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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 ?
Charles Wood
(email point of contact)
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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 Do not cite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
Relationships Between Two Key Events (Including MIEs and AOs)
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Title
Adjacency
Evidence
Quantitative Understanding
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
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Stressors
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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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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.