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Relationship: 1938
Title
Impaired inguinoscrotal phase leads to Malformation, cryptorchidism
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals) | adjacent | High | High | Bérénice COLLET (send email) | Open for citation & comment | |
Decreased Insulin-like peptide 3 (INSL3) leads to Malformation, cryptorchidism - maldescended testis | adjacent | High | Not Specified | John Frisch (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Vertebrates | Vertebrates | Moderate | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Male | High |
Life Stage Applicability
Term | Evidence |
---|---|
Development | High |
Key Event Relationship Description
In this key event relationship we are focused on the impairment of inguinoscrotal phase of testes descent and resulting cryptorchidism. In the inguinoscrotal phase the testes descend from the abdomen into the scrotum. Cryptorchidism is the condition in which testes fail to descend from the abdomen into the scrotum. During development issues arise with proper development of the cranial suspensory ligament and the gubernaculum, manifesting in problems with testes descent and resulting in cryptorchidism. The gubernaculum is a ligament that elongates during development and attaches to the scrotum, responsible for proper testicular descent.
Evidence Collection Strategy
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 1938 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.
Evidence Supporting this KER
Biological Plausibility
Predominantly in laboratory mammal studies, reproductive tissue development has been studied via toxicant exposure as well as knock-out gene studies, and consistently shown impairment of inguinoscrotal descent during development leads to cryptorchidism. Failure of the gubernaculum to elongate prohibits testes from properly descending into the scrotum.
Empirical Evidence
Species |
Duration |
Dose |
Impaired inguinoscrotal phase? |
Increased cryptorchidism? |
Summary |
Citation |
Mouse (Mus musculus) |
3 months |
Knock-out gene study. |
yes |
yes |
Mice, various cell lines with wild-type and knock-out gene expression of INSL3 and GREAT, impaired inguinoscrotal phase, resulting in increased cryptorchidism. |
Bogatcheva et al. (2003) |
Mouse (Mus musculus) |
4 weeks |
Knock-out gene study. |
yes |
yes |
Mice, various cell lines with wild-type and knock-out gene expression of INSL3 and GREAT, impaired inguinoscrotal phase, resulting in increased cryptorchidism. |
Gorlov et al. (2002) |
Mouse (Mus musculus) |
16 days |
Knock-out gene study. |
yes |
yes |
Mice, various cell lines with wild-type and knock-out gene expression of INSL3 and RXFP2, impaired inguinoscrotal phase, resulting in increased cryptorchidism. |
Kaftanovskaya et al. (2011) |
Mouse (Mus musculus) |
6 weeks |
Knock-out gene study. |
yes |
yes |
Mice, various cell lines with wild-type and knock-out gene expression of INSL3, impaired inguinoscrotal phase, resulting in increased cryptorchidism. |
Nef and Parada (1999) |
Rat (Rattus norvegicus) |
120 days |
750 mg/kg/day DEHP in utero, followed through development |
yes |
yes |
Wistar rats, impaired inguinoscrotal phase, resulting in increased cryptorchidism; as predicted Sprague-Dawley rats had neither impaired inguinoscrotal phase nor cryptorchidism as predicted. |
Wilson et al. (2007) |
Mouse (Mus musculus) |
12 weeks |
Knock-out gene study. |
yes |
yes |
Mice, various cell lines with wild-type and knock-out gene expression of INSL3, impaired inguinoscrotal phase, resulting in increased cryptorchidism. |
Zimmerman et al. (1999) |
Uncertainties and Inconsistencies
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Life Stage: Occurs during development.
Sex: Applies to males.
Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats); plausible for all vertebrates with descended testes.
References
Bogatcheva, N.V., Truong, A., Feng, S., Engel, W., Adham, I.M., and Agoulnik, A.I. 2003. GREAT/LGR8 Is the Only Receptor for Insulin-Like 3 Peptide. Molecular Endocrinology 17(12):2639–2646.
Gorlov, I.P., Kamat, A., Bogatcheva, N.V., Jones, E., Lamb, D.J., Truong, A., Bishop, C.E., McElreavey, K., and Agoulnik, A.I. 2002. Mutations of the GREAT gene cause cryptorchidism. Human Molecular Genetics 11(19): 2309–2318.
Kaftanovskaya, E.M., Feng, S., Huang, Z., Tan, Y., Barbara, A.M., Kaur, S., Troung, A., Gorlov, I.P., and Agoulnik, A.I. 2011. Suppression of Insulin-Like3 Receptor Reveals the Role of β-Catenin and Notch Signaling in Gubernaculum Development. Molecular Endocrinology 25: 170–183.
Nef, S. and Parada, L.F. 1999. Cryptorchidism in mice mutant for Insl3. Nature Genetics 22: 295-299.
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.
Wilson, V.S., Howdeshell, K.L., Lambright, C.S., Furr, J., and Gray, Jr., L.E. 2007. Differential expression of the phthalate syndrome in male Sprague–Dawley and Wistar rats after in utero DEHP exposure. Toxicology Letters 170: 177–184.
Zimmermann, S., Steding, G., Emmen, J.M.A., Brinkmann, A.O., Nayernia, K., Holstein, A.F., Engel, W., and Adham, I.M. 1999. Targeted Disruption of the Insl3 Gene Causes Bilateral Cryptorchidism. Molecular Endocrinology 13(5): 681-691.
NOTE: Italics indicate edits from John Frisch