Decreased, Ovarian E2

10540-29-1

NKANXQFJJICGDU-QPLCGJKRSA-N

Tamoxifen

OHT Ethanamine, 2-[4-[(1Z)-1,2-diphenyl-1-butenyl]phenoxy]-N,N-dimethyl- (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine Ethanamine, 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)- Ethanamine, 2-[4-[(1Z)-1,2-diphenyl-1-buten-1-yl]phenoxy]-N,N-dimethyl- Ethylamine, 2-[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)- Mammaton Novaldex Tamoxifen and its salts tamoxifene tamoxifeno trans-Tamoxifen Z-Tamoxifen TAM

DTXSID1034187

84449-90-1

GZUITABIAKMVPG-UHFFFAOYSA-N

Raloxifene

RAL Methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-

DTXSID3023550

129453-61-8

VWUXBMIQPBEWFH-WCCTWKNTSA-N

Fulvestrant

(7alpha,17beta)-7-{9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5(10)-triene-3,17-diol ICI 182,780 Faslodex Estra-1,3,5(10)-triene-3,17-diol, 7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-, (7α,17β)-

DTXSID4022369

50-41-9

PYTMYKVIJXPNBD-UHFFFAOYSA-N

Clomiphene citrate (1:1)

Clomiphene citrate Clomid Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) 1-[p-(β-Diethylaminoethoxy)phenyl]-1,2-diphenyl-2-chloroethylene citrate 2-[4-(2-Chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine 2-hydroxy-1,2,3-propanetricarboxylic acid (1:1) 2-[p-(2-Chloro-1,2-diphenylvinyl)phenoxy]triethylamine dihydrogen citrate Chloramiphene clomifen dihydrogen citrate Clomifendihydrogencitrat Clomifene citrate Clomiphene dihydrogen citrate Clomivid Clomphid Clostilbegit Clostilbegyt dihidrogenocitrato de clomifeno dihydrogenocitrate de clomifen Dyneric Fertivet Genozym Ikaclomin Ikaclomine NSC 35770 Pergotime Racemic clomiphene citrate Serophene Triethylamine, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]-, citrate Triethylamine, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]-, citrate (1:1)

DTXSID8020337

CHEBI:23965

CHEBI estradiol

PR:000007204

PR estrogen receptor

D007987

MESH Gonadotropin Releasing Hormone

CHEBI:81569

CHEBI Follicle stimulating hormone

CHEBI:81568

CHEBI Luteinizing hormone

CL:0002132

CL stromal cell of ovary

UBERON:0004911

UBERON epithelium of female gonad

D000236

MESH Adenoma

D016586

MESH Granular Cell Tumor

CHEBI:16469

CHEBI 17beta-estradiol

GO:0030284

GO estrogen receptor activity

GO:0046879

GO hormone secretion

GO:0046884

GO follicle-stimulating hormone secretion

GO:0032275

GO luteinizing hormone secretion

D006965

MESH hyperplasia

WIKI decreased

WIKI increased

Tamoxifen

2016-11-29T18:42:27

Raloxifene

2016-11-29T18:42:27

Fulvestrant

2016-11-29T18:42:27

Clomiphene citrate (1:1)

2022-02-26T23:24:20

WCS_9606

common toxicological species human

10116

NCBI rat

10095

NCBI mice

10090

NCBI CD-1 mouse

10116

NCBI F344 rat

9913

NCBI cow

Decreased, Ovarian E2

Tissue

UBERON:0000992

UBERON female gonad

AOPWiki 2016-11-29T18:41:28

2017-09-16T10:17:05

Suppression, Estrogen receptor (ER) activity

Molecular

Estrogen receptors are produced in all vertebrates and located in either the cell cytoplasm or nucleus(Bondesson et al., 2015; Eick and Thornton, 2011). Estrogen receptors are localized either in cytoplasm, or on the cell surface.   Site of action: Stressors (e.g., clomiphene) act on neuronal cell in the hypothalamus, where it inhibits hypothalamic Estrogen Receptors selectively. Responses at the macromolecular level: Stressors activate the Estrogen Receptor α in the presence of lower level of estrogen and partially blocks the same for higher level of estrogen and works as antagonist for the Estrogen Receptor β(Trost and Khera, 2014). Stressors appear to act in the brain's pituitary gland to secrete an increased amount of gonadotropins hormone (GnRH) in hypothalamus leading towards increased GnRH level in blood. Estrogen Receptor α: ERα (Estrogen Receptor α or NR3A1 or ESR1) - A nuclear receptor and it is activated by the estrogen (sex hormone). Estrogen located at chromosome number 6 ( 6q25.1) Estrogen Receptor β:  ERβ (Estrogen Receptor β or NR3A2 or  ESR2) – This is also nuclear receptor and  activated by the sex hormone estrogen which is located at chromosome number 14 (14q23.2). I ERβ has  both N-terminal has DNA binding domain and C-terminal has ligand binding domain. This  is localized to the nucleus, cytoplasm, and mitochondria. Selective estrogen receptor modulators (SERM) inhibits the ERβ. Drugs used as SERM are clomiphene, tamoxifen, raloxifene etc. Biological compartments:  Estrogen receptors (ER) are present in the plasma membrane. Both ERα and ERβ have diverse functions depending on cells and organs. ERs have also been loacated in cytoplasmic organelles including mitochondria and the endoplasmic reticulum(Levin, 2009).   General role in biology: Estrogen receptors (both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) binds the estrogens to promote the the biological functions of estrogens. Depending upon a balance between ERα and ERβ activities in target organs, estrogen signaling is selectively stimulated or inhibited (Welboren et al., 2009). ERβ has a high degree of sequence homology with the classical estrogen receptor. Interestingly, ERβ is detected in many tissues, including those previously assumed to be estrogen insensitive. In tissues where both ERs are expressed, such as the hypothalamus, uterus, mammary glands, and immune system, ERα promotes proliferation whereas ERβ has pro-apoptotic and pro-differentiating functions(Morani et al., 2008). ERα is present mainly in ovary (thecal cells) where as ERβ is found mainly in  ovary (granulosa cells)(Paterni et al., 2014). ERα and ERβ is identical approximately 97% in the DNA-binding domain and approximately 56% in the ligand-binding domain(Dahlman-Wright et al., 2006).

Radioreceptor assay/The 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-estradiol (Freyberger et al., 2010).

Neuronal cell in Hypothalamus

UBERON:0001898

UBERON hypothalamus

CL:0000540

CL neuron

High Mixed

High

Not Otherwise Specified

High High High

Adashi, E. Y., Hsueh, A. J., & Yen, S. S. (1980). Alterations induced by clomiphene in the concentrations of oestrogen receptors in the uterus, pituitary gland and hypothalamus of female rats. J Endocrinol. , 87(3), 383-92. Bharti, S., Misro, M., & Rai, U. (2013). Clomiphene citrate potentiates the adverse effects of estrogen on rat testis and down-regulates the expression of steroidogenic enzyme genes. Fertility and sterility, 99(1), 140-148. e5. Bondesson, M., Hao, R., Lin, C.-Y., Williams, C., & Gustafsson, J.-Å. (2015). Estrogen receptor signaling during vertebrate development. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 1849(2), 142-151. Bussenot, I., Parinaud, J., Clamagirand, C., Vieitez, G., & Pontonnier, G. (1990). Effect of clomiphene cirate on oestrogen secretion by human granulosa cells in culture. Human Reproduction, 5(5), 533-536. Dahlman-Wright, K., Cavailles, V., Fuqua, S. A., Jordan, V. C., Katzenellenbogen, J. A., Korach, K. S., et al. (2006). International union of pharmacology. LXIV. Estrogen receptors. Pharmacological reviews, 58(4), 773-781. Dominguez, R., & Micevych, P. (2010). Estradiol rapidly regulates membrane estrogen receptor alpha levels in hypothalamic neurons. J Neurosci, 30(38), 12589-96. doi:30/38/12589 [pii]10.1523/JNEUROSCI.1038-10.2010. Eick, G. N., & Thornton, J. W. (2011). Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Molecular and cellular endocrinology, 334(1-2), 31-38. Freyberger, A., Wilson, V., Weimer, M., Tan, S., Tran, H. S., & Ahr, H. J. (2010). Assessment of a robust model protocol with accelerated throughput for a human recombinant full length estrogen receptor-alpha binding assay: protocol optimization and intralaboratory assay performance as initial steps towards validation. Reprod Toxicol, 30(1), 50-9. doi:S0890-6238(10)00003-1 [pii]. Kerin, J. F., Liu, J. H., Phillipou, G., & Yen, S. S. (1985). Evidence for a hypothalamic site of action of clomiphene citrate in women. J Clin Endocrinol Metab. , 61(2), 65-68. Kettel, L. M., Roseff, S. J., Berga, S. L., Mortola, J. F., & Yen, S. S. (1993). Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome. Fertil Steril. , 59(3), 532-38. Koch, Y., Dikstein, S., Superstine, E., & Sulman, F. G. (1971). THE EFFECT OF PROMETHAZINE AND CLOMIPHENE ON GONADOTROPHIN SECRETION IN THE RAT. Journal of Endocrinology, 49(1), 13-17. doi:10.1677/joe.0.0490013. Kurosawa, T., Hiroi, H., Momoeda, M., Inoue, S., & Taketani, Y. (2010). Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors αand β. Endocrine journal, 57(6), 517-521. Levin, E. R. (2009). Plasma membrane estrogen receptors. Trends in Endocrinology & Metabolism, 20(10), 477-482. Morani, A., Warner, M., & Gustafsson, J. Å. (2008). Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues. Journal of internal medicine, 264(2), 128-142. Oride, A., Kanasaki, H., Tumurbaatar, T., Zolzaya, T., Okada, H., Hara, T., et al. (2020). Effects of the Fertility Drugs Clomiphene Citrate and Letrozole on Kiss-1 Expression in Hypothalamic Kiss-1-Expressing Cell Models. Reproductive sciences (Thousand Oaks, Calif.), 27. doi:10.1007/s43032-020-00154-1. Paterni, I., Granchi, C., Katzenellenbogen, J. A., & Minutolo, F. (2014). Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. Steroids, 90, 13-29. Sutaria, U., Crooke, A., Bertrand, P., & Hodgson, C. (1980). Clomiphene citrate and human chorionic gonadotropin in the treatment of anovulatory infertility. International Journal of Gynecology & Obstetrics, 18(6), 435-437. Taheripanah, R., Kabir-Salmani, M., Favayedi, M., Zamaniyan, M., Malih, N., & Taheripanah, A. (2020). Effects of clomiphene citrate plus estradiol or progesterone on endometrial ultrastructure: An RCT. International Journal of Reproductive BioMedicine, 18(3), 201. Trost, L. W., & Khera, M. (2014). Alternative treatment modalities for the hypogonadal patient. Current urology reports, 15(7), 1-12. Wahab, O. A., Princely, A. C., Oluwadamilare, A. A., Ore-Oluwapo, D. O., Blessing, A. O., & Alfred, E. F. (2019). Clomiphene citrate ameliorated lead acetate-induced reproductive toxicity in male Wistar rats. JBRA assisted reproduction, 23(4), 336-343. doi:10.5935/1518-0557.20190038. Welboren, W.-J., Sweep, F. C., Span, P. N., & Stunnenberg, H. G. (2009). Genomic actions of estrogen receptor?: what are the targets and how are they regulated? Endocrine-related cancer, 16(4), 1073.     AOPWiki 2016-11-29T18:41:28

2022-02-28T23:08:11

Increased, secretion of GnRH from hypothalamus

Cellular

CL:0011111

CL gonadotropin releasing neuron

AOPWiki 2016-11-29T18:41:29

2017-09-16T10:17:06

Increased, secrection of FSH from anterior pituitary

Cellular

AOPWiki 2016-11-29T18:41:29

2016-12-03T16:37:52

Increased, secretion of LH from anterior pituitary

Cellular

AOPWiki 2016-11-29T18:41:29

2016-12-03T16:37:52

Hyperplasia, ovarian stromal cells

Cellular

CL:0002132

CL stromal cell of ovary

AOPWiki 2016-11-29T18:41:29

2017-09-16T10:17:06

Hyperplasia, ovarian epithelium

Tissue

UBERON:0004911

UBERON epithelium of female gonad

AOPWiki 2016-11-29T18:41:29

2017-09-16T10:17:06

Promotion, ovarian adenomas

Tissue

AOPWiki 2016-11-29T18:41:29

2016-12-03T16:37:52

Promotion, ovarian granular cell tumors

Cellular

AOPWiki 2016-11-29T18:41:29

2016-12-03T16:37:52

Decrease, E2 blood concentrations at hypothalamus

Tissue

UBERON:0000178

UBERON blood

AOPWiki 2016-11-29T18:41:29

2017-09-16T10:17:07

<upstream-id>cb1d678e-8c59-4ab2-aec7-e8a3387c426e</upstream-id> <downstream-id>303dba5e-440f-48b4-886b-903a51f8f31b</downstream-id>

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2016-12-03T16:38:03

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9d875a0> AOPWiki 2016-11-29T18:41:36

2016-12-03T16:38:03

<upstream-id>303dba5e-440f-48b4-886b-903a51f8f31b</upstream-id> <downstream-id>0743d47c-db98-4c97-8db1-e1cee2a38ab9</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9dab568> AOPWiki 2016-11-29T18:41:36

2016-12-03T16:38:03

<upstream-id>0743d47c-db98-4c97-8db1-e1cee2a38ab9</upstream-id> <downstream-id>9c15403e-ed09-43ea-85e7-a40966f3bd8c</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9dccd80> AOPWiki 2016-11-29T18:41:36

2016-12-03T16:38:03

<upstream-id>0743d47c-db98-4c97-8db1-e1cee2a38ab9</upstream-id> <downstream-id>d3055f8f-b6b4-4b8c-9da1-ffca9d99d329</downstream-id> The release of gonadotrophin-releasing hormone (GnRH) stimulate the secretion of  luteinising hormone (LH) (Fields et al., 2009). GnRH causes the pituitary gland to secrete LH. Gonadotropin releasing hormone (GnRH) is the key regulator of the secretion of luteinising hormone (Marques et al., 2018; Bowen et al., 1998; Tsutsumi and Webster, 2009). Metastin or kisspeptin in the control of gonadotropin-releasing hormone (GnRH) release and then it causes for pulsatile release of luteinizing hormone(Ohkura et al., 2009).

<ul> <li>Gonadotropin-releasing hormone (GnRH) is the master hormone for regulating the reproduction. GnRH pulses stimulate the synthesis and secretion of LH from the anterior pituitary(Tsutsumi and Webster, 2009).</li> <li>Nicol et al., reported that high GnRH dose enhances the secretion of LH (Nicol et al., 2002)</li> </ul>

GnRH was isolated from porcine hypothalamus. It was structurally identified as a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly·NH2)(AV et al., 971). During the childhood, GnRH levels are low but as puberty begins. GnRH levels start to rise and when the testes and ovaries are fully developed. GnRH regulates  LH and these hormones to control the production of sex hormones in adult (Marques et al., 2018). GnRH secretion have been described in pulsatile (in minutes) and surge modes. Pulsatile mode refers to episodic release of GnRH while the surge mode of GnRH secretion occurs in females during the pre-ovulatory phase (Maeda et al., 2010). Secretion of LH is also in pulsatile nature ( in hrs)(Bolt, 1971).

<table border="1" class="Table" style="border:solid windowtext 1px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> Compound class </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> Species </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px"> Study type </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px"> Dose </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px"> KER findings </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px"> Reference </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> GnRH </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> Cows </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px"> In-vivo </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px"> GnRH dose of 100 micro gram </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px"> GnRH dose increases LH secration </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px"> (Fields et al., 2009) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> GnRH </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> Possums </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px"> In-vivo </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">   </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px"> GnRH dose increases LH secration </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px"> (Crawford et al., 2009) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> GnRH </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> Bitches </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px"> In-vivo </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px"> GnRH dose of 06.-2.4 microgram/kg </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px"> GnRH dose increases LH secration </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px"> (Concannon et al., 2006) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> GnRH agonist (triptorelin acetate) dose </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black"> Humans </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px"> In-vivo </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px"> GnRH dose of 3.75 mg / person </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px"> GnRH agonist (triptorelin acetate) dose decrease LH seccretion </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px"> (Sonntag et al., 2005) </td> </tr> </tbody> </table>

Not Specified

<ul> <li>Protein kinase C cross-talk with gonadotrope progesterone receptor is involved in GnRH-induced LH secretion (Garrido-Gracia et al., 2006)</li> </ul>

<ul> <li>Fields et al., studied the dose response of GnRH (100 micro gram) on cows and observed greater release of LH (25 %) aftrer 12-18 hours (Fields et al., 2009)</li> <li>Crawford et al., used PCR techniques to study the effect of GnRH on LH in vivo on Possums. They reported the increase of LH quantitavely in absence of pulse of LH(Crawford et al., 2009)</li> <li>Guillaume et al., studied the two  GnRH antagonist  Antarelix and Cetrorelix (0.01 mg/kg) on mare and observed that there is strong suppression of LH (Guillaume et al., 2002)</li> <li>Washington et al., developed one mathematical model for the respose of LH under the pulsatile and continuous exposure of GnRH (Washington et al., 2004</li> <li>Shoemaker et al., developed a mathematical model on steroidogenesis in the fathead minnow. They quantified the relationship between GnRH and LH(Shoemaker et al., 2010)</li> </ul>

Not Specified

<ul> <li>Generally time scale is in hours (6-18) between GnRH and LH response (Fields et al., 2009). </li> <li>GnRH is degraded by proteolysis within a few minutes(Kenealy et al., 2011). </li> <li>It has very low activity during childhood, and is activated at puberty or adolescence and in reproductive years, pulse activity is critical for successful reproductive function(Berger et al., 1983). </li> </ul>

Not Specified

High Female Low Male

High

Adult, reproductively mature

High High High Low

Adult

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9f61538> AOPWiki 2016-11-29T18:41:36

2016-12-03T16:38:03

Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse

Antiestrogens and ovarian adenomas/granular cell tumors

Evgeniia Kazymova

Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

BY-SA

1.29

1.0

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.

adjacent

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High adjacent

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High adjacent

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High non-adjacent

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High non-adjacent

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Moderate non-adjacent

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Moderate non-adjacent

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High non-adjacent

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High non-adjacent

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High

High Female Moderate High

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1. Capen, C. C. (2004). Mechanisms of hormone-mediated carcinogenesis of the ovary. Toxicologic pathology 32 Suppl 2, 1-5. 2. Cohen, I. R., Sims, M. L., Robbins, M. R., Lakshmanan, M. C., Francis, P. C., and Long, G. G. (2000). The reversible effects of raloxifene on luteinizing hormone levels and ovarian morphology in mice. Reproductive toxicology 14(1), 37-44. 3. Long, G. G., Cohen, I. R., Gries, C. L., Young, J. K., Francis, P. C., and Capen, C. C. (2001). Proliferative lesions of ovarian granulosa cells and reversible hormonal changes induced in rats by a selective estrogen receptor modulator. Toxicologic pathology 29(6), 719-26. AOPWiki 2016-11-29T18:41:17

2023-09-25T16:26:53