phthalate exposure through review of existing literature, and provided initial network analysis.

Authors of KER 3170 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

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

Predominantly in laboratory mammal studies, malformations from toxicant exposure or genetic damage have resulted in a variety of types of spermatogenesis impairment. Abnormalities in epididymes disrupt the connection to testes and proper organ formation, inhibiting development of sperm with proper fertility, maturation, and reproductive capabilities, as well as proper storage. Empirical studies generally examine sperm counts, the number of abnormal sperm, and whether germ cell formation is limited.

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

Species	Duration	Dose	Increased Epidydimal Agenesis?	Impaired Spermatogenesis?	Summary	Citation
Rat (Rattus norvegicus)	80 days in utero - maturity	500 mg/kg/d DBP 10 days in utero, followed through maturity	yes	yes	Sprague-Dawley rats, increased incidence of epidydimal agenesis and abnormal epididymis, resulting decreased number of spermatocytes and increased number of abnormal gonocytes.	Barlow et al. (2003)
Rat (Rattus norvegicus)	100 days in utero - maturity	50 mg/kg flutamide in utero, single dose on different days, followed through maturity	yes	yes	Sprague-Dawley rats, increased incidence of epididymal agenesis and malformations, resulting decreased number of sperm and areas with sperm cells.	Foster et al. (2005)
Rat (Rattus norvegicus)	10 days	250, 500, 700 mg/kg/d DBP, 1, 12.5, 25 mg/kg/d flutamide in utero	yes	yes	Sprague-Dawley rats, dose-dependent decrease in testosterone levels and increased incidence of epidydimal agenesis and resulting abnormal or reduced spermatogenesis, and decreased sperm count.	Kim et al. (2010)
Rat (Rattus norvegicus)	36 days in utero -maturity	20, 200, 2000, 10000 ppm/d DBP in utero, followed through maturity	yes	yes	CD(SD)IGS rats, dose-dependent increased incidence of epididymis malformations and resulting reduction and loss of spermatocyte development and decreases in sperm count.	Lee et al. (2004)
Mouse (Mus musculus)	3 months	1 mg/50 g bw tamoxifen for 5 consecutive days in utero, knock-out gene study, juvenile exposure.	yes	yes	COUP-TFII flox/flox mice and CAGG-Cre-ERTM mice, increased incidence of abnormal epididymis formation and resulting spermatogenesis defects and arrest.	Qin et al. (2008)
Rat (Rattus norvegicus)	70 days	50, 250, 500 mg/kg/day DBP in utero, followed through maturity	yes	yes	Sprague-Dawley rats, dose dependent increased incidence of epidydimal abnormalities and resulting lower sperm count and decreased sperm motility.	Zhang et al. (2004)

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

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

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

Life Stage: Problems first can be observed during development, with adverse outcome manifesting in mature individuals.

Sex: Applies to males.

Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats); plausible for all vertebrates.

References

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

Barlow, N.J. and Foster, P.M.D. 2003b. Pathogenesis of Male Reproductive Tract Lesions from Gestation Through Adulthood Following in Utero Exposure to Di(n-butyl) Phthalate. Toxicologic Pathology 31:397–410.

Foster, P.M.D. and Harris, M.W. 2005. Changes in Androgen-Mediated Reproductive Development in Male Rat Offspring Following Exposure to a Single Oral Dose of Flutamide at Different Gestational Ages. Toxicological Sciences 85: 1024–1032.

James, E.R., Carrell, D.T., Aston, K.I., Jenkins, T.G., Yeste, M., and Salas-Huetos, A. 2020. The Role of the Epididymis and the Contribution of Epididymosomes to Mammalian Reproduction. International Journal of Molecular Sciences 21: 5377.

Kim, T.S., Jung, K.K., Kim, S.S., Kang, I.H., Baek, J.H., Nam, H.-S., Hong, S.-K., Lee, B.M., Hong, J.T., Oh, K.W., Kim, H.S., Han, S.Y., and Kang, T.S. 2010. Effects of in Utero Exposure to DI(n-Butyl) Phthalate on Development of Male Reproductive Tracts in Sprague-Dawley Rats. Journal of Toxicology and Environmental Health, Part A 73(21-22): 1544-1559.

Lee, K.-Y., Shibutani, M., Takagi, H., Kato, N., Takigami, S., Uneyama, C., and Horose, M. 2003. Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation. Toxicology 203: 221–238.

Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I. 2021. Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development. Current Research in Toxicology 2: 254–271.

Qin, J., Tsai, M.-J., and Tsai S.Y. 2008. Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility. Public Library of Science One 3(9): e3285.

Zhang, Y., Jiang, X., and Chen, B. 2004. Reproductive and developmental toxicity in F1 Sprague–Dawley male rats exposed to di-n-butyl phthalate in utero and during lactation and determination of its NOAEL. Reproductive Toxicology 18: 669–676.

NOTE: Italics indicate edits from John Frisch