To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2665
Activation, estrogen receptor alpha leads to Increased, Kisspeptin signalling
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Estrogen Receptor Alpha Agonism leads to Impaired Reproduction||adjacent||High||Moderate||John Hoang (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
Estrogen receptor alpha (ERα) is a nuclear receptor that can be activated by estrogens, a group of hormones involved in reproductive development. Activation of ERα promotes the transcription and regulation of physiological processes involved with the endocrine system(Christian and Moenter, 2007). Kisspeptins are a family of peptide hormones with varying amino acid lengths derived from the KISS1 gene & neurons (Nejad et al., 2017). Breakthrough research in the 2000s has shown that kisspeptins play a large role in the hypothalamic-pituitary-gonadal axis with gonadotropin circulation(Alcin et al., 2013). In particular, more recent research has shown kisspeptin neurons contain large populations of estrogen receptors, particularly ERα.
Evidence Collection Strategy
The majority of papers used in evidence supporting the key event relationship were found through AbstractSifter, a Microsoft Excel-based application that extracts papers from PubMed. AbstractSifter ranks abstracts based on their relevance through key search and filter terms. Initial papers were found through the search engine, Google Scholar, utilizing the search terms “Kisspeptin” and “estrogen”. This search yielded 11600 search results but only papers found on the first page of results were further examined. These papers were used to help curate search and filter terms used in Abstract Sifter. An additional search using CSU Long Beach’s One Search engine with key terms “GPR54” and “Kisspeptin” was also done in support of further curating search and filter terms for Abstractsifter. In this search, 3395 papers were initially found and only papers on the first page of the search were initially read. In AbstractSifter, 2 different searches were done to curate a subset of 71 papers. Search terms for the 2 searches included “kisspeptin AND GPR54” and “danio rerio AND kisspeptin” which yielded an initial set of 521 and 60 results respectively. Filter terms for the 2 searches included “estr AND LH” and “estr” which yielded 58 and 13 papers. Additional sources used towards the weight of evidence were found through sources in papers curated in the AbstractSifter search.
Evidence Supporting this KER
Concordance Table available here: ERalpha_Kisspeptin_CT
Previous studies have shown that estrogen exposures to organisms have caused increases in gonadotropin levels despite gonadotropin-releasing hormone neurons not expressing estrogen receptors. Recent studies have shown kisspeptin neurons located within the hypothalamus to express estrogen, androgen, and progesterone receptors(Clarkson et al., 2008). Fluorescence-activated cell sorting in mice found 99% and 70% of KISS1 neurons in the arcuate and anteroventral periventricular regions of the hypothalamus express ERα receptors (Smith et al., 2005). Estrogen exposures thereby should elicit an increase in kisspeptin expression.
Uncertainties and Inconsistencies
When young female rhesus macaques were exposed to estradiol and ovariectomized, there was not a significant change in Kiss-1 expression (Eghlidi et al., 2010).
Known modulating factors
Modulating factors haven’t been evaluated yet.
Dose concordance evidence above demonstrates a response-response relationship where lower doses of estradiol don’t elicit changes in kisspeptin levels.
5 hours after an estrogen exposure, there is evidence of a change in kisspeptin expression (Adachi et al., 2007).
Known Feedforward/Feedback loops influencing this KER
ERα and kisspeptins are involved with gonadotropin circulation within the body. It is well known that gonadotropins have both a negative and positive feedback loop depending on the circumstances. In females under proper reproductive conditions, estrogen induces positive feedback for ovulation. Under all other circumstances in females and males, estrogen induces negative feedback action to regulate levels of gonadotropins.
Domain of Applicability
The understanding of kisspeptins on the hypothalamus-gonadotropin- pituitary axis comes largely from rodent and mammal studies. However, there have been more studies recently in other species such as fish to determine if applicability is present which it has shown.
Estrogen is present in both males and females. There is sexual dimorphism in the expression of kisspeptin neurons within the hypothalamus due to the positive feedback actions present in females particularly with reproduction. .
Life Stage Applicability:
Kisspeptin plays a role in gonadotropin circulation. As a result of gonadotropins’ role in reproduction, the applicability can be directed towards reproductively mature organisms and developing organisms.