PR:000027727estrogen receptor alpha complexGO:0030520intracellular estrogen receptor signaling pathway1increasedWikiUser_26rodentsWikiUser_17mammalsWikiUser_6fishIncreased, Kisspeptin signallingIncreased, Kisspeptin signallingMolecular2022-04-05T00:47:462022-04-05T00:47:46Decreased, GonadotropinsDecreased, GonadotropinsMolecular2022-04-05T00:49:162022-04-05T00:49:16Decreased, Androgen and Progestin Decreased , Androgen and Progestin Cellular2022-04-05T00:50:352022-06-06T13:38:25Decreased, Maturation Inducing Steroid Surge by Granulosa cellsDecreased, Maturation Inducing Steroids Surge by Granulosa cellsTissue2022-04-05T00:51:452022-04-05T00:54:34Impaired, Oocyte maturation and ovulationImpaired, Oocyte maturation and ovulationTissue2022-04-05T00:54:112022-04-05T00:54:11Increased, Oocyte AtresiaIncreased, Oocyte AtresiaTissue2022-04-05T00:55:512022-04-05T00:55:51Impaired, ReproductionImpaired, ReproductionPopulation2022-04-05T00:57:202022-04-05T00:57:20Activation, estrogen receptor alphaActivation, estrogen receptor alphaMolecular2016-11-29T18:41:292016-12-03T16:37:531d5a104d-febc-4ee5-826e-b30b8f28ca2695ecbc59-94e3-489b-b795-5292cbb6a0ac<p><strong>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.</strong></p>
<p>Concordance Table available here: <a href="https://aopwiki.org/system/dragonfly/production/2022/04/05/3jmr0krg0b_ERalpha_Kisspeptin_CT_ERa_CKE.pdf">ERalpha_Kisspeptin_CT</a></p>
<p><strong>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.</strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>Dose concordance</strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>When adult female Wistar-Imamichi rats received a low dose of E2 to produce 35.8 pg/mL levels of E2, there was a non-significant change in the relative expression of Kiss-1 compared to controls. When exposed to a high dose of E2 to produce 514.1 pg/mL of E2 levels, there was a significant change in Kiss-1 expression (Kinoshita et al., 2005).</strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>When exposed to 100 pM and 1nM of E2, mice cell lines did not experience a significant increase in relative luciferase Kiss-1 gene activity. At concentrations equal to and greater than 10 nM, mice cell lines experienced a significant increase in relative luciferase Kiss-1 gene activity (Li et al., 2007).</strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>LBT2 gonadotroph cell lines exposed to 10^-9 M estradiol do not experience any changes in relative Kiss-1 mRNA levels compared to control cell lines. When exposed to 10^-7 M of estradiol, cell lines experience a significant increase in relative Kiss-1 mRNA levels (Richard et al., 2008).</strong></p>
</li>
</ul>
</li>
<li dir="ltr">
<p dir="ltr"><strong>Temporal concordance</strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>5 hours after estrogen exposure, adult female Wister-Imamichi strain rats experience a significant increase in cFos expression (Adachi et al., 2007).</strong></p>
</li>
</ul>
</li>
</ul>
<p><strong>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).</strong></p>
<p>Quantitative Understanding of the Linkage shown below. </p>
HighMaleHighFemaleHighAdult, reproductively matureHighHighLow<ul>
<li dir="ltr">
<p dir="ltr"><strong>Taxonomic Applicability:</strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>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.</strong></p>
</li>
</ul>
</li>
<li dir="ltr">
<p dir="ltr"><strong>Sex Applicability: </strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>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. .</strong></p>
</li>
</ul>
</li>
<li dir="ltr">
<p dir="ltr"><strong>Life Stage Applicability: </strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>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.</strong></p>
</li>
</ul>
</li>
</ul>
2022-06-06T13:32:532022-08-15T02:42:4295ecbc59-94e3-489b-b795-5292cbb6a0ac310370af-ee66-47fd-bc6b-48fefdd99e37<p><strong>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. </strong></p>
<p>Concordance Table available here: <a href="https://aopwiki.org/system/dragonfly/production/2022/04/13/939ypit8bw_ERalpha_Kisspeptin_Gonadotropin_ConcordanceTable.pdf">ERalpha_Kisspeptin_Gonadotropin_CT</a></p>
<p><strong>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).</strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>Dose concordance</strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>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). </strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>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. </strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>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). </strong></p>
</li>
</ul>
</li>
<li dir="ltr">
<p dir="ltr"><strong>Temporal concordance</strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>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).</strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>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). </strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>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).</strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>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).</strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>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). </strong></p>
</li>
<li dir="ltr">
<p dir="ltr"><strong>With E2-primed OVX rats, a significant increase in plasma LH can be seen 1-hour post-human metastin injection (Kinoshita et al., 2005).</strong></p>
</li>
</ul>
</li>
</ul>
<p>In the literature reviewed so far, there has been no uncertainities or inconsistencies. </p>
<p>Quantitative understanding is shown below. </p>
HighMaleHighFemaleHighAdult, reproductively matureHighJuvenileHighHighLow<ul>
<li dir="ltr">
<p dir="ltr"><strong>Taxonomic Applicability:</strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>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).</strong></p>
</li>
</ul>
</li>
<li dir="ltr">
<p dir="ltr"><strong>Sex Applicability: </strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>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. </strong></p>
</li>
</ul>
</li>
<li dir="ltr">
<p dir="ltr"><strong>Life Stage Applicability: </strong></p>
<ul>
<li dir="ltr">
<p dir="ltr"><strong>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.</strong></p>
</li>
</ul>
</li>
</ul>
2022-04-05T00:58:112022-08-15T02:43:111d5a104d-febc-4ee5-826e-b30b8f28ca26310370af-ee66-47fd-bc6b-48fefdd99e372022-06-06T13:40:142022-08-15T02:43:48310370af-ee66-47fd-bc6b-48fefdd99e374ea006c2-0c7e-4af2-b5e7-aa3f364ad5852022-04-05T00:58:352022-04-05T00:58:351d5a104d-febc-4ee5-826e-b30b8f28ca26a245c6a7-a988-41e8-9e27-981c45afc7f92022-08-15T02:45:402022-08-15T02:46:404ea006c2-0c7e-4af2-b5e7-aa3f364ad5852bcc40d3-d478-4ebd-85b7-f882d9d7f2d42022-04-05T00:58:462022-04-05T00:58:462bcc40d3-d478-4ebd-85b7-f882d9d7f2d4201895e4-65ec-434b-963e-a27f7fbc80292022-04-05T00:59:052022-04-05T00:59:05201895e4-65ec-434b-963e-a27f7fbc8029633b4817-d6b3-441a-ba64-fc06d3627eb92022-04-05T00:59:192022-04-05T00:59:19633b4817-d6b3-441a-ba64-fc06d3627eb9a245c6a7-a988-41e8-9e27-981c45afc7f92022-04-05T00:59:282022-04-05T00:59:28Estrogen Receptor Alpha Agonism leads to Impaired ReproductionERĪ± Agonism leads to Impaired Reproduction<p>John Hoang, ORISE participant at US Environmental Protection Agency</p>
<p>Michael Ellman, ORISE participant at US Environmental Protection Agency</p>
<p>Jacob Collins, ORISE participant at US Environmental Protection Agency</p>
Under development: Not open for comment. Do not cite<p>Estrogen Receptor Alpha(ERalpha) is a nuclear transcription factor that is activated by estrogens, a group of hormones involved in reproductive development. ERalpha is involved in the transcription and regulation of physiological processes involved in the endocrine system. Birth control pills contain estrogens which often end up in wastewater streams and allow for exogenous exposures to many fish. This AOP connects ERalpha agonism to decreased, cumulative fecundity as a result of impairment within the endocrine system. In particular, the activation of ERalpha in kisspeptin cells located within the hypothalamus causes increased kisspeptin signaling. This increased signaling causes an increase in gonadotropin-releasing hormone(GnRH). The increase of GnRH causes increased negative feedback response on the release of gonadotropins, resulting in a decrease in gonadotropin levels. The decreased gonadotropin levels lead to a decrease in androgen and progestin production by theca cells within the ovary. The decrease in androgen and progestin levels causes a decrease in maturation-inducing steroids by the granulosa cells within the ovary. A reduction in maturation-inducing steroids causes impairment in oocyte maturation and ovulation thereby resulting in an increase in oocyte atresia and a decrease in cumulative fecundity. </p>
adjacentModerateHighadjacentModerateHighadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot Specifiednon-adjacentModerateModeratenon-adjacentModerateHigh2022-04-05T00:44:112023-04-29T13:02:20