Increased Kisspeptin levels in anteroventral periventricular nucleus (AVPV)

CHEBI:80304

CHEBI Metastin

UBERON:0001009

UBERON circulatory system

PR:000027727

PR estrogen receptor alpha complex

GO:0007269

GO neurotransmitter secretion

HP:0030339

HP Decreased circulating gonadotropin level

GO:0030520

GO intracellular estrogen receptor signaling pathway

GO:0030284

GO estrogen receptor activity

WIKI increased

WIKI decreased

WikiUser_17

mammals

WikiUser_28

Vertebrates

WikiUser_26

ApacheUser rodents

WikiUser_6

ApacheUser fish

Increased Kisspeptin levels in anteroventral periventricular nucleus (AVPV)

Increased Kisspeptin levels in AVPV

Cellular

This Key Event represents increased kisspeptin levels measured in the anteroventral periventricular nucleus.  Kisspeptin (also known as metastin) is a key signalling neuropeptide hormone in mammals and some other vertebrates.  The kisspeptin gene (KISS1) encodes a 145 amino acid prepolypeptide that is converted to 4 active peptides with names based on the number of amino acids (kisspeptin-54, 14, 13, 10); each active peptide is able to activate kisspeptin receptor (GPR54, KISS1R) because of a conserved c-terminal region Arg-Phe-NH2 group (Hu et al. 2018).  Positive feedback for kisspeptin hormone production is due to increased levels of estrogen binding to Estrogen Receptor Alpha (ERa) receptors in neurons from the anteroventral periventricular nucleus (AVPV) region of the hypothalamus (Uenoyama et al. 2021).

Kisspeptin can be measured via immunoassay or Western blotting, with immunoassay the preferred technique. Studies that utilized immunoassay include (Adachi et al. 2007; Clarkson et al. 2008; Wang et al. 2014), and include commercially available ELISA kits (e.g. Abcam ab288589 (human); Assay Genie HUDL01615 (human); LS Bio LS-F8897 (mouse)).  Mention of trade names or commercial products does not constitute endorsement or recommendation for use.   Real time PCR can be used to measure kisspeptin transcript abundance, which is an indirect – and only semi-quantitative indicator of kisspeptin hormone levels (studies that utilized this approach include Adachi et al. 2007; Tomikawa et al. 2012; Wang et al. 2014).

Life Stage: Adult, reproductively mature, juveniles. Sex: Applies to both males and females as both sexes require kisspeptin signalling for regulation of various hormone pathways. Taxonomic: Primarily studied in laboratory rodents and humans.  Plausible for most mammals due to conserved hormone pathways regulating hypothalamus-pituitary-gonadal axis processes.  For vertebrates, kisspeptins and kisspeptin receptors are  absent from bird species; present in mammals and fish (Sivalingam et al. 2022).

UBERON:0001898

UBERON hypothalamus

CL:0000540

CL neuron

High Unspecific

Moderate

Adult, reproductively mature

Moderate

Juvenile

Moderate

2026-04-06T14:43:10

Decreased, Gonadotropins

Tissue

Gonadotropins are hormones in mammals that cue development of reproductive organs to maturity (Casarini and Simoni 2021; Howard 2021) and the different phases of the estrus cycle (Uenoyama et al. 2021).  Gonadotropins are composed of two subunits: a 90-100 amino acid alpha subunit that is identical for all gonadotropins for a species, and a 105-150 amino acid beta subunit that are unique to each gonadotropin but exhibit large similarities in order to interact with alpha subunits (Cahoreau et al 2015).  Key gonadotropins include Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH), which are released from the anterior pituitary gland (Howard 2021).

Gonadotropin levels are generally measured from blood or urine samples by immunoassay or Western blotting, with immunoassay the preferred technique. Studies that utilized immunoassay include (Feng et al. 2015; Cao et al. 2018; Wang et al. 2018). Commercially ELISA kits are available for Luteinizing hormone (e.g. Abcam AB303746 (human); Aviva OKCA00156 (mouse); ThermoFisher EHLH (human)) and Follicle-stimulating hormone (e.g. ThermoFisher EH202RB (human); ALPCO 11-FSHHU-E01 (human); ENZO ENZ-KIT108 (human)).  Mention of trade names or commercial products does not constitute endorsement or recommendation for use.   Real time PCR can be used to measure gonadotropin transcript abundance, which is an indirect – and only semi-quantitative indicator of gonadotropin hormone levels.  Since gonadotropins share a common alpha subunit, focus is generally on the beta subunit (studies that utilized this approach include Burger et al. 2004; Schirman-Hildesheim et al. 2008; Oride et al. 2023).

Life Stage: Adult, reproductively mature and juveniles. Sex: Applies to both males and females. Taxonomic: Primarily studied in laboratory rodents and humans.  Plausible for most mammals due to conserved hormone pathways regulating hypothalamus-pituitary-gonadal axis processes.  Gonadotropins widespread among vertebrates, including fish, amphibians, reptiles, birds, and mammals (Hollander-Cohen et al. 2021).

UBERON:0001009

UBERON circulatory system

High Unspecific

Moderate

Adult, reproductively mature

Moderate

Juvenile

High

Burger LL, Haisenleder DJ, Aylor KW, Dalkin AC, Prendergast KA, Marshall JC.  2004. Regulation of Luteinizing Hormone-β and Follicle-Stimulating Hormone (FSH)-β Gene Transcription by Androgens: Testosterone Directly Stimulates FSH-β Transcription Independent from Its Role on Follistatin Gene Expression.  Endocrinology 145(1): 71–78. Cahoreau C, Klett D, Combarnous Y. 2015.  Structure-function relationships of glycoprotein hormones and their subunits' ancestors. Frontiers in Endocrinology 6: 26. Cao XY, Hua X, Xiong JW, Zhu WT, Zhang J, Chen L. 2018.  Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice. Frontiers in  Molecular Neuroscience 11(6). Casarini, L. and Simoni M. 2021.  Recent advances in understanding gonadotropin signaling. Faculty Reviews 10: 41. Feng X, Wang X, Cao X, Xia Y, Zhou R, Chen L. 2015.  Chronic Exposure of Female Mice to an Environmental Level of Perfluorooctane Sulfonate Suppresses Estrogen Synthesis Through Reduced Histone H3K14 Acetylation of the StAR Promoter Leading to Deficits in Follicular Development and Ovulation. Toxicological Sciences 148(2): 368-379. Hollander-Cohen L, Golan M, Levavi-Sivan B. 2021. Differential Regulation of Gonadotropins as Revealed by Transcriptomes of Distinct LH and FSH Cells of Fish Pituitary. International Journal of Molecular Sciences 22(12): 6478.  Howard, S.R. 2021.  Interpretation of reproductive hormones before, during and after the pubertal transition—identifying health and disordered puberty. Clinical Endocrinolology 95: 702-715. Oride A, Kanasaki H, Tumurbaatar, T, Tumurgan Z, Okada H, Cairang Z, Satoru K.  2023.  Impact of Ovariectomy on the Anterior Pituitary Gland in Female Rats.  International Journal of Endocrinology 2023: 3143347. Schirman-Hildesheim TD, Gershon E, Litichever N, Galiani D, Ben-Aroya N, Dekel N, Koch Y. 2008.  Local production of the gonadotropic hormones in the rat ovary. Molecular and Cellular Endocrinology 282(1-2): 32-38. Uenoyama, Y., Inoue, N., Nakamura, S., and Tsukamura, H. 2021. Kisspeptin Neurons and Estrogen–Estrogen Receptor α Signaling: Unraveling the Mystery of Steroid Feedback System Regulating Mammalian Reproduction.  International Journal of Molecular Sciences 22(17): 9229. Wang X, Bai Y, Tang C, Cao X, Chang F, Chen L.  2018.  Impact of Perfluorooctane Sulfonate on Reproductive Ability of Female Mice through Suppression of Estrogen Receptor α-Activated Kisspeptin Neurons. Toxicological Sciences 165(2): 475-486. NOTE: Italics indicate edits from John Frisch October 2025.  A full list of updates can be found in the Change Log on the View History page.   AOPWiki 2022-04-05T00:49:16

2026-04-06T14:41:01

Decreased, Androgen and Progestin

Decreased , Androgen and Progestin

Cellular

AOPWiki 2022-04-05T00:50:35

2022-06-06T13:38:25

Decreased, Maturation Inducing Steroid Surge by Granulosa cells

Decreased, Maturation Inducing Steroids Surge by Granulosa cells

Tissue

AOPWiki 2022-04-05T00:51:45

2022-04-05T00:54:34

Impaired, Oocyte maturation and ovulation

Tissue

AOPWiki 2022-04-05T00:54:11

2022-04-05T00:54:11

Increased, Oocyte Atresia

Tissue

AOPWiki 2022-04-05T00:55:51

2022-04-05T00:55:51

Impaired, Reproduction

Population

AOPWiki 2022-04-05T00:57:20

2022-04-05T00:57:20

Activation, estrogen receptor alpha

Activation, ERα

Molecular

Some sections of the KE description were derived and adapted from the External Scientific Report (Viviani et al., 2023). Biological state Estrogen Receptor Alpha (ERα) is a receptor covalently bound by estrogens, which following the dimerization can translocate to the nucleus (Björnström and Sjöberg, 2005), where it can bind to estrogen responsive elements and recruit co-activators or co-repressors, which can attract co-regulatory proteins, like histone acetyltransferase, ubiquitin ligases, and protein remodelers (Thomas and Gustafsson, 2011) (Fig.1). A non-genomic signalling of Erα is described (Fig. 7), not requiring the dimerization for the induction of kinases and calcium flux (Levin, 2002; Vasudevan and Pfaff, 2008). The non-genomic action of ERα is able to regulate more genes (Gu et al., 2014). Both signalling pathways are important for the human organism (Pedram et al., 2014; Pedram et al., 2016). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/08/14/6fttmbh7wt_figure_7_ke1065.png" /> Figure 7. Genomic and non-genomic signalling pathways of ERα The ER structure is composed by different domains (A-F) which are responsible for the binding to the ligands, the dimerization, the binding to the DNA and for the activation of transcription (Nilsson et al., 2001) (Fig. 8). The A/B domain, or activation function 1 (AF1) is responsible for transactivation and protein-protein interaction, and it acts independently of ligand binding. Then, there is the C-domain, which is responsible for DNA binding and receptor dimerization. The D-domain instead is the phosphorylation site or ER and has nuclear localization sequences. The E-domain, or activation function 2 (AF2) is the ligand binding domain and the site for the binding with co-activators and co-repressors (Ellmann et al., 2009). Lastly, the F-domain that prevents improper ligand activation and dimerization (Yang et al., 2008). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/08/14/4whefkoqkg_figure_8_ke1065.png" style="height:264px; width:1430px" /> Therefore, ligand binding, dimerization and DNA binding processes are the first steps to inducing the transcription of target genes. But the ER activity largely depends also on the presence and recruitment of different co-activators and co-repressors. Once ER is bound to estrogen responsive elements, it can recruit different proteins that can favour or obstruct the action of the receptor (Thomas and Gustafsson, 2011). The main co-activators are the steroid receptor co-activators (SRC-1 and SRC-3), which are able to recruit co-regulatory proteins (Heldring et al., 2007). The main transcription factors that can be regulated by ER are activating protein 1 (AP1), specificity protein 1 (SP1), cAMP response element-binding protein (CREB), nuclear factor-κB (NF-κB) and p53 (Biswas et al., 2005; Björnström and Sjöberg, 2005; Fox et al., 2009). Instead in absence of ligands, ER can be activated by the phosphorylation from protein kinases which are stimulated by hyperactive growth factor receptors (Britton et al., 2006). ER is also able to rapidly activate other pathways, namely MAPK, PI3K, EGFR, and SRC (Kousteni et al., 2001; Song et al., 2002; Razandi et al., 2004; Shupnik, 2004). Biological compartment ERα is mainly expressed in uterus, prostate (stroma), ovary (theca cells), testes (Leydig cells), epididymis, bone, breast, various regions of the brain, liver, and white adipose tissue (Dahlaman-Wright et al., 2006). At the subcellular compartments, estrogen receptors (ERs), are localized in cytoplasm where they exist as monomers bound to heat shock proteins (HSPs). Estrogen binding alters receptor conformation and triggers release from the HSPs, thereby allowing receptor dimerization and translocation in the nucleus where these dimers bind to specific DNA sequences and recruit numerous co-factors to regulate gene transcription. Unliganded ER are also characterized as monomers in the nucleus and at the plasma membrane (Gourdy et al., 2018) General role in biology The main function of ERα is to mediate the action of estrogens, known to be involved in physiological pathological conditions (endometrial proliferation in menstrual cycle and endometrial carcinoma in postmenopausal women). This receptor is also involved in apoptotic and proliferative functions involving the MAPK/ERK pathway, mainly in breast cancer cells (Zheng et al., 2007; Lin et al., 2010; Zhang et al., 2012; Li et al., 2013). Another player involved in the increased proliferation induced by ERα is c-myc (Dubik and Shiu, 1992). The increased proliferation induced by ER has been linked to tumours (Thomas and Gustafsson, 2011). The interaction between estrogen and ERα and the increased proliferation has been proved in breast and uterine tissues (Ellmann et al., 2009).

Note: considering the AOPs under development the stressors interacting with the estrogen metabolism should be tested negative in all the in vitro assays reported below.  Additional proof of concept supporting the chain of the events herein described is given by a negative result in the in vitro assays but positive outcome in the Uterotrophic Bioassays. Uterotrophic Bioassay is indeed indicative of a single endocrine mechanism i.e., estrogenicity that could be related to mechanism other than direct binding to ER alpha or ER beta receptor. In the regulatory area methods are available to measure ER receptor activity.  OECD in the “Revised Guidance document 150” give insightful information, including limits on their use, on validated and/or widely accepted assays with estrogenic active substance specific endpoints. OECD in vitro assays <ul> <li>OECD TG 493 (July 2015): Performance-Based Test Guideline for Human Recombinant Estrogen Receptor (HRER) In Vitro Assays to Detect Chemicals with ER Binding Affinity</li> <li>OECD TG 455 (June 2021): Performance-Based Test Guideline (PGBT) For Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists. It comprises several mechanistically and functionally similar test methods for the identification of estrogen receptor (i.e., ERα, and/or ERβ). The fully validated reference test methods that provide the basis for this PBTG are: 1) The Stably Transfected TA (STTA) assay using the (h) ERα-HeLa-9903 cell line; and 2) The VM7Luc ER TA assay (3) using the VM7Luc4E2 cell line1 which predominately expresses hERα with some contribution from hERβ.</li> <li>OECD TG 457 (October 2012): BG1luc estrogen receptor transactivation test method for identifying estrogen receptor agonists and antagonists.</li> </ul> OECD in vitro screens assays (non-mammalian) <ul> <li>OECD TG 250 (June 2021): EASZY assay - Detection of Endocrine Active Substances, acting through estrogen receptors, using transgenic tg (CYP19A1b:GFP) Zebrafish embryo</li> <li>OECD TG 230 (September 2009): 21-Day Fish Assay a Short-Term Screening for Oestrogenic and Androgenic Activity, and Aromatase Inhibition</li> </ul>  OECD in vivo mammalian screens and test <ul> <li>OECD TG 440 (October 2007): Uterotrophic bioassay in rodents</li> </ul> Others non-OECD tests <ul> <li>US EPA (2009) Estrogen Receptor Binding Assay Using Rat Uterine Cytosol: This assay identifies chemicals that have the potential to interact with the estrogen receptor (ER) in vitro.  Principle of this particular assay is based on the competitive protein-binding methods. A radiolabelled ligand and an unlabelled ligand are presented together to a specific receptor. The radioactivity measurement provides the quantitative estimation of the bound and unbound fraction of the ligand with the receptor. All cytosolic estrogen receptor subtypes that are expressed in the specific tissue, including ERα and ERβ are used for the determination of estrogen receptor binding. This assay is simple and rapid to perform when optimal conditions for binding are determined. Assay determines if a ligand/chemical can interact and displace the endogenous hormone 17β-oestradiol (Freyberger et al., 2010, from KE ID 1046, AOP Wiki)</li> <li>Yeast estrogen screen (YES) (ISO 19040-1 and 19040-2)</li> <li>T47D-Kbluc assay (Wilson et al., 2004);</li> <li>ToxCast Estrogen Receptor Agonist Pathway Model: The ToxCast estrogen receptor (ER) pathway model is a mathematical model that combines the results from 18 high-throughput screening (HTS) assays from the ToxCast and Tox21 research programs. The HTS assays measure ER binding, dimerization, chromatin binding, transcriptional activation and ER-dependent cell proliferation. The model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform (“assay interference”). The output of the model provides an area under the curve (AUC) value for the potential of a chemical to cause ER agonism, normalized with respect to the positive control chemical, oestradiol.</li> <li>QSAR models for ER interaction are available at the website of Danish (<a href="https://qsar.food.dtu.dk/">https://qsar.food.dtu.dk/</a>) and US (<a href="https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface">https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface</a>) EPA and OECD (<a href="https://www.oecd.org/chemicalsafety/risk-assessment/oecdquantitativestructure-activityrelationshipsprojectqsars.htm">https://www.oecd.org/chemicalsafety/risk-assessment/oecdquantitativestructure-activityrelationshipsprojectqsars.htm</a>).</li> </ul>

Endocrine systems with respect to hormone structure, receptors, synthesis pathways, hormonal axes and degradation pathways are well conserved across vertebrate taxa especially in the case of estrogen, androgen and thyroid hormones and steroidogenesis (OECD TG 150) Taxonomic applicability: mammals and vertebrates due to evolutionarily conserved hormone pathways. Life stage Applicability: This KE is applicable to juvenile; adulthood; reproductive and post reproductive (menopausal, aging) phases Sex Applicability: This KE is applicable to females and males.

Not Specified Female Not Specified Male

Not Specified

Adult

Not Specified

Adult, reproductively mature

Not Specified

Old Age

Not Specified

Juvenile

Not Specified Not Specified

Björnström L and Sjöberg M, 2005. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Molecular endocrinology, 19 4:833-842 Gu Y, Chen T, López E, Wu W, Wang X, Cao J and Teng L, 2014. The therapeutic target of estrogen receptor-alpha36 in estrogen-dependent tumors. J Transl Med, 12:16. doi: 10.1186/1479-5876-12-16 Levin ER, 2002. Cellular functions of plasma membrane estrogen receptors. Steroids, 67:471-475. doi: 10.1016/s0039-128x(01)00179-9 Lin SL, Yan LY, Zhang XT, Yuan J, Li M, Qiao J, Wang ZY and Sun QY, 2010. ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways. PLoS One, 5:e9013. doi: 10.1371/journal.pone.0009013 Pedram A, Razandi M, Blumberg B and Levin ER, 2016. Membrane and nuclear estrogen receptor α collaborate to suppress adipogenesis but not triglyceride content. Faseb j, 30:230-240. doi: 10.1096/fj.15-274878 Pedram A, Razandi M, Lewis M, Hammes S and Levin ER, 2014. Membrane-localized estrogen receptor α is required for normal organ development and function. Dev Cell, 29:482-490. doi: 10.1016/j.devcel.2014.04.016 Razandi M, Pedram A, Merchenthaler I, Greene GL and Levin ER, 2004. Plasma membrane estrogen receptors exist and functions as dimers. Mol Endocrinol, 18:2854-2865. doi: 10.1210/me.2004-0115 Thomas C and Gustafsson J-Å, 2011. The different roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer, 11:597-608. doi: 10.1038/nrc3093 Vasudevan N and Pfaff DW, 2008. Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol, 29:238-257. doi: 10.1016/j.yfrne.2007.08.003 Viviani B, Bernardini E, Galbiati V, Maddalon A, Melzi A, Midali M, Serafini M, Corsini E, Melcangi RC, Scanziani E, 2023. Development of Adverse Outcome Pathways relevant for the identification of substances having endocrine disruptors properties. EFSA supporting publication 2023:EN-7748 47 pp. doi:10.2903/sp.efsa.2023.EN-7748. NOTE: Italics indicate edits from John Frisch October 2025.  A full list of updates can be found in the Change Log on the View History page. AOPWiki 2016-11-29T18:41:29

2026-01-28T14:32:29

<upstream-id>f6f7bf77-2b89-491a-ae79-96a353f12daf</upstream-id> <downstream-id>09af4224-748d-4fa9-81e4-b841665f3be5</downstream-id> 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. Kisspeptin is a key signalling neuropeptide hormone in mammals and some other vertebrates.  Positive feedback for kisspeptin hormone production is due to increased levels of estrogen binding to Estrogen Receptor Alpha (ERa) receptors in neurons from the anteroventral periventricular nucleus (AVPV) region of the hypothalamus, while negative feedback for kisspeptin hormone production is due to ERa receptor activation of the neurons from the arcuate nucleus (ARC) region of the hypothalamus (Uenoyama et al. 2021).  Increased activation of ERa leads to increased kisspeptin in the AVPV region.

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. This Key Event Relationship was part of an Environmental Protection Agency effort to develop AOPs that establish scientifically supported causal linkages between alternative endpoints measured using new approach methodologies (NAMs) and guideline apical endpoints measured in Tier 1 and Tier 2 test guidelines (U.S. EPA, 2024) employed by the Endocrine Disruptor Screening Program (EDSP). A series of key events that represent significant, measurable, milestones connecting molecular initiation to apical endpoints indicative of adversity were identified based on scientific review articles and empirical studies. Additionally, scientific evidence supporting the causal relationships between each pair of key events was assembled and evaluated.   The present effort focused primarily on empirical studies with laboratory rodents and other mammals.   Empirical studies are focused on increased activation of estrogen receptor alpha and resulting increased release of kisspeptin from anteroventral periventricular nucleus (AVPV) neurons, in support of development of AOP 623. Authors of KER 2665 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.  The literature used to support this KER began with the test guidelines and followed to primary, secondary, and/or tertiary works concerning the relevant underlying biology.  In addition, search engines were used to target journal articles with terms ‘estrogen receptor alpha’ and ‘kisspeptin’ ’ in order to locate representative empirical studies that support the key event relationship.

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>

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. Increased activation of estrogen receptor alpha and resulting increased release of kisspeptin from anteroventral periventricular nucleus (AVPV) neurons have been studied in laboratory mammals by addition of estrogenic compounds (Adachi et al. 2007; Clarkson et al. 2008; Tomikawa et al. 2012) and toxicants (Wang et al. 2014) known to increase estrogen receptor activation.  Studies involving dosing of laboratory mammals with various forms of estrogen (e.g. estradiol benzoate, 17beta-estradiol) are supportive of the mechanism of exposure to estrogen compounds causing an increase in kisspeptin from anteroventral periventricular nucleus (AVPV) neurons (Adachi et al. 2007; Clarkson et al. 2008; Tomikawa et al. 2012).  Increased activation of estrogen receptor alpha, or estrogenicity, has also been studied in mammalian cell lines in vitro (U.S. EPA 2024).  Gene knock-out and ovariectomized animal studies have been useful in establishing essentiality of ERa and kisspeptin genes in the hypothalamus- pituitary-gonadal (HPG) axis, with hormone addition restoring function (Adachi et al. 2007; Clarkson et al. 2008; Tomikawa et al. 2012).

<ul> <li dir="ltr"> Dose concordance <ul> <li dir="ltr"> 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). </li> <li dir="ltr"> 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). </li> <li dir="ltr"> 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). </li> </ul> </li> <li dir="ltr"> Temporal concordance <ul> <li dir="ltr"> 5 hours after estrogen exposure, adult female Wister-Imamichi strain rats experience a significant increase in cFos expression (Adachi et al., 2007). </li> </ul> </li> </ul>   <table cellspacing="0" class="Table" style="border-collapse:collapse; width:683px"> <tbody> <tr> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:93px"> Species </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:61px"> Duration </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:96px"> Dose </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:78px"> Increased AVPV ERa activation? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:68px"> Increased AVPV kisspeptin? </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:188px"> Summary </td> <td style="background-color:#d9d9d9; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:100px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:93px"> Rats (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:61px"> 2 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:96px"> 35.8, 514.1 pg/ml estradiol, ovariectomized. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:78px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:188px"> Female ovariectomized rats exposed to estradiol had ERa immunoreactivity in the AVPV (90.4%) leading to increased kisspeptin immunoactivity and KISS-1 mRNA expression in the AVPV. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:100px"> Adachi et al. (2007) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:93px"> Mice (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:61px"> 1 week </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:96px"> 1 ug/20 ug BW 17B-estradiol, ovariectomized. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:78px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:188px"> Female ovariectomized mice exposed to estradiol had percentages of kisspeptin neurons expressing ERa within the AVPV, rPVpo, and cPVpo divisions of the RP3V of 64%, 45%, and 36% leading to statistically significant increased kisspeptin activity by signalling by c-FOS expression. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:100px"> Clarkson et al. (2008) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:93px"> Mice (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:61px"> 1 week </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:96px"> 200 ug/mL estradiol-17B in peanut oil, ovariectomized. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:78px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:188px"> Female ovariectomized mice exposed to estradiol had increased ERa binding in the Kiss1 promoter region in the AVPV by CHiP assays using anti-ERa antibody and significant histone acetylation in the AVPV Kiss1 promoter region leading to increased KISS-1 mRNA expression in the AVPV. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:100px"> Tomikawa et al. (2012) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:93px"> Mice (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:61px"> 6 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:96px"> 20 ug/kg/bw BPA, 50 nmol/mouse MPP </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:78px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px"> yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:188px"> Female mice exposed to BPA had statistically significant increased AVPV-Kiss1 mRNA and statistically significant increased AVPV kisspeptin protein at proestrus; production of AVPV-Kiss1 mRNA was statistically significant decreased when ERa antagonist MPP was added before BPA. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:100px"> Wang et al. (2014) </td> </tr> </tbody> </table>

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). Activation of estrogen receptor alpha can lead to either increase or decrease of AVPV kisspeptin release depending on the stressor and age at exposure.  Broadly, stressor exposure can lead to increased AVPV kisspeptin release and subsequent increased hormone levels (Adachi et al. 2007; Clarkson et al. 2008; Tomikawa et al. 2012; Wang et al. 2014), accelerating the response to hormones in the expected direction from estrogen receptor alpha activation to increased AVPV kisspeptin release.  Alternatively, neonatal developmental stressor exposure can disrupt the Hypothalamic-Pituitary-Gonadal axis, decreasing AVPV kisspeptin release and subsequently decreasing hormone levels (Bateman and Patisaul 2008; Homma et al. 2009; Navarro et al. 2009; Patisaul et al. 2009; Ichimura et al. 2015a; Ichimura et al. 2015b), dampening response to hormones.

Modulating factors haven’t been evaluated yet.

Quantitative Understanding of the Linkage shown below.

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).

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.

High Male High Female

High

Adult, reproductively mature

High

Juvenile

High High Low

<ul> <li dir="ltr"> Taxonomic Applicability: <ul> <li dir="ltr"> 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 (Sivalingam et al. 2022). </li> </ul> </li> <li dir="ltr"> Sex Applicability:   <ul> <li dir="ltr"> 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. . </li> </ul> </li> <li dir="ltr"> Life Stage Applicability:  <ul> <li dir="ltr"> 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. </li> </ul> </li> </ul>

Adachi S, Yamada S, Takatsu Y, Matsui H, Kinoshita M, Takase K, Sugiura H, Ohtaki T, Matsumoto H, Uenoyama Y, Tsukamura H, Inoue K, Maeda K. 2007. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. Journal of Reproduction and Development 53(2): 367-378.  Bateman HL, Patisaul HB. 2008.  Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus. Neurotoxicology 29(6): 988-997. Clarkson J, d’Anglemont de Tassigny X, Moreno AS, Colledge WH,  Herbison AE. 2008. Kisspeptin–GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. Journal of Neuroscience 28(35): 8691–8697. Homma T, Sakakibara M, Yamada S, Kinoshita M, Iwata K, Tomikawa J, Kanazawa T, Matsui H, Takatsu Y, Ohtaki T, Matsumoto H, Uenoyama Y, Maeda K, Tsukamura H. 2009. Significance of neonatal testicular sex steroids to defeminize anteroventral periventricular kisspeptin neurons and the GnRH/LH surge system in male rats. Biology of  Reproduction 81(6): 1216-25. Ichimura R, Takahashi M, Morikawa T, Inoue K, Maeda J, Usuda K, Yokosuka M, Watanabe G, Yoshida M. 2015a. Prior attenuation of KiSS1/GPR54 signaling in the anteroventral periventricular nucleus is a trigger for the delayed effect induced by neonatal exposure to 17alpha-ethynylestradiol in female rats. Reproductive Toxicology 51: 145-156. Ichimura R, Takahashi M, Morikawa T, Inoue K, Kuwata K, Usuda K, Yokosuka M, Watanabe G, Yoshida M. 2015b. The Critical Hormone-Sensitive Window for the Development of Delayed Effects Extends to 10 Days after Birth in Female Rats Postnatally Exposed to 17alpha-Ethynylestradiol. Biology of Reproduction 93(2): 32. Navarro VM, Sánchez-Garrido MA, Castellano JM, Roa J, García-Galiano D, Pineda R, Aguilar E, Pinilla L, Tena-Sempere M. 2009. Persistent impairment of hypothalamic KiSS-1 system after exposures to estrogenic compounds at critical periods of brain sex differentiation. Endocrinology. 150(5): 2359-2367.  Patisaul HB, Todd KL, Mickens JA, Adewale HB. 2009. Impact of neonatal exposure to the ERalpha agonist PPT, bisphenol-A or phytoestrogens on hypothalamic kisspeptin fiber density in male and female rats. Neurotoxicology. 30(3): 350-357. Sivalingam M, Ogawa S, Trudeau VL, Parhar IS. 2022. Conserved functions of hypothalamic kisspeptin in vertebrates. General and  Comparative Endocrinology 317: 113973. Tomikawa J, Uenoyama Y, Ozawa M, Fukanuma T, Takase K, Goto T, Abe H, Ieda N, Minabe S, Deura C, Inoue N, Sanbo M, Tomita K, Hirabayashi M, Tanaka S, Imamura T, Okamura H, Maeda K, Tsukamura H. 2012. Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain. Proceedings of the National Academy of Science 109(20): E1294-E1301. Uenoyama, Y., Inoue, N., Nakamura, S., and Tsukamura, H. Kisspeptin Neurons and Estrogen–Estrogen Receptor α Signaling: Unraveling the Mystery of Steroid Feedback System Regulating Mammalian Reproduction.  2021. International Journal of Molecular Sciences 22(17): 9229. U.S. Environmental Protection Agency.  2004.  EDSP Test Guidelines and Guidance Document. https://www.epa.gov/test-guidelines-pesticides-and-toxic-substances/edsp-test-guidelines-and-guidance-document (retrieved 25 July 2025). Wang X, Chang F, Bai Y, Chen F, Zhang J, Chen L. 2014. Bisphenol A enhances kisspeptin neurons in anteroventral periventricular nucleus of female mice. Journal of Endocrinology 28(35): 201-213. Italics indicate edits from John Frisch February 2026.  A full list of updates can be found in the Change Log on the View History page.   AOPWiki 2022-06-06T13:32:53

2026-03-18T16:13:00

<upstream-id>09af4224-748d-4fa9-81e4-b841665f3be5</upstream-id> <downstream-id>b31dec37-dd75-4b28-9420-c2564a9e8cb7</downstream-id> 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.

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>

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).

<ul> <li dir="ltr"> Dose concordance <ul> <li dir="ltr"> 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).  </li> <li dir="ltr"> 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.  </li> <li dir="ltr"> 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).  </li> </ul> </li> <li dir="ltr"> Temporal concordance <ul> <li dir="ltr"> 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). </li> <li dir="ltr"> 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).  </li> <li dir="ltr"> 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). </li> <li dir="ltr"> 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). </li> <li dir="ltr"> 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).  </li> <li dir="ltr"> With E2-primed OVX rats, a significant increase in plasma LH can be seen 1-hour post-human metastin injection (Kinoshita et al., 2005). </li> </ul> </li> </ul>

In the literature reviewed so far, there has been no uncertainities or inconsistencies.

Modulating factors haven’t been evaluated yet.

Quantitative understanding is shown below.

Dose concordance evidence above demonstrates a response-response relationship where lower doses of kisspeptin don’t elicit changes in LH/FSH levels.

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).

High Male High Female

High

Adult, reproductively mature

High

Juvenile

High High Low

<ul> <li dir="ltr"> Taxonomic Applicability: <ul> <li dir="ltr"> 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). </li> </ul> </li> <li dir="ltr"> Sex Applicability:  <ul> <li dir="ltr"> 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.  </li> </ul> </li> <li dir="ltr"> Life Stage Applicability:  <ul> <li dir="ltr"> 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. </li> </ul> </li> </ul>

AOPWiki 2022-04-05T00:58:11

2022-08-15T02:43:11

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AOPWiki 2022-06-06T13:40:14

2022-08-15T02:43:48

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AOPWiki 2022-04-05T00:58:35

2022-04-05T00:58:35

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The majority of papers used in evidence supporting the non-direct key event relationship between activation of estrogen receptor alpha and impaired reproduction were found through the Ecotox knowledgebase search. In this search, papers were found using 4 estrogen chemicals(17β-estradiol(E2), 17α-Ethinylestradiol(EE2), estrone(E1), and diethylstilbestrol) and 4 model fish species(Danio rerio, Oncorhynchus mykiss, Pimephales promelas, Oryzias latipes). This yielded 326 references which were then subsequently filtered in Swift Review using the chemicals and fish species as filters. An initial subset of 47 papers was used towards compiling the weight of evidence for this relationship with Pimephales promelas as the primary fish filter. Additional sources used in the weight of evidence were provided through expert knowledge.

AOPWiki 2022-08-15T02:45:40

2022-08-15T02:46:40

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AOPWiki 2022-04-05T00:58:46

2022-04-05T00:58:46

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AOPWiki 2022-04-05T00:59:05

2022-04-05T00:59:05

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AOPWiki 2022-04-05T00:59:19

2022-04-05T00:59:19

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AOPWiki 2022-04-05T00:59:28

2022-04-05T00:59:28

Estrogen Receptor Alpha Agonism leads to Impaired Reproduction

ERα Agonism leads to Impaired Reproduction

John Hoang

John Hoang, ORISE participant at US Environmental Protection Agency Michael Ellman, ORISE participant at US Environmental Protection Agency Jacob Collins, ORISE participant at US Environmental Protection Agency

BY-SA

2.0

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.

adjacent

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AOPWiki 2022-04-05T00:44:11

2023-04-29T16:03:06