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Aop: 165

AOP Title

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Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse

Short name:

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Antiestrogens and ovarian adenomas/granular cell tumors

Graphical Representation

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Click to download graphical representation template

Authors

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Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

Point of Contact

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Charles Wood   (email point of contact)

Contributors

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  • Charles Wood

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite 1.29 Under Development

This AOP was last modified on January 27, 2018 15:34

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Revision dates for related pages

Page Revision Date/Time
Decreased, Ovarian E2 September 16, 2017 10:17
Suppression, Estrogen receptor (ER) activity December 03, 2016 16:37
Increased, secretion of GnRH from hypothalamus September 16, 2017 10:17
Increased, secrection of FSH from anterior pituitary December 03, 2016 16:37
Increased, secretion of LH from anterior pituitary December 03, 2016 16:37
Hyperplasia, ovarian stromal cells September 16, 2017 10:17
Hyperplasia, ovarian epithelium September 16, 2017 10:17
Promotion, ovarian adenomas December 03, 2016 16:37
Promotion, ovarian granular cell tumors December 03, 2016 16:37
Decrease, E2 blood concentrations at hypothalamus September 16, 2017 10:17
Decreased, Ovarian E2 leads to Decrease, E2 blood concentrations at hypothalamus December 03, 2016 16:38
Suppression, Estrogen receptor (ER) activity leads to Decrease, E2 blood concentrations at hypothalamus December 03, 2016 16:38
Decrease, E2 blood concentrations at hypothalamus leads to Increased, secretion of GnRH from hypothalamus December 03, 2016 16:38
Increased, secretion of GnRH from hypothalamus leads to Increased, secrection of FSH from anterior pituitary December 03, 2016 16:38
Increased, secretion of GnRH from hypothalamus leads to Increased, secretion of LH from anterior pituitary December 03, 2016 16:38
Increased, secrection of FSH from anterior pituitary leads to Hyperplasia, ovarian stromal cells December 03, 2016 16:38
Increased, secrection of FSH from anterior pituitary leads to Hyperplasia, ovarian epithelium December 03, 2016 16:38
Increased, secretion of LH from anterior pituitary leads to Hyperplasia, ovarian stromal cells December 03, 2016 16:38
Hyperplasia, ovarian epithelium leads to Promotion, ovarian adenomas December 03, 2016 16:38
Hyperplasia, ovarian stromal cells leads to Promotion, ovarian granular cell tumors December 03, 2016 16:38
Tamoxifen November 29, 2016 18:42
Raloxifene November 29, 2016 18:42
Fulvestrant November 29, 2016 18:42

Abstract

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This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 KE 1045 Decreased, Ovarian E2 Decreased, Ovarian E2
2 KE 1046 Suppression, Estrogen receptor (ER) activity Suppression, Estrogen receptor (ER) activity
3 KE 1047 Increased, secretion of GnRH from hypothalamus Increased, secretion of GnRH from hypothalamus
4 KE 1049 Increased, secrection of FSH from anterior pituitary Increased, secrection of FSH from anterior pituitary
5 KE 1050 Increased, secretion of LH from anterior pituitary Increased, secretion of LH from anterior pituitary
6 KE 1051 Hyperplasia, ovarian stromal cells Hyperplasia, ovarian stromal cells
7 KE 1052 Hyperplasia, ovarian epithelium Hyperplasia, ovarian epithelium
8 KE 1056 Decrease, E2 blood concentrations at hypothalamus Decrease, E2 blood concentrations at hypothalamus
9 AO 1053 Promotion, ovarian adenomas Promotion, ovarian adenomas
10 AO 1054 Promotion, ovarian granular cell tumors Promotion, ovarian granular cell tumors

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Decreased, Ovarian E2 leads to Decrease, E2 blood concentrations at hypothalamus adjacent High
Decrease, E2 blood concentrations at hypothalamus leads to Increased, secretion of GnRH from hypothalamus adjacent High
Increased, secretion of GnRH from hypothalamus leads to Increased, secrection of FSH from anterior pituitary adjacent High
Increased, secretion of GnRH from hypothalamus leads to Increased, secretion of LH from anterior pituitary adjacent High
Suppression, Estrogen receptor (ER) activity leads to Decrease, E2 blood concentrations at hypothalamus non-adjacent High
Increased, secrection of FSH from anterior pituitary leads to Hyperplasia, ovarian stromal cells non-adjacent Moderate
Increased, secrection of FSH from anterior pituitary leads to Hyperplasia, ovarian epithelium non-adjacent Moderate
Increased, secretion of LH from anterior pituitary leads to Hyperplasia, ovarian stromal cells non-adjacent High
Hyperplasia, ovarian epithelium leads to Promotion, ovarian adenomas non-adjacent High
Hyperplasia, ovarian stromal cells leads to Promotion, ovarian granular cell tumors non-adjacent High

Network View

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Stressors

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Name Evidence Term
Tamoxifen
Raloxifene
Fulvestrant

Life Stage Applicability

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Taxonomic Applicability

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Term Scientific Term Evidence Link
CD-1 mouse Mus musculus Moderate NCBI
F344 rat Rattus norvegicus High NCBI

Sex Applicability

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Sex Evidence
Female High

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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1. Capen, C. C. (2004). Mechanisms of hormone-mediated carcinogenesis of the ovary. Toxicologic pathology 32 Suppl 2, 1-5.

2. Cohen, I. R., Sims, M. L., Robbins, M. R., Lakshmanan, M. C., Francis, P. C., and Long, G. G. (2000). The reversible effects of raloxifene on luteinizing hormone levels and ovarian morphology in mice. Reproductive toxicology 14(1), 37-44.

3. Long, G. G., Cohen, I. R., Gries, C. L., Young, J. K., Francis, P. C., and Capen, C. C. (2001). Proliferative lesions of ovarian granulosa cells and reversible hormonal changes induced in rats by a selective estrogen receptor modulator. Toxicologic pathology 29(6), 719-26.