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Early-life estrogen receptor activity leading to endometrial carcinoma in the mouse.
Point of Contact
- Charles Wood
|Handbook Version||OECD status||OECD project|
This AOP was last modified on April 29, 2023 16:02
|prepubertal increase, Estrogen receptor (ER) activity||December 03, 2016 16:37|
|Activation, estrogen receptor alpha||December 03, 2016 16:37|
|Promotion, SIX-1 postive basal-type progenitor cells||September 16, 2017 10:17|
|Proliferation/Clonal Expansion, aberrant basal cells||September 16, 2017 10:17|
|squamous metaplasia, aberrant basal cells||December 03, 2016 16:37|
|Increased, Hyperplasia (glandular epithelial cells of endometrium)||September 16, 2017 10:17|
|Increased, adenosquamous carcinomas of endometrium||September 16, 2017 10:17|
|prepubertal increase, Estrogen receptor (ER) activity leads to Activation, estrogen receptor alpha||December 03, 2016 16:38|
|Activation, estrogen receptor alpha leads to Promotion, SIX-1 postive basal-type progenitor cells||December 03, 2016 16:38|
|Promotion, SIX-1 postive basal-type progenitor cells leads to Proliferation/Clonal Expansion, aberrant basal cells||December 03, 2016 16:38|
|Proliferation/Clonal Expansion, aberrant basal cells leads to squamous metaplasia, aberrant basal cells||December 03, 2016 16:38|
|squamous metaplasia, aberrant basal cells leads to Increased, Hyperplasia (glandular epithelial cells of endometrium)||December 03, 2016 16:38|
|Increased, Hyperplasia (glandular epithelial cells of endometrium) leads to Increased, adenosquamous carcinomas of endometrium||December 03, 2016 16:38|
|Diethylstilbestrol||November 29, 2016 18:42|
|Genistein||November 29, 2016 18:42|
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
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||1064||prepubertal increase, Estrogen receptor (ER) activity||prepubertal increase, Estrogen receptor (ER) activity|
|KE||1065||Activation, estrogen receptor alpha||Activation, estrogen receptor alpha|
|KE||1066||Promotion, SIX-1 postive basal-type progenitor cells||Promotion, SIX-1 postive basal-type progenitor cells|
|KE||1067||Proliferation/Clonal Expansion, aberrant basal cells||Proliferation/Clonal Expansion, aberrant basal cells|
|KE||1068||squamous metaplasia, aberrant basal cells||squamous metaplasia, aberrant basal cells|
|KE||1069||Increased, Hyperplasia (glandular epithelial cells of endometrium)||Increased, Hyperplasia (glandular epithelial cells of endometrium)|
|AO||1070||Increased, adenosquamous carcinomas of endometrium||Increased, adenosquamous carcinomas of endometrium|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
|Fetal to Parturition||Moderate|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Known Modulating Factors
Considerations for Potential Applications of the AOP (optional)
1. Klaunig, J. E., Babich, M. A., Baetcke, K. P., Cook, J. C., Corton, J. C., David, R. M., DeLuca, J. G., Lai, D. Y., McKee, R. H., Peters, J. M., Roberts, R. A., and Fenner-Crisp, P. A. (2003). PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Critical reviews in toxicology 33(6), 655-780, 10.1080/713608372.
2. Newbold, R. R., Banks, E. P., Bullock, B., and Jefferson, W. N. (2001). Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer research 61(11), 4325-8.
3. Suen, A. A., Jefferson, W. N., Wood, C. E., Padilla-Banks, E., Bae-Jump, V. L., and Williams, C. J. (2016). SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer. Molecular cancer research : MCR doi: 10.1158/1541-7786.MCR-16-0084, 10.1158/1541-7786.MCR-16-0084.