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Relationship: 2627
Title
Increased, Kisspeptin signalling leads to Decreased, Gonadotropins
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
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Estrogen Receptor Alpha Agonism leads to Impaired Reproduction | adjacent | High | Moderate | Evgeniia Kazymova (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
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Male | High |
Female | High |
Life Stage Applicability
Term | Evidence |
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Adult, reproductively mature | High |
Juvenile | High |
Key Event Relationship Description
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). As Kisspeptins are natural ligands for G-protein-coupled receptor-54 (GPR-54), a nuclear receptor located on gonadotropin-releasing hormone(GnRH) neurons in the pituitary, exposures from kisspeptins would result in the activation of GnRH neurons and increase of gonadotropins(Clarke et al., 2009). As Kisspeptins play a large role in gonadotropin signaling, we believe that changes in kisspeptin signaling also leads to decreased overall gonadotropins through negative feedback loop mechanisms.
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_Gonadotropin_CT
Biological Plausibility
As Kisspeptins are natural ligands for G-protein-coupled receptor-54 (GPR-54), a nuclear receptor located on gonadotropin-releasing hormone(GnRH) neurons in the pituitary, exposures from kisspeptins would result in the activation of GnRH neurons and increase of gonadotropins(Clarke et al., 2009).
Empirical Evidence
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Dose concordance
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At 0.5, 5, and 50 nM of kisspeptin-10, control mice did not experience a significant increase in GnRH released. At 500 nM of kisspeptin-10, control mice saw a significant increase in GnRH released in controls (D’Angelmont de Tassigny et al., 2008).
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Infusion of kisspeptin-54 in human males at rates above 0.25 pmol/kg*min resulted in a significant increase in mean LH and FSH over time (Dhillo et al., 2005) with dose dependence occurring up to 12 pmol/kg*min. At 0.125 pmol/kg*min, human males did not experience a significant increase in LH.
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When exposed to 10^-14 M of Kisspeptin-10, primary pituitary cell cultures did not experience a significant increase in LH secretion. However beginning at 10^-12 M of kisspeptin-10, there is a dose-dependent significant increase in LH secretion (Luque et al., 2011).
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Temporal concordance
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When exposed continuously to kisspeptin-10 50 nM, control mice saw a significant increase in GnRH released after an hour of being exposed (D’Angelmont de Tassigny et al., 2008).
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Human males received a 90 minute IV infusion of kisspeptin-54(4 pmol/kg*min). There was a significant increase in LH 30 minutes into the infusion (Dhillo et al., 2005).
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When adult male sea bass are exposed to sea bass Kiss-2, there is a significant increase of LH and FSH beginning at 120 and 60 minutes post-injection. For Kiss-1, there is a significant increase of LH beginning at 120 minutes (Felipe et al., 2008).
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Adult Wistar male rats exposed to sea bass Kiss-1(100pmol i.c.v.) begin to experience a significant increase in LH and FSH at 15 and 30 minutes post-injection. When exposed to sea bass Kiss-2(100pmol i.c.v), the same rats only experience a significant increase in LH 15 minutes post-injection before returning to basal levels. When injected i.p.(15 ug) Instead of i.c.v., adult male rats only experience a significant increase in LH with Kiss-1 15 minutes post-injection (Felipe et al., 2008).
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In human females after receiving a kisspeptin-54 injection, a significant increase in kisspeptin-54 can be seen 60 minutes post-injection. A significant increase in FSH and LH can be seen after 240 and 180 minutes (Jayasena et al., 2014).
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With E2-primed OVX rats, a significant increase in plasma LH can be seen 1-hour post-human metastin injection (Kinoshita et al., 2005).
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Uncertainties and Inconsistencies
In the literature reviewed so far, there has been no uncertainities or inconsistencies.
Known modulating factors
Modulating factors haven’t been evaluated yet.
Quantitative Understanding of the Linkage
Quantitative understanding is shown below.
Response-response Relationship
Dose concordance evidence above demonstrates a response-response relationship where lower doses of kisspeptin don’t elicit changes in LH/FSH levels.
Time-scale
At 300 plasma kisspeptin-IR(pmol/L), plasma LH levels reach a plateau where concentrations above this do not change LH levels. From 0 to 300 plasma kisspeptin-IR(pmol/L), there is an exponential increase in plasma LH levels(Dhillo et al., 2005).
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
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Taxonomic Applicability:
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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(Felip et al., 2008).
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Sex Applicability:
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Kisspeptins and its role on gonadotropin circulation is present in both males and females. However, there is sexual dimorphism in the expression of kisspeptin neurons within the hypothalamus due to positive feedback actions present in females particularly with reproduction.
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Life Stage Applicability:
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Kisspeptin and its relationship with gonadotropins does not seem to have major life stage-differences. However, with the role that gonadotropins play on reproduction, the applicability can be directed towards reproductively mature organisms and developing organisms.
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