This AOP is licensed under a Creative Commons Attribution 4.0 International License.
GnRH pulse disruption leading to mammary adenomas and carcinomas in the SD rat.
Point of Contact
- Charles Wood
|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 13:38
|Decreased, GnRH pulsatility/release in hypothalamus||September 16, 2017 10:17|
|Decreased, LH Surge from anterior pituitary||December 03, 2016 16:37|
|interruption, Ovulation||December 03, 2016 16:37|
|prolonged, estrus||December 03, 2016 16:37|
|Increased, circulating estrogen levels||December 03, 2016 16:37|
|Increased, prolactin exposure||December 03, 2016 16:37|
|Hyperplasia, Mammary gland||September 16, 2017 10:17|
|Increased, Adenomas/carcinomas (mammary)||September 16, 2017 10:17|
|Increased, latency period||December 03, 2016 16:37|
|Decreased, GnRH pulsatility/release in hypothalamus leads to Decreased, LH Surge from anterior pituitary||December 03, 2016 16:38|
|Decreased, LH Surge from anterior pituitary leads to interruption, Ovulation||December 03, 2016 16:38|
|Decreased, LH Surge from anterior pituitary leads to prolonged, estrus||December 03, 2016 16:38|
|prolonged, estrus leads to Increased, circulating estrogen levels||December 03, 2016 16:38|
|prolonged, estrus leads to Increased, prolactin exposure||December 03, 2016 16:38|
|Increased, circulating estrogen levels leads to Hyperplasia, Mammary gland||December 03, 2016 16:38|
|Increased, prolactin exposure leads to Hyperplasia, Mammary gland||December 03, 2016 16:38|
|Hyperplasia, Mammary gland leads to Increased, latency period||December 03, 2016 16:38|
|Hyperplasia, Mammary gland leads to Increased, Adenomas/carcinomas (mammary)||December 03, 2016 16:38|
|Increased, latency period leads to Increased, Adenomas/carcinomas (mammary)||December 03, 2016 16:38|
|atrazine||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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||KE||1071||Decreased, GnRH pulsatility/release in hypothalamus||Decreased, GnRH pulsatility/release in hypothalamus|
|2||KE||1072||Decreased, LH Surge from anterior pituitary||Decreased, LH Surge from anterior pituitary|
|3||KE||1074||interruption, Ovulation||interruption, Ovulation|
|4||KE||1075||prolonged, estrus||prolonged, estrus|
|5||KE||1076||Increased, circulating estrogen levels||Increased, circulating estrogen levels|
|6||KE||1077||Increased, prolactin exposure||Increased, prolactin exposure|
|7||KE||1078||Hyperplasia, Mammary gland||Hyperplasia, Mammary gland|
|8||KE||1080||Increased, latency period||Increased, latency period|
|9||AO||1079||Increased, Adenomas/carcinomas (mammary)||Increased, Adenomas/carcinomas (mammary)|
Relationships Between Two Key Events (Including MIEs and AOs)
|Decreased, LH Surge from anterior pituitary leads to prolonged, estrus||non-adjacent||High|
|Increased, circulating estrogen levels leads to Hyperplasia, Mammary gland||non-adjacent||High|
|Hyperplasia, Mammary gland leads to Increased, latency period||non-adjacent||High|
|Hyperplasia, Mammary gland leads to Increased, Adenomas/carcinomas (mammary)||non-adjacent||High|
|Increased, latency period leads to Increased, Adenomas/carcinomas (mammary)||non-adjacent||Moderate|
Life Stage Applicability
|SD rat||Rattus norvegicus||High||NCBI|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
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.