This AOP is licensed under a Creative Commons Attribution 4.0 International License.

Aop: 165

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

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

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Antiestrogens and ovarian adenomas/granular cell tumors

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Charles Wood (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Charles Wood

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help

Author status	OECD status	OECD project	SAAOP status
Under Development: Contributions and Comments Welcome		1.29	Under Development

This AOP was last modified on June 04, 2021 13:35

Revision dates for related pages

Page	Revision Date/Time
Decreased, Ovarian E2	September 16, 2017 10:17
Suppression, Estrogen receptor (ER) activity	February 28, 2022 23:08
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	March 01, 2022 06:01
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

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

KE	1045	Decreased, Ovarian E2	Decreased, Ovarian E2
KE	1046	Suppression, Estrogen receptor (ER) activity	Suppression, Estrogen receptor (ER) activity
KE	1047	Increased, secretion of GnRH from hypothalamus	Increased, secretion of GnRH from hypothalamus
KE	1049	Increased, secrection of FSH from anterior pituitary	Increased, secrection of FSH from anterior pituitary
KE	1050	Increased, secretion of LH from anterior pituitary	Increased, secretion of LH from anterior pituitary
KE	1051	Hyperplasia, ovarian stromal cells	Hyperplasia, ovarian stromal cells
KE	1052	Hyperplasia, ovarian epithelium	Hyperplasia, ovarian epithelium
KE	1056	Decrease, E2 blood concentrations at hypothalamus	Decrease, E2 blood concentrations at hypothalamus

AO	1053	Promotion, ovarian adenomas	Promotion, ovarian adenomas
AO	1054	Promotion, ovarian granular cell tumors	Promotion, ovarian granular cell tumors

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

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

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Name
Tamoxifen
Raloxifene
Fulvestrant

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

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

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Female	High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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

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.