10161-33-8 MEHHPFQKXOUFFV-OWSLCNJRSA-N MEHHPFQKXOUFFV-OWSLCNJRSA-N 17beta-Trenbolone DTXSID0034192 52-01-7 LXMSZDCAJNLERA-ZHYRCANASA-N LXMSZDCAJNLERA-ZHYRCANASA-N Spironolactone Pregn-4-ene-21-carboxylic acid, 7-(acetylthio)-17-hydroxy-3-oxo-, γ-lactone, (7α,17α)- (7α,17α)-7-(Acetylthio)-17-hydroxy-3-oxo-pregn-4-ene-21-carboxylic acid γ-lactone 17-Hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone 7-acetate 17α-Pregn-4-ene-21-carboxylic acid, 17-hydroxy-7α-mercapto-3-oxo-, γ-lactone, acetate 3-(3-keto-7α-Acetylthio-17β-hydroxy-4-androsten-17α-yl)propionic acid lactone 3-(3-Oxo-7α-acetylthio-17β-hydroxy-4-androsten-17α-yl)propionic acid-γ-lactone 3'-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)-propionic acid lactone 7α-(Acetylthio)-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone Abbolactone Aldactone Aldactone A Aldopur Almatol Aquareduct Deverol Diatensec Duraspiron espironolactona Euteberol Lacalmin Lacdene Laractone Nefurofan NSC 150399 Quimolactona Sagisal Sincomen Spiresis Spiretic Spiridon Spiroctan Spiroderm Spirolactone Spirolang Spirolone Spirone Spironolacton Spironolactone A Spiro-Tablinen Supra-Puren Suracton Uractone Urusonin Verospiron Verospirone Xenalon DTXSID6034186 521-18-6 NVKAWKQGWWIWPM-ABEVXSGRSA-N NVKAWKQGWWIWPM-ABEVXSGRSA-N 5alpha-Dihydrotestosterone Dihydrotestosterone (DHT) (5alpha dihydrotestosterone) (5alpha-Androstan-17beta-ol-3-one) Androstan-3-one, 17-hydroxy-, (5α,17β)- (+)-Androstan-17β-ol-3-one 17β-Hydroxy-3-androstanone 17β-Hydroxy-5α-androstan-3-one 17β-Hydroxy-5α-androstane-3-one 4-Dihydrotestosterone 5α,17β-Hydroxyandrostan-3-one 5α-Androstan-17β-ol-3-one 5α-Androstan-3-one, 17β-hydroxy- 5α-Androstanolone 5α-Dihydrotestosterone Anaboleen Anabolex Andractim Androlone Androstan-17β-ol-3-one Androstanolon androstanolona androstanolone Cristerona MB Dihydrotestosterone Neodrol NSC 10972 Proteina Protona Stanaprol Stanolone Testosterone, dihydro- DTXSID9022364 13674-87-8 ASLWPAWFJZFCKF-UHFFFAOYSA-N ASLWPAWFJZFCKF-UHFFFAOYSA-N Tris(1,3-dichloro-2-propyl) phosphate Tris(1,3-dichloro-2-propyl)phosphate 2-Propanol, 1,3-dichloro-, phosphate (3:1) DTXSID9026261 PR:000004191 PR androgen receptor CHEBI:16469 CHEBI 17beta-estradiol D014819 MESH vitellogenins GO:0004882 GO androgen receptor activity GO:0006898 GO receptor-mediated endocytosis GO:0001555 GO oocyte growth GO:0048599 GO oocyte development VT:1000294 VT egg quantity PCO:0000008 PCO population growth rate 1 WIKI increased 2 WIKI decreased 17beta-Trenbolone 2016-11-29T18:42:08 2016-11-29T18:42:08 Spironolactone 2016-11-29T18:42:23 2016-11-29T18:42:23 5alpha-Dihydrotestosterone 2017-03-14T12:44:51 2017-03-14T12:44:51 Tris(1,3-dichloropropyl)phosphate - TDCPP 2018-06-19T07:35:30 2018-06-19T07:59:12 WCS_90988 common ecological species fathead minnow 8090 NCBI medaka 10116 NCBI rat WCS_9606 common toxicological species human 8078 NCBI Fundulus heteroclitus 8090 NCBI Oryzias latipes WCS_7955 common ecological species Danio rerio WCS_7955 common ecological species zebrafish Agonism, Androgen receptor Molecular <p><strong>Site of action</strong>: The molecular site of action is the ligand binding domain of the AR. This particular key event specifically refers to interaction with nuclear AR. &nbsp;Downstream KE responses to activation of membrane ARs may be different. The cellular site of action for the molecular initiating event is undefined.</p> <p><strong>Responses at the macromolecular level</strong>: Binding of a ligand, including xenobiotics that act as AR agonists, to the cytosolic AR mediates a conformational shift that facilitates dissociation from accompanying heat shock proteins and dimerization with another AR (Prescott and Coetzee 2006; Claessens et al. 2008; Centenera et al. 2008). Homodimerization unveils a nuclear localization sequence, allowing the AR-ligand complex to translocate to the nucleus and bind to androgen-response elements (AREs) (Claessens et al. 2008; Cutress et al. 2008). This elicits recruitment of additional transcription factors and transcriptional activation of androgen-responsive genes (Heemers and Tindall 2007).</p> <p><strong>AR paralogs</strong>:</p> <ul> <li>Most vertebrates have a single gene coding for nuclear AR. However, most fish have two AR genes (AR-A, AR-B) as a result of a whole genome duplication event after the split of Acipenseriformes from teleosts but before the divergence of Osteoglossiformes (Douard et al. 2008).</li> <li>AR-B has been lost in Cypriniformes, Siluriformes, Characiformes, and Salmoniformes (Douard et al. 2008).</li> <li>In Percomorphs, AR-B has accumulated significant substitutions in the both ligand binding and DNA binding domains (Douard et al. 2008).</li> <li>Differential ligand selectivity and subcellular localization has been reported for AR paralogs in some fish species (e.g., Bain et al. 2015), but the difference is not easily generalized based on available data in the literature.&nbsp;</li> </ul> <p><strong>Measurement/detection</strong>:</p> <ul> <li><strong>In vitro methods:</strong> <ul> <li>OECD Test No. 458: Stably transfected human androgen receptor transcriptional activation assay for detection of androgen agonists and antagonists has been reviewed and validated by OECD and is well suited for detection of this key event (<a href="http://www.oecd.org/env/test-no-458-stably-transfected-human-androgen-receptor-transcriptional-activation-assay-for-detection-of-androgenic-agonist-9789264264366-en.htm">OECD 2016</a>).</li> <li>Binding to the androgen receptor can be directly measured in cell free systems based on displacement of a radio-labeled standard (generally testosterone or DHT) in a competitive binding assay (e.g., (Olsson et al. 2005; Sperry and Thomas 1999; Wilson et al. 2007; Tilley et al. 1989; Kim et al. 2010).</li> <li>Cell based transcriptional activation assays are typically required to differentiate agonists from antagonists, in vitro. A number of reporter gene assays have been developed and used to screen chemicals for AR agonist and/or antagonist activity (e.g., (Wilson et al. 2002; van der Burg et al. 2010; Mak et al. 1999; Araki et al. 2005).</li> <li>Expression of androgen responsive proteins like spiggin in primary cell cultures has also been used to detect AR agonist activity (Jolly et al. 2006).</li> </ul> </li> <li><strong>In vivo methods</strong>:&nbsp; <ul> <li>In fish, phenotypic masculinization of females has frequently been used as an indirect measurement of in vivo androgen receptor agonism. <ul> <li>Development of nuptial tubercles, a dorsal fatpad, and a characteristic banding pattern has been observed in female fathead minnows exposed to androgen agonists (Ankley et al. 2003; Jensen et al. 2006; Ankley et al. 2010; LaLone et al. 2013; <a href="http://www.oecd-ilibrary.org/environment/test-no-229-fish-short-term-reproduction-assay_9789264185265-en">OECD 2012</a>).</li> <li>Anal fin elongation in female western mosquitofish (<em>Gambusia affinis</em>) has similarly been viewed as evidence of AR activation (Raut et al. 2011; Sone et al. 2005).</li> <li>In medaka, development of papillary processes, which normally only appear on the second to seventh or eighth fin aray of the anal fin, has also been used as an indirect measure of androgen receptor agonism (<a href="http://www.oecd-ilibrary.org/environment/test-no-229-fish-short-term-reproduction-assay_9789264185265-en">OECD 2012</a>).</li> <li>Production of the nest building glue, spiggin, in three female 3-spined sticklebacks (Gasterosteus aculeatus) has also been well documented as an indicator of androgen receptor agonism (Jakobsson et al. 1999; Hahlbeck et al. 2004). Quantification of the spiggin protein in exposed female 3-spined stickleback&nbsp;or green fluorescence protein expression in&nbsp;a transgenic spg1-gfp&nbsp;medaka line (S&eacute;billot et al. 2014) can be used to detect androgen receptor agonism.</li> </ul> </li> </ul> </li> <li><strong>High Throughput Screening</strong> <ul> <li>​Measures of AR agonism have been included in high throughput screening programs, such as US EPA&#39;s Toxcast program. Toxcast assays relevant for screening chemicals for their ability to bind and/or activate the AR include: <ul> <li>ATG_AR_TRANS A cell based assay that can differentiate agonism from antagonism</li> <li>NVS_NR_hAR A cell free assay using recombinant human AR. Can detect binding, but cannot distinguish agonism from antagonism.</li> <li>NVS_NR_rAR A cell free assay using recombinant rat AR. Can detect binding, but cannot distinguish agonism from antagonism.</li> <li>OT_AR_ARELUC_AG_1440 A cell based assay that measures expression of a reporter gene under control of androgen-responsive elements. Can distinguish agonism from antagonism.</li> <li>Tox21_AR_BLA_Agonist_ratio A cell based assay with an inducible reporter. Can distinguish agonists from antagonists.</li> <li>Tox21_AR_LUC_MDAKB2_agonist A cell based assay with an inducible reporter. Can distinguish agonists from antagonists.</li> </ul> </li> <li><a href="https://actorws.epa.gov/actorws/edsp21/v02/assays">Assay descriptions</a></li> </ul> </li> </ul> <p><strong>Taxonomic applicability</strong>: Androgen receptor orthologs are primarily limited to vertebrates (Baker 1997; Thornton 2001; Eick and Thornton 2011; Markov and Laudet 2011). Therefore, this MIE would generally be viewed as relevant to vertebrates, but not invertebrates.</p> High Female High Adult, reproductively mature High High <ul> <li>Ankley GT, Gray LE. Cross-species conservation of endocrine pathways: a critical analysis of tier 1 fish and rat screening assays with 12 model chemicals. Environ Toxicol Chem. 2013 Apr;32(5):1084-7. doi: 10.1002/etc.2151. Epub 2013 Mar 19. PubMed PMID: 23401061.</li> <li>Ankley GT, Jensen KM, Kahl MD, Durhan EJ, Makynen EA, Cavallin JE, Martinović D, Wehmas LC, Mueller ND, Villeneuve DL. Use of chemical mixtures to differentiate mechanisms of endocrine action in a small fish model. Aquat Toxicol. 2010 Sep 1;99(3):389-96. doi: 10.1016/j.aquatox.2010.05.020. Epub 2010 Jun 4. PubMed PMID: 20573408.</li> <li>Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MC, Hartig PC, Gray LE. Effects of the androgenic growth promoter 17-beta-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ Toxicol Chem. 2003 Jun;22(6):1350-60. PubMed PMID: 12785594.</li> <li>Araki N, Ohno K, Nakai M, Takeyoshi M, Iida M. 2005. Screening for androgen receptor activities in 253 industrial chemicals by in vitro reporter gene assays using AR-EcoScreen cells. Toxicology in vitro&nbsp;: an international journal published in association with BIBRA 19(6): 831-842.</li> <li>Bain PA, Ogino Y, Miyagawa S, Iguchi T, Kumar A. Differential ligand selectivity of androgen receptors &alpha; and &beta; from Murray-Darling rainbowfish (Melanotaenia fluviatilis). Gen Comp Endocrinol. 2015 Feb 1;212:84-91. doi: 10.1016/j.ygcen.2015.01.024. PubMed PMID: 25644213.</li> <li>Baker ME. 1997. Steroid receptor phylogeny and vertebrate origins. Molecular and cellular endocrinology 135(2): 101-107.</li> <li>Bohl CE, Chang C, Mohler ML, Chen J, Miller DD, Swaan PW, et al. 2004. A ligand-based approach to identify quantitative structure-activity relationships for the androgen receptor. Journal of medicinal chemistry 47(15): 3765-3776.</li> <li>Centenera MM, Harris JM, Tilley WD, Butler LM. 2008. The contribution of different androgen receptor domains to receptor dimerization and signaling. Molecular endocrinology 22(11): 2373-2382.</li> <li>Claessens F, Denayer S, Van Tilborgh N, Kerkhofs S, Helsen C, Haelens A. 2008. Diverse roles of androgen receptor (AR) domains in AR-mediated signaling. Nuclear receptor signaling 6: e008.</li> <li>Cutress ML, Whitaker HC, Mills IG, Stewart M, Neal DE. 2008. Structural basis for the nuclear import of the human androgen receptor. Journal of cell science 121(Pt 7): 957-968.</li> <li>Douard V, Brunet F, Boussau B, Ahrens-Fath I, Vlaeminck-Guillem V, Haendler B, Laudet V, Guiguen Y. The fate of the duplicated androgen receptor in fishes: a late neofunctionalization event? BMC Evol Biol. 2008 Dec 18;8:336. doi: 10.1186/1471-2148-8-336. PubMed PMID: 19094205</li> <li>Eick GN, Thornton JW. 2011. Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Molecular and cellular endocrinology 334(1-2): 31-38.</li> <li>Hahlbeck E, Katsiadaki I, Mayer I, Adolfsson-Erici M, James J, Bengtsson BE. The juvenile three-spined stickleback (Gasterosteus aculeatus L.) as a model organism for endocrine disruption II--kidney hypertrophy, vitellogenin and spiggin induction. Aquat Toxicol. 2004 Dec 20;70(4):311-26</li> <li>Hong H, Fang H, Xie Q, Perkins R, Sheehan DM, Tong W. 2003. Comparative molecular field analysis (CoMFA) model using a large diverse set of natural, synthetic and environmental chemicals for binding to the androgen receptor. SAR and QSAR in environmental research 14(5-6): 373-388.</li> <li>Jakobsson, S., Borg, B., Haux, C. et al. Fish Physiology and Biochemistry (1999) 20: 79. doi:10.1023/A:1007776016610</li> <li>Jensen KM, Makynen EA, Kahl MD, Ankley GT. Effects of the feedlot contaminant 17alpha-trenbolone on reproductive endocrinology of the fathead minnow. Environ Sci Technol. 2006 May 1;40(9):3112-7. PubMed PMID: 16719119.</li> <li>Jolly C, Katsiadaki I, Le Belle N, Mayer I, Dufour S. 2006. Development of a stickleback kidney cell culture assay for the screening of androgenic and anti-androgenic endocrine disrupters. Aquatic toxicology 79(2): 158-166.</li> <li>Kim TS, Yoon CY, Jung KK, Kim SS, Kang IH, Baek JH, et al. 2010. In vitro study of Organization for Economic Co-operation and Development (OECD) endocrine disruptor screening and testing methods- establishment of a recombinant rat androgen receptor (rrAR) binding assay. The Journal of toxicological sciences 35(2): 239-243.</li> <li>LaLone CA, Villeneuve DL, Cavallin JE, Kahl MD, Durhan EJ, Makynen EA, Jensen KM, Stevens KE, Severson MN, Blanksma CA, Flynn KM, Hartig PC, Woodard JS, Berninger JP, Norberg-King TJ, Johnson RD, Ankley GT. Cross-species sensitivity to a novel androgen receptor agonist of potential environmental concern, spironolactone. Environ Toxicol Chem. 2013 Nov;32(11):2528-41. doi: 10.1002/etc.2330. Epub 2013 Sep 6. PubMed PMID: 23881739.</li> <li>Mak P, Cruz FD, Chen S. 1999. A yeast screen system for aromatase inhibitors and ligands for androgen receptor: yeast cells transformed with aromatase and androgen receptor. Environmental health perspectives 107(11): 855-860.</li> <li>Markov GV, Laudet V. 2011. Origin and evolution of the ligand-binding ability of nuclear receptors. Molecular and cellular endocrinology 334(1-2): 21-30.</li> <li>Norris JD, Joseph JD, Sherk AB, Juzumiene D, Turnbull PS, Rafferty SW, et al. 2009. Differential presentation of protein interaction surfaces on the androgen receptor defines the pharmacological actions of bound ligands. Chemistry &amp; biology 16(4): 452-460.</li> <li>OECD&nbsp;(2012),&nbsp;<em>Test No. 229: Fish Short Term Reproduction Assay</em>, OECD Publishing, Paris.<br /> DOI: <a href="http://dx.doi.org/10.1787/9789264185265-en" target="_blank" title="http://dx.doi.org/10.1787/9789264185265-en">http://dx.doi.org/10.1787/9789264185265-en</a></li> <li>OECD&nbsp;(2016),&nbsp;<em>Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals</em>, OECD Publishing, Paris.<br /> DOI: <a href="http://dx.doi.org/10.1787/9789264264366-en" target="_blank" title="http://dx.doi.org/10.1787/9789264264366-en">http://dx.doi.org/10.1787/9789264264366-en</a></li> <li>Olsson P-E, Berg A, von Hofsten J, Grahn B, Hellqvist A, Larsson A, et al. 2005. Molecular cloning and characterization of a nuclear androgen receptor activated by 11-ketotestosterone. Reproductive Biology and Endocrinology 3: 1-17.</li> <li>Prescott J, Coetzee GA. 2006. Molecular chaperones throughout the life cycle of the androgen receptor. Cancer letters 231(1): 12-19.</li> <li>Serafimova R, Walker J, Mekenyan O. 2002. Androgen receptor binding affinity of pesticide &quot;active&quot; formulation ingredients. QSAR evaluation by COREPA method. SAR and QSAR in environmental research 13(1): 127-134.</li> <li>Sone K, Hinago M, Itamoto M, Katsu Y, Watanabe H, Urushitani H, Tooi O, Guillette LJ Jr, Iguchi T. Effects of an androgenic growth promoter 17beta-trenbolone on masculinization of Mosquitofish (Gambusia affinis affinis). Gen Comp Endocrinol. 2005 Sep 1;143(2):151-60. Epub 2005 Apr 13. PubMed PMID: 16061073.</li> <li>Sperry TS, Thomas P. 1999. Identification of two nuclear androgen receptors in kelp bass (Paralabrax clathratus) and their binding affinities for xenobiotics: comparison with Atlantic croaker (Micropogonias undulatus) androgen receptors. Biology of reproduction 61(4): 1152-1161.</li> <li>Stanko JP, Angus RA. In vivo assessment of the capacity of androstenedione to masculinize female mosquitofish (Gambusia affinis) exposed through dietary and static renewal methods. Environ Toxicol Chem. 2007 May;26(5):920-6. PubMed PMID: 17521138.</li> <li>Thornton JW. 2001. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proceedings of the National Academy of Sciences of the United States of America 98(10): 5671-5676.</li> <li>Tilley WD, Marcelli M, Wilson JD, McPhaul MJ. 1989. Characterization and expression of a cDNA encoding the human androgen receptor. Proceedings of the National Academy of Sciences of the United States of America 86(1): 327-331.</li> <li>Todorov M, Mombelli E, Ait-Aissa S, Mekenyan O. 2011. Androgen receptor binding affinity: a QSAR evaluation. SAR and QSAR in environmental research 22(3): 265-291.</li> <li>van der Burg B, Winter R, Man HY, Vangenechten C, Berckmans P, Weimer M, et al. 2010. Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reproductive toxicology 30(1): 18-24.</li> <li>Waller CL, Juma BW, Gray EJ, Kelce WR. 1996. Three-dimensional quantitative structure-activity relationships for androgen receptor ligands. Toxicology and Applied Pharmacolgy 137: 219-227.</li> <li>Wilson VS, Bobseine K, Lambright CR, Gray LE. 2002. A novel cell line, MDA-kb2, that stably expresses an androgen- and glucocorticoid-responsive reporter for the detection of hormone receptor agonists and antagonists. Toxicological Sciences 66: 69-81.</li> <li>Wilson VS, Cardon MC, Gray LE, Jr., Hartig PC. 2007. Competitive binding comparison of endocrine-disrupting compounds to recombinant androgen receptor from fathead minnow, rainbow trout, and human. Environmental toxicology and chemistry / SETAC 26(9): 1793-1802.</li> <li>Yin D, He Y, Perera MA, Hong SS, Marhefka C, Stourman N, et al. 2003. Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. Molecular pharmacology 63(1): 211-223.</li> </ul> AOPWiki 2016-11-29T18:41:22 2017-03-20T17:44:57 Increase, Gonadotropins concentration in plasma Tissue AOPWiki 2023-05-16T21:50:02 2023-05-16T21:50:02 Reduction,Testosterone concentration in plasma Tissue AOPWiki 2023-05-16T21:54:43 2023-05-16T21:54:43 Reduction, Plasma 17beta-estradiol concentrations Organ <p>Estradiol synthesized by the gonads is transported to other tissues via blood circulation. The gonads are generally considered to be the primary source of estrogens in systemic circulation.</p> <p>Total concentrations of 17&beta;-estradiol in plasma can be measured by radioimmunoassay (e.g., (Jensen et al. 2001)), enzyme-linked immunosorbent assay (available through many commercial vendors), or by analytical chemistry (e.g., LC/MS; Owen et al. 2014). Total steroid hormones are typically extracted from plasma or serum via liquid-liquid or solid phase extraction prior to analysis.</p> <p>Given that there are numerous genes, like those coding for vertebrate vitellogenins, choriongenins, cyp19a1b, etc. which are known to be regulated by estrogen response elements, targeted qPCR or proteomic analysis of appropriate targets could also be used as an indirect measure of reduced circulating estrogen concentrations. However, further support for the specificity of the individual gene targets for estrogen-dependent regulation should be established in order to support their use.</p> <p>A line of transgenic zebrafish employing green fluorescence protein under control of estrogen response elements could also be used to provide direct evidence of altered estrogen, with decreased GFP signal in estrogen responsive tissues like liver, ovary, pituitary, and brain indicating a reduction in circulating estrogens (Gorelick and Halpern 2011).</p> <p>Key enzymes needed to synthesize 17&beta;-estradiol first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates.</p> UBERON:0001969 UBERON blood plasma Not Specified Unspecific High Adult High High High High <ul> <li>Jensen K, Korte J, Kahl M, Pasha M, Ankley G. 2001. Aspects of basic reproductive biology and endocrinology in the fathead minnow (Pimephales promelas). Comparative Biochemistry and Physiology Part C 128: 127-141.</li> <li>Baker ME. 2011. Origin and diversification of steroids: co-evolution of enzymes and nuclear receptors. Molecular and cellular endocrinology 334(1-2): 14-20.</li> <li>Owen LJ, Wu FC, Keevil BG. 2014. A rapid direct assay for the routine measurement of oestradiol and oestrone by liquid chromatography tandem mass spectrometry. Ann. Clin. Biochem. 51(pt 3):360-367.</li> <li>Gorelick DA, Halpern ME. Visualization of estrogen receptor transcriptional activation in zebrafish. Endocrinology. 2011 Jul;152(7):2690-703. doi: 10.1210/en.2010-1257. Epub 2011 May 3. PubMed PMID: 21540282</li> </ul> AOPWiki 2016-11-29T18:41:23 2017-09-26T11:30:57 Reduction, the ratio of E2/11-KT in plasma Organ AOPWiki 2023-05-16T22:04:24 2023-05-16T22:04:24 Reduction, Plasma vitellogenin concentrations Organ <p>Vitellogenin synthesized in the liver is secreted into the blood and circulates to the ovaries for uptake.</p> <p>Vitellogenin concentrations in plasma are typically detected using enzyme linked Immunosorbent assay (ELISA; e.g., (Korte et al. 2000; Tyler et al. 1996; Holbech et al. 2001; Fenske et al. 2001). Although less specific and/or sensitive, determination of alkaline-labile phosphate or Western blotting has also been employed.</p> <p>Oviparous vertebrates synthesize yolk precursor proteins that are transported in the circulation for uptake by developing oocytes. Many invertebrates also synthesize vitellogenins that are taken up into developing oocytes via active transport mechanisms. However, invertebrate vitellogenins are transported in hemolymph or via other transport mechanisms rather than plasma.</p> UBERON:0001969 UBERON blood plasma High Adult, reproductively mature High High High <ul> <li>Fenske M, van Aerle R, Brack S, Tyler CR, Segner H. Development and validation of a homologous zebrafish (Danio rerio Hamilton-Buchanan) vitellogenin enzyme-linked immunosorbent assay (ELISA) and its application for studies on estrogenic chemicals. Comp Biochem Physiol C Toxicol Pharmacol. 2001. Jul;129(3):217-32.</li> <li>Holbech H, Andersen L, Petersen GI, Korsgaard B, Pedersen KL, Bjerregaard P. Development of an ELISA for vitellogenin in whole body homogenate of zebrafish (Danio rerio). Comp Biochem Physiol C Toxicol Pharmacol. 2001 Sep;130(1):119-31.</li> <li>Korte JJ, Kahl MD, Jensen KM, Mumtaz SP, Parks LG, LeBlanc GA, et al. 2000. Fathead minnow vitellogenin: complementary DNA sequence and messenger RNA and protein expression after 17B-estradiol treatment. Environmental Toxicology and Chemistry 19(4): 972-981.</li> <li>Tyler C, van der Eerden B, Jobling S, Panter G, Sumpter J. 1996. Measurement of vitellogenin, a biomarker for exposure to oestrogenic chemicals, in a wide variety of cyprinid fish. Journal of Comparative Physiology and Biology 166: 418-426.</li> <li>Wahli W. 1988. Evolution and expression of vitellogenin genes. Trends in Genetics. 4:227-232.</li> </ul> AOPWiki 2016-11-29T18:41:23 2017-09-16T10:14:37 Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development Cellular <p>Vitellogenin from the blood is selectively taken up by competent oocytes via receptor-mediated endocytosis. Although vitellogenin receptors mediate the uptake, opening of intercellular channels through the follicular layers to the oocyte surface as the oocyte reaches a &ldquo;critical&rdquo; size is thought to be a key trigger in allowing vitellogenin uptake (Tyler and Sumpter 1996). Once critical size is achieved, concentrations in the plasma and temperature are thought to impose the primary limits on uptake (Tyler and Sumpter 1996). Uptake of vitellogenin into oocytes causes considerable oocyte growth during vitellogenesis, accounting for up to 95% of the final egg size in many fish (Tyler and Sumpter 1996). Given the central role of vitellogenesis in oocyte maturation, vitellogenin accumulation is a prominent feature used in histological staging of oocytes (e.g., (Leino et al. 2005; Wolf et al. 2004).</p> <p>Relative vitellogenin accumulation can be evaluated qualitatively using routine histological approaches (Leino et al. 2005; Wolf et al. 2004). Oocyte size can be evaluated qualitatively or quantitatively using routine histological and light microscopy and/or imaging approaches.</p> <p>Oviparous vertebrates and invertebrates. Although hormonal regulation of vitellogenin synthesis and mechanisms of vitellogenin transport from the site of synthesis to the ovary vary between vertebrates and invertebrates (Wahli 1988), in both vertebrates and invertebrates, vitellogenin is incorporated into oocytes and cleaved to form yolk proteins.</p> CL:0000023 CL oocyte High Female High Adult, reproductively mature Moderate Moderate <ul> <li>Leino R, Jensen K, Ankley G. 2005. Gonadal histology and characteristic histopathology associated with endocrine disruption in the adult fathead minnow. Environmental Toxicology and Pharmacology 19: 85-98.</li> <li>Tyler C, Sumpter J. 1996. Oocyte growth and development in teleosts. Reviews in Fish Biology and Fisheries 6: 287-318.</li> <li>Wolf JC, Dietrich DR, Friederich U, Caunter J, Brown AR. 2004. Qualitative and quantitative histomorphologic assessment of fathead minnow Pimephales promelas gonads as an endpoint for evaluating endocrine-active compounds: a pilot methodology study. Toxicol Pathol 32(5): 600-612.</li> </ul> AOPWiki 2016-11-29T18:41:23 2017-09-16T10:14:38 Reduction, Cumulative fecundity and spawning Individual <p>Spawning refers to the release of eggs. Cumulative fecundity refers to the total number of eggs deposited by a female, or group of females over a specified period of time.</p> <p>In laboratory-based reproduction assays (e.g., OECD Test No. 229; OECD Test No. 240), spawning and cumulative fecundity can be directly measured through daily observation of egg deposition and egg counts.</p> <p>In some cases, fecundity may be estimated based on gonado-somatic index (<a href="http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2008)22&amp;doclanguage=en">OECD 2008</a>).</p> <p>Cumulative fecundity and spawning can, in theory, be evaluated for any egg laying animal.</p> High Female High Adult, reproductively mature High High High <ul> <li>OECD 2008. Series on testing and assessment, Number 95. Detailed Review Paper on Fish Life-cycle Tests. OECD Publishing, Paris. ENV/JM/MONO(2008)22.</li> <li>OECD&nbsp;(2015),&nbsp;<em>Test No. 240: Medaka Extended One Generation Reproduction Test (MEOGRT)</em>, OECD Publishing, Paris.<br /> DOI:&nbsp;<a href="http://dx.doi.org/10.1787/9789264242258-en" target="_blank" title="http://dx.doi.org/10.1787/9789264242258-en">http://dx.doi.org/10.1787/9789264242258-en</a></li> <li>OECD. 2012a. Test no. 229: Fish short term reproduction assay. Paris, France:Organization for Economic Cooperation and Development.</li> </ul> AOPWiki 2016-11-29T18:41:22 2017-03-20T17:52:57 Decreased, Population trajectory Population AOPWiki 2016-11-29T18:41:24 2017-04-18T16:19:22 Increased, gene expression of AR Molecular AOPWiki 2023-05-18T02:05:02 2023-05-18T02:05:02 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9b1ec28> AOPWiki 2023-05-22T21:36:45 2023-05-22T21:36:45 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9b309a0> AOPWiki 2023-05-22T21:45:26 2023-05-22T21:45:26 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9b4a148> AOPWiki 2023-05-22T21:37:09 2023-05-22T21:37:09 <p>There is not a direct structural/functional relationship between reduced concentrations of 17&szlig;-estradiol in plasma and reduced plasma VTG concentrations. The relationship is thought to be mediated through additional events of hepatic estrogen receptor activation, vitellogenin protein synthesis in the liver, and subsequent secretion of vitellogenin into the plasma.&nbsp;</p> <p>Updated 2017-03-17</p> <p>The mechanisms through which 17&szlig;-estradiol stimulates the transcription and translation of hepatic vitellogenin are well understood.</p> <ul> <li>In fish, see: &nbsp;Tyler et al. 1996; Tyler and Sumpter 1996; Arukwe and Goks&oslash;yr 2003;&nbsp;Teo et al. 1998</li> <li>In frogs:&nbsp;Chang et al. 1992; Wangh and Knowland 1975</li> <li>In reptiles: Ho et al. 1980&nbsp;</li> <li>Ho (1987)</li> <li>In birds:&nbsp;Deeley et al. 1975;</li> </ul> <p>17&szlig;-estradiol is not synthesized in significant amounts in the liver. Its synthesis originates in other tissues, principally the gonads. It is then transported to the liver and other tissues via circulation (Norris 2007; Payne and Hales 2004; Miller 1988; Nagahama et al. 1993).</p> <ul> <li>Under conditions of continuous flow through exposure to 17&szlig;-trenbolone (a non-aromatizable androgen receptor agonist), plasma E2 concentrations were reduced in female fathead minnows after 2,&nbsp;4, or 8&nbsp;d of exposure to concentrations of 0.05 ug/L or greater. Plasma VTG concentrations were significantly reduced only after 4 or 8 d of exposure, and at 4 d, only at a concentration of 0.5 ug/L, not 0.05 ug/L (Ekman et al. 2011).</li> <li>In the same study by Ekman et al. (2011), once exposure ceased, plasma E2 concentrations returned to control levels within 48 h, while plasma VTG concentrations remained significantly depressed until d. 4, post-exposure.</li> <li>&nbsp;Ankley et al. (2003) detected reductions in both plasma E2 and plasma VTG in female fathead minnows following 21 d of continuous exposure to 17&szlig;-trenbolone. At 21 d, plasma E2 concentrations were impacted at concentrations of 0.5 ug/L or greater, while plasma VTG was significantly reduced at 0.05 ug/L or greater.</li> <li>Villeneuve et al. (2016) observed significant reductions in both plasma E2 and plasma VTG in female fathead minnows exposed to 0.5 ug/L 17&szlig;-trenbolone for 14 d.</li> <li>Jensen et al. (2006) observed significant reductions in both plasma E2 and plasma VTG following exposure to 0.03 ug/L 17alpha-trenbolone for 21 d.</li> <li>Following 21 d of continuous exposure to spironolactone, plasma E2 and plasma VTG were both significantly reduced in female fathead minnows. The lowest effect concentration for plasma E2 was 0.5 ug/L, while that for plasma VTG was 5 ug/L (LaLone et al. 2013).</li> <li>&nbsp;In female Fundulus heteroclitus exposed to 5alpha-dihydrotestosterone for 14 d, plasma E2 was significantly reduced following exposure to 10 ug/L, while plasma VTG was reduced at 100 ug/L (Rutherford et al. 2015).</li> <li>In two experiments in which female Fundulus heteroclitus were exposed to 17alpha-methyltestosterone, both plasma E2 and plasma VTG were significantly reduced. In both cases, plasma E2 was impacted at lower concentrations (0.25 ug/L in a 7 d study; 0.01 ug/L in a 14 d study) than plasma VTG (1 ug/L in the 7 d study; 0.1 ug/L in the 14 d study; Sharpe et al. 2004).</li> <li>In two experiments where plasma E2 and plasma VTG were measured in female fathead minnows (Pimephales promelas)&nbsp;in a time-course following continuous exposure the aromatase inhibitor fadrozole, both plasma VTG and plasma E2 were depressed (Villeneuve et. al. 2009; 2013). In both cases, following cessation of exposure, plasma E2 concentrations recovered to control levels before plasma VTG concentrations recovered (Villeneuve et al. 2009; 2013).</li> <li>Shroeder et al. (in preparation) reported effects on plasma E2 concentrations within 4 h of initiating exposure to 5 or 50 ug/L fadrozole. Plasma VTG concentrations did not decline until 24 h or later (Schroeder et al. 2009; Villeneuve et al. 2009; 2013).</li> <li>In female fathead minnows exposed to 300 ug/L prochloraz, plasma E2 concentrations were significantly reduced after 12 h of exposure, while plasma VTG concentrations were not significantly reduced until 24 h of exposure (Skolness et al. 2011).</li> <li>Ankley et al. (2009) reported significant reductions in plasma E2 in female fathead minnows following 24 h of exposure to 30 ug/L prochloraz. In the same study, plasma VTG concentrations did not significantly decline until 48 h of exposure, and then only at 300 ug/L prochloraz.</li> <li>In a 21 d exposure to prochloraz, plasma E2 was significantly reduced in females exposed to 300 ug prochloraz/L, while plasma VTG was significantly reduced in females exposed to 100 ug/L (Ankley et al. 2005).&nbsp; &nbsp;</li> </ul> <ul> <li>In several studies, significant decreases in plasma vitellogenin are detected at lower concentrations than those that result in significant decreases in plasma E2. However, detection of differences in plasma VTG is ofen enhanced by the greater dynamic range in the concentrations of the protein that occur in plasma, compared to the dynamic range of steroid hormone concentrations.</li> </ul> <ul> <li>A computational model developed by Cheng et al. (2016) is capable of simulating altered plasma VTG concentrations associated with changes in plasma E2 concentrations in female fathead minnows. This model has been used to generate a quantitative response-response relationship that can predict steady state plasma VTG concentrations for a given steady state plasma E2 concentration (Conolly et al. 2017).&nbsp; <ul> <li>The model and response-response relationship were developed based on data from exposures to the model aromatase inhibitor fadrozole. The validity of the model-based predictions/relationships for other stressors and species has not yet been established.</li> </ul> </li> <li>Li et al. (2011) also developed a physiologically-based computational model of the adult female fathead minnow (<em>Pimephales promelas</em>) hypothalamic-pituitary-gonadal axis. Conceptually, this model could also be applied to derive a quantitative response-response relationship between plasma E2 and plasma VTG concentrations. The Li et al. model was calibrated based on data from exposures to 17alpha-ethynylestradiol and 17&szlig;-trenbolone. Neither its validity for other stressors or speices, nor its agreement with the Cheng et al. (2016) model have been examined in detail.</li> </ul> <p><img alt="" src="https://aopwiki.org/system/dragonfly/production/2018/10/18/6jgav91rlv_VTG_E2.pdf" />Under long term, steady state exposure conditions, the following equation can be used to estimate the&nbsp;&micro;M concentration of plasma vitellogenin (downstream event) from the&nbsp;&micro;M concentration of plasma 17&szlig;-estradiol.</p> <p><a href="https://aopwiki.org/system/dragonfly/production/2018/10/18/6jgav91rlv_VTG_E2.pdf" target="_self">y=0.2855e^(365.55x)<img alt="Response-response plot" longdesc="https://aopwiki.org/system/dragonfly/production/2018/10/18/6jgav91rlv_VTG_E2.pdf" src="https://aopwiki.org/system/dragonfly/production/2018/10/18/6jgav91rlv_VTG_E2.pdf" style="border-style:solid; border-width:5px; height:30px; margin:5px; width:60px" /></a></p> High Female High Adult, reproductively mature High High <p>This key event relationship likely applies to oviparous vertebrates only.</p> <ul> <li>Key enzymes needed to synthesize 17&beta;-estradiol first appear in the common ancestor of amphioxus and vertebrates (Baker 2011).&nbsp;</li> <li>Vitellogenesis is common to a range of egg-laying vertebrates and invertebrates. &nbsp;However, in the case of invertebrates, vitellogenins are transported via hemolymph rather than plasma and vitellogenesis is regulated by invertebrate hormones, not estradiol.</li> </ul> #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9baedc8> AOPWiki 2017-03-17T17:13:26 2018-10-18T11:02:14 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9ba2cd0> AOPWiki 2023-05-22T21:37:40 2023-05-22T21:37:40 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9bf7320> AOPWiki 2023-05-22T22:19:11 2023-05-22T22:19:11 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9c140b0> AOPWiki 2023-05-22T21:38:20 2023-05-22T21:38:20 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9c43978> AOPWiki 2023-05-22T21:39:52 2023-05-22T21:39:52 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9c6b9f0> AOPWiki 2023-05-22T21:40:23 2023-05-22T21:40:23 <p>SEE BIOLOGICAL PLAUSIBILITY BELOW</p> <p>Vitellogenin synthesized in the liver and transported to the ovary via the circulation is the primary source of egg yolk proteins in fish (Wallace and Selman 1981; Tyler and Sumpter 1996; Arukwe and Goks&oslash;yr 2003). In many teleosts vitellogenesis can account for up to 95% of total egg size (Tyler and Sumpter 1996).</p> <p>In some (Ankley et al. 2002; Ankley et al. 2003; Lalone et al. 2013), but not all (Ankley et al. 2005; Sun et al. 2007; Skolness et al. 2013) fish reproduction studies, reductions in plasma vitellogenin have been associated with visible decreases in yolk protein content in oocytes and overall reductions in ovarian stage.</p> <p>Not all fish reproduction studies showing reductions in plasma vitellogenin have caused visible decreases in yolk protein content in oocytes and overall reductions in ovarian stage. (Ankley et al. 2005; Sun et al. 2007; Skolness et al. 2013).</p> <p>While plasma vitellogenin is well established as the only major source of vitellogenins to the oocyte, the extent to which a decrease will impact an ovary that has already developed vitellogenic staged oocytes is less certain. It would be assumed that the more rapid the turn-over of oocytes in the ovary, the tighter the linkage between these KEs. Thus, repeat spawning species with asynchronous oocyte development that spawn frequently would likely be more vulnerable than annual spawning species with synchronous oocyte development that had already reached late vitellogenic stages.</p> <ul> <li>Rates of vitellogenin uptake as a function of ovarian follicle surface area have been estimated for rainbow trout, an annual spawning fish species, and may exceed 700 ng/mm2 follicle surface per hour (Tyler and Sumpter 1996).</li> <li>Comparable data are lacking for repeat-spawning species and kinetic relationships between plasma concentrations and uptake rates within the ovary have not been defined.</li> <li>A model based on a statistical relationship between plasma E2 concentrations, spawning interval, and cumulative fecundity has been developed to predict changes in cumulative fecundity from plasma VTG (Li et al. 2011b), but it does not incorporate a model of the kinetics of VTG uptake nor the influence of VTG uptake on oocyte growth.</li> </ul> High Female High Adult, reproductively mature Moderate Moderate <p>This KER is expected to be primarily applicable to oviparous vertebrates that synthesize vitellogenin in hepatic tissue which is ultimately incorporated into oocytes present in the ovary.</p> #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9cf4778> AOPWiki 2016-11-29T18:41:33 2017-03-20T13:21:09 <p>SEE BIOLOGICAL PLAUSIBILITY BELOW</p> <p>Vitellogenesis is a critical stage of oocyte development and accumulated lipids and yolk proteins make up the majority of oocyte biomass (Tyler and Sumpter 1996). At least in mammals, maintenance of meiotic arrest is supported by signals transmitted through gap junctions between the granulosa cells and oocytes (Jamnongjit and Hammes 2005). Disruption of oocyte-granulosa contacts as a result of cell growth has been shown to coincide with oocyte maturation (Eppig 1994). However, it remains unclear whether the relationship between vitellogenin accumulation and oocyte growth and eventual maturation is causal or simply correlative.</p> <ul> <li>At present, to our best knowledge there are no studies that definitively demonstrate a direct cause-effect relationship between impaired VTG accumulation into oocytes and impaired spawning. There is, however, strong correlative evidence. Across a range of laboratory studies with small fish, there is a robust and statistically significant correlation between reductions in circulating VTG concentrations and reductions in cumulative fecundity (Miller et al. 2007). To date, we are unaware of any fish reproduction studies which show a large reduction in circulating VTG concentrations, but not reductions in cumulative fecundity.</li> <li>Ankley et al. (2003) reported significant reductions in VTG accumulation in oocytes along with significant reductions in cumulative fecundity, although fecundity was significantly impacted at a lower dose (0.05 ug/L 17beta-trenbolone versus 0.5 ug/L for VTG accumulation).</li> <li>Kang et al. (2008) reported significant reductions in both VTG accumulation in occytes and cumulative fecundity in Japanese medaka, with cumulative fecundity being impacted at slightly lower concentrations (0.047 ug 17alpha-methyltestosterone/L versus 0.088 ug/L).</li> <li>&nbsp;</li> </ul> <p>Based on the limited number of studies available that have examined both of these KEs, there are no known, unexplained, results that are inconsistent with this relationship.</p> <p>Across a range of laboratory studies with fathead minnow, there is a robust and statistically significant correlation between reductions in circulating VTG concentrations and reductions in cumulative fecundity (Miller et al. 2007). At present it is unclear how well that relationship may hold for other fish species or feral fish under the influence of environmental variables. A model based on a statistical relationship between plasma E2 concentrations, spawning interval, and cumulative fecundity has been developed to predict changes in cumulative fecundity from plasma VTG (Li et al. 2011b). However, to date, such models do not specifically consider vitellogenin uptake into oocytes as a quantitative predictor of fecundity. Furthermore, with the exception of a few specialized studies, quantitative measures of VTG content in oocytes are rarely measured in toxicity studies. In contrast, plasma VTG is routinely measured.</p> High Female High Adult, reproductively mature Moderate Moderate <p>On the basis of the taxonomic relevance of the two KEs linked via this KER, this KER is likely applicable to aquatic, oviparous, vertebrates which both produce vitellogenin and deposit eggs/sperm into an aquatic environment.</p> #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9d9bbe0> AOPWiki 2016-11-29T18:41:33 2017-03-20T13:35:29 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9dc3960> AOPWiki 2023-05-22T21:44:46 2023-05-22T21:44:46 Androgen receptor agonism leading to reproduction dysfunction Arthur Author All rights reserved 2.5 <p><span style="font-size:12.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">This adverse outcome pathway&nbsp;is a further development and improvement for AOP 23 and details the linkage of androgen receptor agonism in female zebrafish with reproductive dysfunction and reductions of cumulative fecundity and spawning as adverse effect. Based on AOP 23,&nbsp; it also adds some new KEs for the pathway and quantitative understanding for key events through experiments data.&nbsp;This work found that there are some differences and similarities in KEs between zebrafish and <em>Pimephales promelas</em> induced by androgen receptor&nbsp;agonism.&nbsp;</span></span><span style="font-size:12pt"><span style="font-family:Arial,sans-serif">The impairments in zebrafish <em>in vivo </em>is connected with androgen receptor&nbsp;activities <em>in vitro</em> by agonism.&nbsp;</span></span></p> <p><span style="font-size:12pt"><span style="font-family:Arial,sans-serif">The 21-day exposure experiments to adult&nbsp;zebrafish revealed that female zebrafish showed strong dose-response relationships to the androgen receptor agonism (17beta-trenbolone) at the genetic, enzymatic, tissue, and individual levels than male zebrafish. The quantitative relationships from experiments and evidence analysis revealed stronger evidence of androgen agonism, <em>ar</em> gene expression, circulating E2 and VTG concentrations in plasma, and spawning, while weaker evidence and dose-effect results in GtH and T concentrations in plasma, and oocytes development. In addition, it was the ratio of E2/11-KT rather than E2/T that became an important KE to reveal the transformation of T to E2 when qualitative and quantitative relationship were considered, since T will be catalyzed by aromatase (CYP19A1A and CYP11C1) and transform into E2 or 11-KT. </span></span></p> <p>&nbsp;</p> <p><strong>Characterization of chemical properties</strong>: Androgen receptor binding chemicals can be grouped into two broad structural domains, steroidal and non-steroidal (Yin et al. 2003). Steroidal androgens consist primarily of testosterone and its derivatives (Yin et al. 2003). Many of the non-steroidal AR binding chemicals studied are derivatives of well known non-steroidal AR antagonists like bicalutamide, hydroxyflutamide, and nilutamide (Yin et al. 2003). Nonetheless, a number of QSARs and SARs that consider AR binding of both these pharmaceutical agents as well as environmental chemicals have been developed (Waller et al. 1996; Serafimova et al. 2002; Todorov et al. 2011; Hong et al. 2003; Bohl et al. 2004). However, it has been shown that very minor structural differences can dramatically impact function as either an agonist or antagonist (Yin et al. 2003; Bohl et al. 2004; Norris et al. 2009), making it difficult at present to predict agonist versus antagonist activity based on chemical structure alone.</p> <p><strong>In vivo considerations</strong>: A variety of steroidal androgens can be converted to estrogens in vitro through the action of cytochrome P450 19 (aromatase). Structures subject to aromatization may behave in vivo as estrogens despite exhibiting potent androgen receptor agonism in vitro.</p> adjacent Moderate High adjacent Low Low adjacent Low Moderate adjacent Moderate High adjacent Moderate High adjacent High High adjacent Moderate Moderate adjacent Moderate High adjacent Moderate High non-adjacent Moderate Moderate non-adjacent High High non-adjacent Moderate Moderate High Female High Adult, reproductively mature High <div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td>&nbsp;</td> <td>&nbsp;</td> <td>&nbsp;</td> </tr> </tbody> </table> </div> Not Specified AOPWiki 2023-05-16T21:08:20 2023-09-25T16:27:14