Aop:168

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/168


AOP Title

GnRH pulse disruption leading to mammary adenomas and carcinomas in the SD rat.
Short name: GnRH pulse disruption and mammary tumors.

Authors

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)

Status

Please follow the link to snapshots page to view and create Snapshots of this AOP.

Under development: Do not distribute or cite.

OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

This AOP page was last modified on 12/11/2016.

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Abstract

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)

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality

Key Events

Event Support for Essentiality
GnRH pulsatility/release in hypothalamus, Decreased Strong
LH Surge from anterior pituitary, Decreased Strong
Ovulation, interruption Strong
estrus, prolonged Strong
circulating estrogen levels, Increased Strong
prolactin exposure, Increased Strong
Mammary gland, Hyperplasia Strong
latency period, Increased Strong

Adverse Outcome

Adverse Outcome
Adenomas/carcinomas (mammary), Increased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
GnRH pulsatility/release in hypothalamus, Decreased Directly Leads to LH Surge from anterior pituitary, Decreased Strong
LH Surge from anterior pituitary, Decreased Directly Leads to Ovulation, interruption Strong
LH Surge from anterior pituitary, Decreased Indirectly Leads to estrus, prolonged Strong
estrus, prolonged Directly Leads to circulating estrogen levels, Increased Strong
estrus, prolonged Directly Leads to prolactin exposure, Increased Moderate
circulating estrogen levels, Increased Indirectly Leads to Mammary gland, Hyperplasia Strong
prolactin exposure, Increased Directly Leads to Mammary gland, Hyperplasia Strong
Mammary gland, Hyperplasia Indirectly Leads to latency period, Increased Strong
Mammary gland, Hyperplasia Indirectly Leads to Adenomas/carcinomas (mammary), Increased Strong
latency period, Increased Indirectly Leads to Adenomas/carcinomas (mammary), Increased Moderate

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
SD rat Rattus norvegicus Strong NCBI

Sex Applicability

Sex Evidence Links
Female Strong

Graphical Representation

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References

1. Meek, B., Renwick, A., Sonich-Mullin, C., and International Programme on Chemical, S. (2003a). Practical application of kinetic data in risk assessment--an IPCS initiative. Toxicology letters 138(1-2), 151-60.

2. Meek, M. E., Bucher, J. R., Cohen, S. M., Dellarco, V., Hill, R. N., Lehman-McKeeman, L. D., Longfellow, D. G., Pastoor, T., Seed, J., and Patton, D. E. (2003b). A framework for human relevance analysis of information on carcinogenic modes of action. Critical reviews in toxicology 33(6), 591-653, 10.1080/713608373.

3. Rudmann, D., Cardiff, R., Chouinard, L., Goodman, D., Kuttler, K., Marxfeld, H., Molinolo, A., Treumann, S., Yoshizawa, K., Inhand Mammary, Z. s. P., and Clitoral Gland Organ Working, G. (2012). Proliferative and nonproliferative lesions of the rat and mouse mammary, Zymbal's, preputial, and clitoral glands. Toxicologic pathology 40(6 Suppl), 7S-39S, 10.1177/0192623312454242.

4. Simpkins, J. W., Swenberg, J. A., Weiss, N., Brusick, D., Eldridge, J. C., Stevens, J. T., Handa, R. J., Hovey, R. C., Plant, T. M., Pastoor, T. P., and Breckenridge, C. B. (2011). Atrazine and breast cancer: a framework assessment of the toxicological and epidemiological evidence. Toxicological sciences : an official journal of the Society of Toxicology 123(2), 441-59, 10.1093/toxsci/kfr176.