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Relationship: 3173

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

Impaired, urethral tube closure leads to Hypospadias

Upstream event

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

Impaired, urethral tube closure

Downstream event

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

Hypospadias

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 Hypospadias, increased	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 Do not cite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	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

In this key event relationship we are focused on the impairment of urethral tube closure and resulting increase in hypospadias. Hypospadias is a congenital condition in which the opening of the urethra occurs on the underside of the penis rather than at the tip. During development issues arise in organ formation, with resulting impairment observed in mature individuals.

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 3173 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 the observed impairment. Abnormalities in the urethra cause difficulty in passing urine, and in males difficulty in passing semen.

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	Impaired, urethral tube closure?	Hypospadias?	Summary	Citation
Rat (Rattus norvegicus)	5 days	75 mg/kg/d linuron, 500 mg/kg/d BBP, or mixture of 75 mg/kg/d linuron and 500 mg/kg/d BBP in utero	yes	yes	Sprague-Dawley rats, increased impairment of urethral tube closure and resulting hypospadias for linuron/BBP treatment.	Hotchkiss et al. (2004)
Rat (Rattus norvegicus)	40 days	250, 500, 700 mg/kg/d DBP, 1, 12.5, 25 mg/kg/d flutamide in utero, followed through development.	yes	yes	Sprague-Dawley rats, increased impairment of urethral tube closure and resulting hypospadias for 700 mg/kg/d DBP and 12.5, 25 mg/kg/d flutamide.	Kim et al. (2010)
Rat (Rattus norvegicus)	8 days	500, 750, 1000 mg/kg/d DEHP, mixture treatment with genstein to study moderation of DEHP response in utero	yes	yes	Sprague-Dawley rats, increased impairment of urethral tube closure and resulting hypospadias for all DEHP doses, with genstein lowering the number of rats affected.	Shi et al. (2024)
Mouse (Mus musculus)	7 days	100 mg/kg/bw/day tamoxifen in utero, gene knockout study.	yes	yes	C57BL/6 mice, Mafb mutant mice, increased impairment of urethral tube closure and resulting hypospadias for knock-out mice.	Suzuki et al. (2014)
Mouse (Mus musculus)	4 days	100, 200, 300 mg/kg/day finasteride in utero, gene knockout study.	yes	yes	C57BL/6 mice, Mafb mutant mice, increased impairment of urethral tube closure and resulting hypospadias for all doses.	Suzuki et al. (2015)
Rat (Rattus norvegicus)	6 days	100 mg/kg/day flutamide in utero.	yes	yes	Wistar rats, increased impairment of urethral tube closure and resulting hypospadias in 15.5-17.5 weeks EW (early gestation window and 17.5-19.5 weeks MW (middle gestation window).	Welsh et al. (2008)

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 with penises.

References

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

Hotchkiss, A.K., Parks-Saldutti, L.G., Ostby, J.S., Lambright, C., Furr, J., Vandenbergh, J.G., and Gray, Jr., L.E. 2004. A Mixture of the ‘‘Antiandrogens’’ Linuron and Butyl Benzyl Phthalate Alters Sexual Differentiation of the Male Rat in a Cumulative Fashion. Biology of Reproduction 71: 1852–1861.

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.

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.

Shi, B. He, E., Chang, K., Xu, G., Meng, Q., Xu, H., Chen, Z., Wang, X., Jia, M., Sun, W., Zhao, W., Zhao, H., Dong, L., and Cui, H. 2024. Genistein prevents the production of hypospadias induced by Di-(2-ethylhexyl) phthalate through androgen signaling and antioxidant response in rats. Journal of Hazardous Materials 466: 133537. Suzuki, K., Numata, T., Suzuki, H., Raga, D.D., Ipulan, L.A., Yokoyama, C., Matsushita, S., Hamada, M., Nakagata, N., Nishinakamura, R., Kume, S., Takahashi, S., and Yamada, G. 2014. Sexually dimorphic expression of Mafb regulates masculinization of the embryonic urethral formation. The Proceedings of the National Academy of Sciences 111(46): 16407–16412.

Suzuki, H., Suzuki, K., and Yamada, G. 2015. Systematic analyses of murine masculinization processes based on genital sex differentiation parameters. Development, Growth, and Differentiation 57: 639–647.

Welsh, M., Saunders, P.T.K., Fisken, M., Scott, H.M., Hutchison, G.R., Smith, L.B., and Sharpe, R.M. 2008. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. The Journal of Clinical Investigation 118(4): 1479–1490.

NOTE: Italics indicate edits from John Frisch