Decreased, Insulin-like peptide 3 (INSL3)

GO:0010467

GO gene expression

GO:0048513

GO animal organ development

WIKI decreased

WIKI abnormal

WikiUser_17

mammals

WikiUser_28

Vertebrates

Decreased, Insulin-like peptide 3 (INSL3)

Decreased, INSL3

Molecular

Insulin-like peptide 3 (INSL3) has been studied for roles during development.  In animals that have a sexually dimorphic position of gonads, a key developmental pathway is reproductive tissue and organ development enabling male or female fertility in full capability of producing offspring.  Particularly focus for INSL3 has been placed on decreased INSL3 gene expression in Leydig cells and failure of male development of the cranial suspensory ligament and the gubernaculum, resulting in cryptorchidism (Nef and Parada 1999, Zimmerman et al. 1999, Kaftanovskaya  et al. 2011).  Evidence suggests that INSL3 activates the GREAT (LGR8) receptor (Bogatcheva et al. 2003).  Targeted disruption of INSL3 through toxicant exposure has been used in laboratory mammal studies to further investigate resulting effects (from phthalates see Wilson et al. 2004; Wilson et al. 2007).

INSL3 is measured by changes in gene expression and protein levels.  Effects of INSL3 on expression of downstream genes can be investigating using metabolomics and RT-qPCR approaches.  In addition, targeted ToxCast assays using SeqAPASS evaluations can evaluate gene expression changes from chemical exposure for model species (NCBI Accession Number NP_005534.2 for INSL3 in GenBank).

Life Stage: Predominately studied during development; likely present during all lifestages. Sex: Applies to both males and females. Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats); plausible for all vertebrates.

CL:0000255

CL eukaryotic cell

Moderate Unspecific

Moderate

Development

Moderate

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. 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. National Center for Biotechnology Information (NCBI)[Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; [1988] – [cited 2024 Apr 18]. Available from: https://www.ncbi.nlm.nih.gov/ Nef, S. and Parada, L.F.  1999.  Cryptorchidism in mice mutant for Insl3.  Nature Genetics 22: 295-299. Wilson, V.S., Lambright, C., Furr, J., Ostby, J., Wood, C., Held, G., and Gray, Jr., L.E.  2004.  Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis.  Toxicology Letters 146: 207–215. 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 symbolize edits from John Frisch     AOPWiki 2024-03-19T13:41:50

2024-04-18T10:40:35

Impaired inguinoscrotal testicular descent phase

Impaired inguinoscrotal phase

Organ

Testis descent is based on a two-phase process: the transabdominal phase (INSL3-mediated) and the inguinoscrotal phase (Androgen-dependent). The transabdominal phase takes place in the first months of pregnancy, between 10 and 15 weeks. The inguinoscrotal phase occurs later in the fetus development, about 25-35 weeks of gestation. During this second phase, the testis is supposed to get into the scrotum. A defect in the inguinoscrotal phase results in a dysfunction in testis migration: the testis is stuck in the abdominal part of the body.1 Any impairment in testis migration, either through the transabdominal phase or the inguinoscrotal phase, will directly result in the absence of one or both testes from the scrotum.

Issues during development can be detected by histological exam, with physical manifestation of abnormal development visible in mature individuals.

Life Stage: Problems first can be observed during development, with adverse outcome manifesting in mature individuals. Sex: Applies to males. Taxonomic: Appears to be present broadly in mammals, with most representative studies in mammals (humans, lab mice, lab rats).

High Male

Moderate

During development and at adulthood

Moderate

1 Hutson J.M., Li R., Southwell B.R., Newgreen D., and Cousinery M. (2015) Regulation of testicular descent. Pediatric Surgery International, 31(4): 317-325 <a href="https://www.google.com/url?q=https://doi.org/10.1007/s00383-015-3673-4&sa=D&ust=1554891396640000">https://doi.org/10.1007/s00383-015-3673-4</a>  NOTE: Italics symbolize edits from John Frisch     AOPWiki 2019-04-10T05:05:26

2024-04-18T11:23:40

Malformation, cryptorchidism - maldescended testis

Malformation, cryptorchidism

Organ

Undescended testis is a testicular disorder syndrome known as  cryptorchidism. Testis migration is a major event in male fetus development, as it will directly affect his reproductive health. Cryptorchidism can defined itself as the insertion of the testis in another position than the scrotum. Although the events leading to this pathology occurred during development, cryptorchidism can only be defined after birth though clinical examination as palpation. Cryptorchidism can be either uni- or bilateral and has been reported to increase in incidence over the decades (Denmark, UK, India…). The maldescended testis will experiment heat stress (37 against 33C outside the body) interfering with testicular physiology and development of germ cells into spermatogonia. Germ cells maturation failure will induce a non-reversible reduction in fertility power of the individual. Cryptorchidism is an established risk factor for infertility and is known to increase the incidence of testicular germ cell tumors (TGCT) 123   Remark:  <table> <tbody> <tr> <td colspan="1" rowspan="1"> Cryptorchidism is the first AO of a larger list including raise in testicular cancer and germ cell tumor incidence, as well as reduced fertility due to impairment in germ cells maturation. </td> </tr> </tbody> </table>

Cryptorchidism is a birth defect that can be highlighted by a clinical examination. The aim of this palpation is to locate the gonad and determine its lowest position without causing painful traction on the spermatic cord. 4

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) with clinical observations in humans; plausible for all vertebrates.     NOTE: Italics symbolize edits from John Frisch

High Male

Moderate

During development and at adulthood

Moderate

1 Hutson J.M., Li R., Southwell B.R., Newgreen D., and Cousinery M. (2015) Regulation of testicular descent. Pediatric Surgery International, 31(4): 317-325. <a href="https://www.google.com/url?q=https://doi.org/10.1007/s00383-015-3673-4&sa=D&ust=1554891396648000">https://doi.org/10.1007/s00383-015-3673-4</a>  2 Boisen K.A., Kaleva M., Main K.M., Virtanen H.E., Haavisto A.M., Schmidt I.M., Chellakooty M., Damgaard I.N., Mau C., Reunanen M., Skakkebaek N.E. and Toppari J. (2004) Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet, 17;363(9417):1264-9 <a href="https://www.google.com/url?q=https://doi.org/10.1016/S0140-6736(04)15998-9&sa=D&ust=1554891396649000">https://doi.org/10.1016/S0140-6736(04)15998-9</a>  3 Acerini C.L., Miles H.L., Dunger D.B., Ong K.K. and Hughes I.A. (2009) The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Archives of disease in childhood, 94(11):868-72 https://doi.org10.1136/adc.2008.150219  4 Hutson J.M., et al. (2015) Cryptorchidism and Hypospadias. Endotext<a href="https://www.google.com/url?q=https://www.ncbi.nlm.nih.gov/books/NBK279106/&sa=D&ust=1554891396651000">https://www.ncbi.nlm.nih.gov/books/NBK279106/</a>  AOPWiki 2019-04-10T05:06:57

2024-04-18T13:55:57

<upstream-id>fb62f85a-a910-49c4-a244-29e2da71d673</upstream-id> <downstream-id>4169b1dd-3121-4c62-bf55-164ce0c2e6e8</downstream-id> In this key event relationship we are focused on the decrease in Insulin-like 3 peptide (INSL3) gene expression, and corresponding impairment of inguinoscrotal phase of testes descent.  Here we focus on the indirect relationship of gene expression to abnormal development.  Literature suggests that androgen levels are responsible for proper development of the cranial suspensory ligament and the gubernaculum (Zimmerman et al. 1999; Nef and Parada 1999 Wilson et al. 2007), but whether testosterone and/or other androgens are the causative hormone(s) has not been determined.

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 3174 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

The biological plausibility linking decrease of INSL3 gene expression to impaired inguinoscrotal descent of testes is strong.   Predominately in laboratory mammal studies, INSL3 gene expression has been studied via toxicant exposure as well as contrasting wild-type strains to strains with decreased INSL3 and related gene function, and consistently shown impairment of inguinoscrotal descent during development.

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:91px"> Species </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:65px"> Duration </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:108px"> Dose </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:83px"> Decreased INSL3? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:86px"> Impaired inguinoscrotal phase? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:103px"> Summary </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:87px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 3 months </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3 and GREAT, decreased INSL3 expression resulting in impaired inguinoscrotal phase, identified GREAT (LGR8) as key receptor. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Bogatcheva et al. (2003) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 16 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3 and RXFP2, decreased INSL3 expression resulting in impaired inguinoscrotal phase. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Kaftanovskaya et al. (2011) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 6 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3, decreased INSL3 expression resulting in impaired inguinoscrotal phase. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Nef and Parada (1999) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 8 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> 1 g/kg/day DEHP, DBP, BBP in utero </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Sprague-Dawley rats, DEHP, DBP, BBP decreased INSL3 expression resulting in impaired inguinoscrotal phase; 200 mg/kg/d vinclozin, 100 mg/kg/d linuron, 250 mg/kg/d prochlaz did not affect INSL3 as predicted. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Wilson et al. (2004) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 120 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> 750 mg/kg/day DEHP in utero, followed through development </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Wistar rats, decreased INSL3 expression resulting in impaired inguinoscrotal phase; as predicted Sprague-Dawley rats had neither decreased INSL3 nor impaired inguinoscrotal phase. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Wilson et al. (2007) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:91px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 12 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3, decreased INSL3 expression resulting in impaired inguinoscrotal phase. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Zimmerman et al. (1999) </td> </tr> </tbody> </table>

High Male

High

Development

Moderate

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.

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. 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., Lambright, C., Furr, J., Ostby, J., Wood, C., Held, G., and Gray, Jr., L.E.  2004.  Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis.  Toxicology Letters 146: 207–215. 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 symbolize edits from John Frisch   AOPWiki 2024-03-20T08:53:53

2024-04-12T10:22:33

<upstream-id>4169b1dd-3121-4c62-bf55-164ce0c2e6e8</upstream-id> <downstream-id>a1ff99e3-9d32-40cb-899b-aad137f37b16</downstream-id> In this key event relationship we are focused on the impairment of inguinoscrotal phase of testes descent and resulting cryptorchidism.  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.

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.

The biological plausibility linking impaired inguinoscrotal descent to cryptorchidism is strong.   Predominately 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.

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:86px"> Species </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:63px"> Duration </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:102px"> Dose </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:86px"> Impaired inguinoscrotal phase? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:98px"> Increased cryptorchidism? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:101px"> Summary </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:87px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> 3 months </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:98px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3 and GREAT, impaired inguinoscrotal phase, resulting in increased cryptorchidism. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Bogatcheva et al. (2003) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> 4 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:98px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3 and GREAT, impaired inguinoscrotal phase, resulting in increased cryptorchidism. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Gorlov et al. (2002) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> 16 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:98px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3 and RXFP2, impaired inguinoscrotal phase, resulting in increased cryptorchidism. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Kaftanovskaya et al. (2011) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> 6 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:98px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3, impaired inguinoscrotal phase, resulting in increased cryptorchidism. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Nef and Parada (1999) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Rat (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> 120 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> 750 mg/kg/day DEHP in utero, followed through development </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:98px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> Wistar rats, impaired inguinoscrotal phase, resulting in increased cryptorchidism; as predicted Sprague-Dawley rats had neither impaired inguinoscrotal phase nor cryptorchidism as predicted. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Wilson et al. (2007) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> Mouse (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> 12 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Knock-out gene study. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:86px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:98px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:101px"> Mice, various cell lines with wild-type and knock-out gene expression of INSL3, impaired inguinoscrotal phase, resulting in increased cryptorchidism. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:87px"> Zimmerman et al. (1999) </td> </tr> </tbody> </table>

High Male

High

Development

Moderate

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 symbolize edits from John Frisch   AOPWiki 2019-06-03T08:42:05

2024-04-12T11:13:29

Decreased Insulin-like peptide 3 (INSL3) leads to Malformation, cryptorchidism - maldescended testis

Decreased INSL3 leads to Increased, cryptorchidism

Allie Always

Of the originating work: Christine M. Palermo and Jennifer E. Foreman, ExxonMobile; Daniele S. Wikoff, Isabel Lea, ToxStrategies. Of the content populated in the AOP-Wiki:  John R. Frisch and Travis Karschnik, General Dynamics Information Technology; Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division.

BY-SA

2.6

Cryptorchidism is an adverse outcome often observed among a group of male reproductive abnormalities caused by organ malformation (epididymis, vas deferens, seminal vesicles, prostate, external genitalia) during development (Drake et al. 2009; Palermo et al. 2021).  These reproductive abnormalities have been observed in studies of laboratory mice and rats exposed to phthalates during in utero development, and clinical studies of humans, in attempts to understand the gene expression/inhibition, hormone levels, and other factors leading to the observed adverse outcomes.  Although a molecular initiating event isn’t well established, decreased Insulin-like peptide 3 (INSL3) has been linked to failure of ligaments to develop properly, with resulting cryptorchidism (failure of testes to descend properly; Nef and Parada 1999; Zimmermann et al. 1999); Bogatcheva et al. 2003; Wilson et al. 2007; Kaftanovskaya et al. 2011).  Decreased androgen(s) levels have been advanced as plausible hormones responsible for abnormal development, but whether testosterone or another hormone is responsible has not yet been definitively demonstrated. This Adverse Outcome Pathway (AOP) 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.  The originating work for this AOP was: 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.  This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.  Phthalates are of increasing human health concern because of increased use and accumulating evidence of disruption of reproductive development in vertebrates.  First detected in laboratory mammals, exposure to phthalates and other toxicants in utero when male sexual differentiation is occurring have resulted in increased malformation of reproductive organs, failure of male characteristics to develop, and failure of proper positioning of organs (ex. hypospadias and cryptorchidism).  Clinical studies in humans have used laboratory mammal data to help understand and treat conditions exhibited by individual people.   This AOP focuses on the pathway leading to increased cryptorchidism, via impaired testicular descent, and initiated by decreased Insulin-like peptide 3 (INSL3) gene expression. The focus of the originating work was to use an AOP framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD).  Palermo et al. (2021) provided network analysis based on two literature searches: 1. rodent male reproductive development abnormalities using key terms; 2. effects of low molecular weight phthalates (LMWPs) during the rodent male programming window (MPW) of development.  Relevant key events and key event relationships were narrowed by focusing on empirical studies related to ‘rat phthalate syndrome’ which resulted in 3 recommended Adverse Outcome Pathways: 1. INSL expression to cryptorchidism (see this AOP 528 for related content); 2. COUP-TFII expression to hypospadias (see AOP 527 for related content); 3. COUP-TFII expression to altered sperm maturation (see AOP 526 for related content).

The originating authors conducted a literature search to develop a database of publications categorized by discipline or field of study: toxicology, epidemiology, exposure, and gene-environment interaction. The literature search relied on standard search engines such as Web of Science and Google Scholar, and the search strategy focused on toxicants known to disrupt lipid pathways in organisms, and diet studies with elevated levels of lipids. The originating authors reviewed references from individual citations to identify additional studies not captured through the literature search itself. They then included all relevant publications through 2023. Only studies focused primarily on developmental or neurotoxic endpoints were included; those focused on carcinogenesis or other systemic effects were not included unless there was a particular relevance to a neurotoxic or developmental outcome. The scope of the aforementioned EPA project was limited to re-representing the AOP(s) as presented in the originating publication. The literature used to support this AOP and its constituent pages began with the originating publication and followed to the primary, secondary, and tertiary works cited therein. KE and KER page creation and re-use was determined using Handbook principles where page re-use was preferred.     <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/04/23/7d3mwuiavf_Citation_workflow_graphic.png" /> The authors of AOP 528 also referred to existing AOP-wiki content on disruption of steroidogenesis pathways, especially work by Gary Klinefelter (ex. AOP 70, 71).  We found existing Adverse Outcome Pathway content documented different series of key events then the pathways provided by Palermo et al. (2021), and therefore initiated AOP 528 and updated existing AOP-wiki key events when available.

adjacent

Not Specified

High non-adjacent

Not Specified

High

High Male

High

During development and at adulthood

Moderate

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top"> 1. Support for Biological Plausibility of Key Event Relationships: Is there a mechanistic relationship  between KEup and KEdown consistent with established biological knowledge? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event Relationship (KER) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support   Strong = Extensive understanding of the KER based on extensive previous documentation and broad acceptance. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3174: Decreased Insulin-like peptide 3 (INSL3) leads to Impaired inguinoscrotal testicular descent phase </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  The relationship between decrease in Insulin-like peptide 3 (INSL3) expression to impaired inguinoscrotal testicular descent is broadly accepted and consistently supported across lab mice, lab rats, and clinical human studies. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 1938: Impaired inguinoscrotal testicular descent phase leads to Malformation, cryptorchidism - maldescended testis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Impaired inguinoscrotal testicular descent is the mechanism in which cryptorchidism results, and is broadly accepted and consistently supported across lab mice, lab rats, and clinical human studies. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Extensive understanding of the relationships between events from empirical studies from a variety of taxa, including frequent testing in lab mammals. </td> </tr> </tbody> </table> Life Stage: Problems first can be observed during development, with adverse outcome manifesting in mature individuals. Sex: Applies to males. Taxonomic: Appears to be present broadly in mammals, with most representative studies in mammals (humans, lab mice, lab rats).

<table cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:775px"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> 2. Essentiality of Key Events: Are downstream KEs and/or the AO prevented if an upstream KE is blocked? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event (KE) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support Strong = Direct evidence from specifically designed experimental studies illustrating essentiality and direct relationship between key events. Moderate = Indirect evidence from experimental studies inferring essentiality of relationship between key events due to difficulty in directly measuring at least one of key events. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 2214: Decreased Insulin-like peptide 3 (INSL3) </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate support.  Decrease in Insulin-like peptide 3 (INSL3) expression has been linked to impaired inguinoscrotal testicular descent.  Decreased androgen(s) levels have been advanced as plausible hormones responsible for abnormal development, but whether testosterone or another hormone is responsible has not yet been definitively demonstrated. Evidence is available from toxicant, gene-knockout, and histology studies. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> KE 1615 Impaired inguinoscrotal testicular descent phase </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Impaired inguinoscrotal testicular descent is the mechanism in which cryptorchidism results.   Evidence is available from toxicant and histology studies. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> AO 1616 Malformation, cryptorchidism - maldescended testis </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support. Increased cryptorchidism is often caused by development issues in formation of reproductive tissues, including failure of ligaments to develop properly.  Evidence is available from toxicant and histology studies. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Moderate to strong support.  Direct evidence from empirical studies from laboratory mammals for most key events, with more inferential evidence for gene expression and protein studies. </td> </tr> </tbody> </table>

<table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> 3. Empirical Support for Key Event Relationship: Does empirical evidence support that a  change in KEup leads to an appropriate change in KEdown? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Key Event Relationship (KER) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Level of Support  Strong =  Experimental evidence from exposure to toxicant shows consistent change in both events across taxa and study conditions.  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 3174: Decreased Insulin-like peptide 3 (INSL3) leads to Impaired inguinoscrotal testicular descent phase </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  The relationship between decrease in Insulin-like peptide 3 (INSL3) expression and impaired inguinoscrotal testicular descent phase is broadly accepted and consistently supported across lab mice, lab rats, and clinical human studies. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Relationship 1938: Impaired inguinoscrotal testicular descent phase leads to Malformation, cryptorchidism - maldescended testis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  The relationship between impaired inguinoscrotal testicular descent phase and increased cryptorchidism is broadly accepted and consistently supported across lab mice, lab rats, and clinical human studies. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top"> Overall </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top"> Strong support.  Extensive understanding of the relationships between events from empirical studies from a variety of taxa, including frequent testing in lab mammals. </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

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. Drake, A.J., van den Driesche, S., Scott, H.M., Hutchinson, G.R., Seckl, J.R. and Sharpe, R.M.  2009.  Glucocorticoids Amplify Dibutyl Phthalate-Induced Disruption of Testosterone Production and Male Reproductive Development.  Endocrinology 150(11): 5055–5064. 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. AOPWiki 2024-03-19T11:12:33

2024-05-26T20:40:00