<!DOCTYPE html><html lang="en"><div class="pull-right"><h1>SNAPSHOT</h1><h4>Created at: 2020-08-28 19:54</h4></div><!-- Title Section, includes id, name and short name --><div id="title"><h2>AOP ID and Title:</h2><hr><div class="title">AOP 305: 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</div><strong>Short Title: 5α-reductase inhibition leading to short AGD</strong><br></div><!-- graphical representation --><h2>Graphical Representation</h2><img src="https://aopwiki.org/system/dragonfly/production/2019/08/30/7lpbwt4ree_AOP_Graphic_5a_reductase_inhibition_leading_to_short_AGD.jpg" , height="500" , width="700"> </img><!-- end graphical representation --><hr><!-- Author section, includes text of author names as they have been entered by the user --><div id="authors"><h2>Authors</h2><hr><p>Terje Svingen; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark</p><br></div><!-- Status Section, lists status of aop --><div id="status"><h2>Status</h2><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><th>Author status</th><th>OECD status</th><th>OECD project</th><th>SAAOP status</th></thead><tr><td>Under development: Not open for comment. Do not cite</td><td></td><td></td><td></td></tr></table></div></div><!-- Abstract Section, text as generated by author --><div id="abstract"><h2>Abstract</h2><hr><p>This AOP links 5α-reductase inhibition during fetal life with short anogenital distance (AGD) in male offspring. A short AGD around birth is a marker for feminization of male fetuses and is associated with male reproductive disorders, including reduced fertility in adulthood. Although a short AGD is not necessarily ‘adverse’ from a human health perspective, it is considered an ‘adverse outcome’ in OECD test guidelines; AGD measurements are mandatory in specific tests for developmental and reproductive toxicity in chemical risk assessment (TG 443, TG 421/422, TG 414).</p><p>5α-reductase is an enzyme responsible for the conversion of testosterone to DHT in target tissues. DHT is more potent agonist of the Androgen receptor (AR) than testosterone, so that DHT is necessary for proper masculinization of e.g. male external genitalia. Under normal physiological conditions, testosterone produced mainly by the testicles, is converted in peripheral tissues by 5α-reductase into DHT, which in turn binds AR and activates downstream target genes. AR signaling is necessary for masculinization of the developing fetus, including differentiation of the levator ani/bulbocavernosus (LABC) muscle complex in males. The LABC complex does not develop in the absence, or low levels of, androgen signaling, as in female fetuses.</p><p>The key events in this pathway is inhibition of 5α-reductase that converts testosterone into the more potent DHT in androgen sensitive target tissues. This includes developing perineal region, which, when DHT levels are low or absent, leads to inactivation of the AR and failure to properly masculinize the perineum/LABC complex.</p><br></div><!-- Background Section, text as generated by author --><div id="background"><br></div><!-- AOP summary, includes summary of each of the events associated with this aop --><div id="aop_summary"><h2>Summary of the AOP</h2><!-- event table --><h3>Events</h3><h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Sequence</th><th>Type</th><th>Event ID</th><th>Title</th><th>Short name</th></tr></thead><tbody><tr><td></td><td>MIE</td><td>1617</td><td><a href="/events/1617">5α-reductase, inhibition</a></td><td>5α-reductase, inhibition</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td>KE</td><td>1613</td><td><a href="/events/1613">Decrease, dihydrotestosterone (DHT) level</a></td><td>Decrease, DHT level</td></tr><tr><td></td><td>KE</td><td>1614</td><td><a href="/events/1614">Decrease, androgen receptors (AR) activation</a></td><td>Decrease, AR activation</td></tr><tr><td></td><td>KE</td><td>1687</td><td><a href="/events/1687">decrease, transcription of genes by AR </a></td><td>decrease, transcription of genes by AR </td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td>AO</td><td>1688</td><td><a href="/events/1688">decrease, male anogenital distance</a></td><td>short male AGD</td></tr></tbody></table></div><!-- rel table --><h3>Key Event Relationships</h3><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Upstream Event</th><th>Relationship Type</th><th>Downstream Event</th><th>Evidence</th><th>Quantitative Understanding</th></tr></thead><tbody><tr><td><a href="/relationships/1880">5α-reductase, inhibition</a></td><td>adjacent</td><td>Decrease, dihydrotestosterone (DHT) level</td><td>High</td><td>High</td></tr><tr><td><a href="/relationships/1935">Decrease, dihydrotestosterone (DHT) level</a></td><td>adjacent</td><td>Decrease, androgen receptors (AR) activation</td><td>High</td><td>Moderate</td></tr><tr><td><a href="/relationships/2128">Decrease, androgen receptors (AR) activation</a></td><td>adjacent</td><td>decrease, transcription of genes by AR </td><td>Moderate</td><td>Low</td></tr><tr><td><a href="/relationships/2129">decrease, transcription of genes by AR </a></td><td>adjacent</td><td>decrease, male anogenital distance</td><td>Moderate</td><td>Low</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr></tbody></table></div><!-- stressor table --><h3>Stressors</h3><br><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Name</th><th>Evidence</th></tr></thead><tbody><tr><td>Finasteride</td><td>High</td></tr></tbody></table></div><h4>Finasteride</h4><p>Finasteride is a type II 5alpha-reductase inhibitor that blocks conversion of testosterone to dihydrotestosterone (Clark et al 1990; Imperato-McGinley et al 1992). Intrauterine exposure in rats can result in shorter male AGD in male offspring (Bowman et al 2003; Christiansen et al 2009; Schwartz et al 2019)</p><p><strong>References:</strong></p><p>Bowman et al (2003), Toxicol Sci 74:393-406; doi: 10.1093/toxsci/kfg128</p><p>Christiansen et al (2009), Environ Health Perspect 117:1839-1846; doi: 10.1289/ehp.0900689</p><p>Clark et al (1990), Teratology 42:91-100; doi: 10.1002/tera.1420420111</p><p>Imperato-McGinley (1992), J Clin Endocrinol Metab 75:1022-1026; doi: 10.1210/jcem.75.4.1400866</p><p>Schwartz et al (2019), Toxicol Sci 169:303-311; doi: 10.1093/toxsci/kfz046</p></div><!-- end summary --><!-- Overall assessment section, *** what is included here? *** --><div id="overall_assessment"><h2>Overall Assessment of the AOP</h2><hr><h3>Domain of Applicability</h3><strong>Life Stage Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Life Stage</th><th>Evidence</th></tr></thead><tbody><tr><td>Pregnancy</td><td>High</td></tr></tbody></table></div><strong>Taxonomic Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Term</th><th>Scientific Term</th><th>Evidence</th><th>Links</th></tr></thead><tbody><tr><td>human</td><td>Homo sapiens</td><td>Moderate</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a></td></tr><tr><td>rat</td><td>Rattus norvegicus</td><td>High</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" , target="_blank">NCBI</a></td></tr><tr><td>mouse</td><td>Mus musculus</td><td>Moderate</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" , target="_blank">NCBI</a></td></tr></tbody></table></div><strong>Sex Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Sex</th><th>Evidence</th></tr></thead><tbody><tr><td>Male</td><td>High</td></tr></tbody></table></div></div><!-- potential consierations, text as entered by author --><div id="considerations_for_potential_applicaitons"></div><!-- reference section, text as of right now but should be changed to be handled as table --><div id="references"><h2>References</h2><hr><ol><li>Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U and <strong>Svingen T</strong> (2019), Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. <em>Arch Toxicol</em> 93: 253-272.</li></ol><br></div><div id="appendicies"><h2>Appendix 1</h2><h3>List of MIEs in this AOP</h3><div><div><h4><a href="/events/1617">Event: 1617: 5α-reductase, inhibition</a><br></h4><h5>Short Name: 5α-reductase, inhibition</h5></div><div><!-- loop to find all aops that use this event --><h4>AOPs Including This Key Event</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP ID and Name</th><th>Event Type</th></tr></thead><tbody><tr><td><a href="/aops/289">Aop:289 - Inhibition of 5α-reductase leading to impaired fecundity in female fish</a></td><td>MolecularInitiatingEvent</td></tr><tr><td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>MolecularInitiatingEvent</td></tr></tbody></table></div></div><!-- loop to find stressors under event --><div></div><br><!-- biological organization --><div><h4>Biological Context</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Level of Biological Organization</th></tr></thead><tbody><tr><td>Molecular</td></tr></tbody></table></div></div><!-- end of bio org --><!-- cell term --><div></div><!-- end of cell term --><!-- organ term --><div></div><!-- end of organ term --><!-- Evidence for Perturbation of This Event by Stressors --><!-- end Evidence for Perturbation of This Event by Stressors --><!-- event text --><!-- end event text --></div><h3>List of Key Events in the AOP</h3><div><div><h4><a href="/events/1613">Event: 1613: Decrease, dihydrotestosterone (DHT) level</a><br></h4><h5>Short Name: Decrease, DHT level</h5></div><div><!-- loop to find all aops that use this event --><h4>AOPs Including This Key Event</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP ID and Name</th><th>Event Type</th></tr></thead><tbody><tr><td><a href="/aops/288">Aop:288 - Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></td><td>KeyEvent</td></tr><tr><td><a href="/aops/289">Aop:289 - Inhibition of 5α-reductase leading to impaired fecundity in female fish</a></td><td>KeyEvent</td></tr><tr><td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>KeyEvent</td></tr><tr><td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>KeyEvent</td></tr></tbody></table></div></div><!-- loop to find stressors under event --><div></div><br><!-- biological organization --><div><h4>Biological Context</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Level of Biological Organization</th></tr></thead><tbody><tr><td>Cellular</td></tr></tbody></table></div></div><!-- end of bio org --><!-- cell term --><div></div><!-- end of cell term --><!-- organ term --><div></div><!-- end of organ term --><!-- Evidence for Perturbation of This Event by Stressors --><!-- end Evidence for Perturbation of This Event by Stressors --><!-- event text --><h4>Key Event Description</h4><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Reduction in DHT synthesis leads to a reduction in DHT circulating levels. <sup>12</sup></span></span></p><br><h4>How it is Measured or Detected</h4><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">DHT levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, DHT can be identify by comparison with internal standards spectrum. Quantification of DHT levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling).<sup>3</sup></span></span></p><br><h4>References</h4><table><tbody><tr><td colspan="1" rowspan="1"><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>1 </sup>Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318.<a href="https://www.google.com/url?q=https://doi.org/10.1210/edrv-9-3-295&sa=D&ust=1554891396614000">https://doi.org/10.1210/edrv-9-3-295</a> </span></span></p><p style="text-align: justify;"> </p><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>2 </sup>Miller W.L. and Auchus R.J. (2011) The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1): 81-151.<a href="https://www.google.com/url?q=https://doi.org/10.1210/er.2010-0013&sa=D&ust=1554891396616000">https://doi.org/10.1210/er.2010-0013</a> </span></span></p><p style="text-align: justify;"> </p><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>3</sup> Shiraishi S., Lee P.W., Leung A., Goh V.H., Swerdloff R.S. and Wang C. (2008) Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clinical chemistry, 54(11): 1855-63.<a href="https://www.google.com/url?q=https://doi.org/10.1373/clinchem.2008.103846&sa=D&ust=1554891396617000">https://doi.org/10.1373/clinchem.2008.103846</a></span></span></p></td></tr></tbody></table><br><!-- end event text --></div><div><div><h4><a href="/events/1614">Event: 1614: Decrease, androgen receptors (AR) activation</a><br></h4><h5>Short Name: Decrease, AR activation</h5></div><div><!-- loop to find all aops that use this event --><h4>AOPs Including This Key Event</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP ID and Name</th><th>Event Type</th></tr></thead><tbody><tr><td><a href="/aops/288">Aop:288 - Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></td><td>KeyEvent</td></tr><tr><td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>KeyEvent</td></tr><tr><td><a href="/aops/306">Aop:306 - Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>KeyEvent</td></tr><tr><td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>KeyEvent</td></tr><tr><td><a href="/aops/344">Aop:344 - Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring</a></td><td>KeyEvent</td></tr></tbody></table></div></div><!-- loop to find stressors under event --><div></div><br><!-- biological organization --><div><h4>Biological Context</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Level of Biological Organization</th></tr></thead><tbody><tr><td>Cellular</td></tr></tbody></table></div></div><!-- end of bio org --><!-- cell term --><div></div><!-- end of cell term --><!-- organ term --><div></div><!-- end of organ term --><!-- Evidence for Perturbation of This Event by Stressors --><!-- end Evidence for Perturbation of This Event by Stressors --><!-- event text --><h4>Key Event Description</h4><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Androgen receptor activation is regulated by the binding of androgens. AR activity can be decreased by either a lack of steroidal ligands (testosterone, DHT) or the presence of antagonist compounds. <sup>12</sup></span></span></p><br><h4>How it is Measured or Detected</h4><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Significance of AR signaling in fetal development can be studied through a conditional deletion of the androgen receptor using a Cre/loxP approach. The recommended animal model for reproductive study is the mouse.<sup>3</sup></span></span></p><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Also, epidemiological case-studies following mouse or humans expressing a complete androgen insensitivity allow to directly assess the effects of a lack of AR activation on the development.<sup>4</sup></span></span></p><p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Enzyme immunoassay (ELISA) kits for in vitro quantitative measurement of AR activity are available. Androgen receptors activity can be measured using bioassay such as the (Anti-)Androgen Receptor CALUX reporter gene assay.<sup>5</sup></span></span></p><br><h4>References</h4><table><tbody><tr><td colspan="1" rowspan="1"><p> </p></td><td colspan="1" rowspan="1"><p><sup>1</sup> Davey R.A and Grossmann M. (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clinical Biochemist Reviews, 37(1): 3-15. PCM4810760</p><p><sup>2 </sup>Gao W., Bohl C.E. and Dalton J.T. (2005) Chemistry and Structural Biology of Androgen Receptor. Chemical Reviews 105(9): 3352-3370<a href="https://www.google.com/url?q=https://doi.org/10.1021/cr020456u&sa=D&ust=1554891396627000">https://doi.org/10.1021/cr020456u</a> </p><p><sup>3</sup> Kaftanovskaya E.M., Huang Z., Barbara A.M., De Gendt K., Verhoeven G., Ivan P. Gorlov, and Agoulnik A.I. (2012) Cryptorchidism in Mice with an Androgen Receptor Ablation in Gubernaculum Testis. Molecular Endocrinology, 26(4): 598-607.<a href="https://www.google.com/url?q=https://doi.org/10.1210/me.2011-1283&sa=D&ust=1554891396628000">https://doi.org/10.1210/me.2011-1283</a> </p><p><sup>4</sup> Hutson J.M. (1985) A biphasic model for the hormonal control of testicular descent. Lancet, 24;2(8452): 419-21<a href="https://www.google.com/url?q=http://dx.doi.org/10.1016/S0140-6736(85)92739-4&sa=D&ust=1554891396629000">http://dx.doi.org/10.1016/S0140-6736(85)92739-4</a> </p><p><sup>5</sup> van der Burg B., Winter R., Man HY., Vangenechten C., Berckmans P., Weimer M., Witters M. and van der Linden S. (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 <a href="https://www.google.com/url?q=https://doi.org/0.1016/j.reprotox.2010.04.012&sa=D&ust=1554891396630000">https://doi.org/0.1016/j.reprotox.2010.04.012</a> </p></td></tr></tbody></table><br><!-- end event text --></div><div><div><h4><a href="/events/1687">Event: 1687: decrease, transcription of genes by AR </a><br></h4><h5>Short Name: decrease, transcription of genes by AR </h5></div><div><!-- loop to find all aops that use this event --><h4>AOPs Including This Key Event</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP ID and Name</th><th>Event Type</th></tr></thead><tbody><tr><td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>KeyEvent</td></tr><tr><td><a href="/aops/306">Aop:306 - Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>KeyEvent</td></tr></tbody></table></div></div><!-- loop to find stressors under event --><div></div><br><!-- biological organization --><div><h4>Biological Context</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Level of Biological Organization</th></tr></thead><tbody><tr><td>Cellular</td></tr></tbody></table></div></div><!-- end of bio org --><!-- cell term --><div></div><!-- end of cell term --><!-- organ term --><div></div><!-- end of organ term --><!-- Evidence for Perturbation of This Event by Stressors --><!-- end Evidence for Perturbation of This Event by Stressors --><!-- event text --><!-- end event text --></div><h3>List of Adverse Outcomes in this AOP</h3><div><div><h4><a href="/events/1688">Event: 1688: decrease, male anogenital distance</a><br></h4><h5>Short Name: short male AGD</h5></div><h4>Key Event Component</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Process</th><th>Object</th><th>Action</th></tr></thead><tbody><tr><td>androgen receptor signaling pathway</td><td>Musculature of male perineum</td><td>disrupted</td></tr></tbody></table></div><div><!-- loop to find all aops that use this event --><h4>AOPs Including This Key Event</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP ID and Name</th><th>Event Type</th></tr></thead><tbody><tr><td><a href="/aops/305">Aop:305 - 5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>AdverseOutcome</td></tr><tr><td><a href="/aops/306">Aop:306 - Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>AdverseOutcome</td></tr><tr><td><a href="/aops/307">Aop:307 - Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></td><td>AdverseOutcome</td></tr></tbody></table></div></div><!-- loop to find stressors under event --><div><h4>Stressors</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Name</th></tr></thead><tbody><tr><td>Butylparaben</td></tr><tr><td>p,p'-DDE</td></tr><tr><td>Bis(2-ethylhexyl) phthalate</td></tr><tr><td>Dexamethasone</td></tr><tr><td>Fenitrothion</td></tr><tr><td>Finasteride</td></tr><tr><td>Flutamide</td></tr><tr><td>Ketoconazole</td></tr><tr><td>Linuron</td></tr><tr><td>Prochloraz</td></tr><tr><td>Procymidone</td></tr><tr><td>Triticonazole</td></tr><tr><td>Vinclozolin</td></tr><tr><td>di-n-hexyl phthalate</td></tr><tr><td>Dicyclohexyl phthalate</td></tr><tr><td>butyl benzyl phthalate</td></tr><tr><td>monobenzyl phthalate</td></tr><tr><td>di-n-heptyl phthalate</td></tr></tbody></table></div></div><br><!-- biological organization --><div><h4>Biological Context</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Level of Biological Organization</th></tr></thead><tbody><tr><td>Tissue</td></tr></tbody></table></div></div><!-- end of bio org --><!-- cell term --><div></div><!-- end of cell term --><!-- organ term --><div><h4>Organ term</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Organ term</th></tr></thead><tbody><tr><td>perineum</td></tr></tbody></table></div></div><!-- end of organ term --><!-- Evidence for Perturbation of This Event by Stressors --><h3>Evidence for Perturbation by Stressor</h3><hr><br><h4>Butylparaben</h4><p><p>Butylparaben has been shown to cause decreased male AGD in rats following intrauterine exposure to 500 and 1000 mg/kg bw/day (<a href="#_ENREF_1" title="Boberg, 2016 #12">Boberg et al, 2016</a>; <a href="#_ENREF_39" title="Zhang, 2014 #148">Zhang et al, 2014</a>). A separate study using 600 mg/kg bw/day did not see an effect on male AGD (<a href="#_ENREF_2" title="Boberg, 2008 #45">Boberg et al, 2008</a>).</p></p><br><h4>p,p'-DDE</h4><p><p>p,p,DDE has been shown to cause decreased male AGD in rats following intrauterine exposure to 100-200 mg/kg bw/day (<a href="#_ENREF_20" title="Loeffler, 1999 #60">Loeffler & Peterson, 1999</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p></p><br><h4>Bis(2-ethylhexyl) phthalate</h4><p><p>DEHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 300-1500 mg/kg bw/day (<a href="#_ENREF_4" title="Christiansen, 2010 #13">Christiansen et al, 2010</a>; <a href="#_ENREF_8" title="Gray, 2000 #110">Gray et al, 2000</a>; <a href="#_ENREF_13" title="Howdeshell, 2007 #111">Howdeshell et al, 2007</a>; <a href="#_ENREF_15" title="Jarfelt, 2005 #113">Jarfelt et al, 2005</a>; <a href="#_ENREF_16" title="Kita, 2016 #34">Kita et al, 2016</a>; <a href="#_ENREF_18" title="Li, 2013 #71">Li et al, 2013</a>; <a href="#_ENREF_19" title="Lin, 2009 #120">Lin et al, 2009</a>; <a href="#_ENREF_25" title="Moore, 2001 #124">Moore et al, 2001</a>; <a href="#_ENREF_27" title="Nardelli, 2017 #149">Nardelli et al, 2017</a>; <a href="#_ENREF_30" title="Saillenfait, 2009 #134">Saillenfait et al, 2009</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p></p><br><h4>Dexamethasone</h4><p><p>Dexamethasone has been shown to cause decreased male AGD in rats following intrauterine exposure to 0.1 mg/kg bw/day (<a href="#_ENREF_35" title="Van den Driesche, 2012 #144">Van den Driesche et al, 2012</a>).</p></p><br><h4>Fenitrothion</h4><p><p>Fenitrothion has been shown to cause decreased male AGD in rats following intrauterine exposure to 25 mg/kg bw/day (<a href="#_ENREF_34" title="Turner, 2002 #213">Turner et al, 2002</a>).</p></p><br><h4>Finasteride</h4><p><p>Finasteride has been shown to cause decreased male AGD in rats following intrauterine exposure to 100 mg/kg bw/day (<a href="#_ENREF_3" title="Bowman, 2003 #29">Bowman et al, 2003</a>).</p></p><br><h4>Flutamide</h4><p><p>Flutamide has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 16-100 mg/kg bw/day (<a href="#_ENREF_7" title="Foster, 2005 #53">Foster & Harris, 2005</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_16" title="Kita, 2016 #34">Kita et al, 2016</a>; <a href="#_ENREF_23" title="McIntyre, 2001 #36">McIntyre et al, 2001</a>; <a href="#_ENREF_26" title="Mylchreest, 1999 #126">Mylchreest et al, 1999</a>; <a href="#_ENREF_32" title="Scott, 2007 #139">Scott et al, 2007</a>; <a href="#_ENREF_36" title="Welsh, 2007 #56">Welsh et al, 2007</a>).</p></p><br><h4>Ketoconazole</h4><p><p>Ketoconazole has been shown to cause decreased male AGD in rats following intrauterine exposure to 50 mg/kg bw/day in one study (<a href="#_ENREF_33" title="Taxvig, 2008 #184">Taxvig et al, 2008</a>), but no effect in another study using same dose (<a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p></p><br><h4>Linuron</h4><p><p>Linuron has been shown to cause decreased male AGD in rats following intrauterine exposure to 50-100 mg/kg bw/day (<a href="#_ENREF_12" title="Hotchkiss, 2004 #40">Hotchkiss et al, 2004</a>; <a href="#_ENREF_24" title="McIntyre, 2002 #38">McIntyre et al, 2002</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p></p><br><h4>Prochloraz</h4><p><p>Prochloraz has been shown to cause decreased male AGD in rats following intrauterine exposure to 150-250 mg/kg bw/day (<a href="#_ENREF_17" title="Laier, 2006 #15">Laier et al, 2006</a>; <a href="#_ENREF_28" title="Noriega, 2005 #54">Noriega et al, 2005</a>).</p></p><br><h4>Procymidone</h4><p><p style="margin-left:18.0pt">Procymidone has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 50-150 mg/kg bw/day (<a href="#_ENREF_10" title="Hass, 2012 #220">Hass et al, 2012</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_38" title="Wolf, 1999 #146">Wolf et al, 1999</a>).</p></p><br><h4>Triticonazole</h4><p><p>Triticonazole has been shown to cause decreased male AGD in rats following intrauterine exposure to 150 and 450 mg/kg bw/day (<a href="#_ENREF_6" title="Draskau, 2019 #258">Draskau et al, 2019</a>).</p></p><br><h4>Vinclozolin</h4><p><p>Vinclozolin has been shown to cause decreased male AGD in rats following intrauterine exposure to doses between 50-200 mg/kg bw/day (<a href="#_ENREF_5" title="Christiansen, 2009 #14">Christiansen et al, 2009</a>; <a href="#_ENREF_9" title="Gray, 1994 #109">Gray et al, 1994</a>; <a href="#_ENREF_11" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_22" title="Matsuura, 2005 #243">Matsuura et al, 2005</a>; <a href="#_ENREF_29" title="Ostby, 1999 #78">Ostby et al, 1999</a>; <a href="#_ENREF_31" title="Schneider, 2011 #245">Schneider et al, 2011</a>; <a href="#_ENREF_37" title="Wolf, 2004 #51">Wolf et al, 2004</a>).</p></p><br><h4>di-n-hexyl phthalate</h4><p><p>DnHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 500-750 mg/kg bw/day (<a href="#_ENREF_35" title="Saillenfait, 2009 #133">Saillenfait et al, 2009a</a>; <a href="#_ENREF_36" title="Saillenfait, 2009 #134">Saillenfait et al, 2009b</a>).</p></p><br><h4>Dicyclohexyl phthalate</h4><p><p>DCHP has been shown to cause decreased male AGD in rats following intrauterine exposure to 350-750 mg/kg bw/day (<a href="#_ENREF_1" title="Aydoğan Ahbab, 2015 #95">Aydoğan Ahbab & Barlas, 2015</a>; <a href="#_ENREF_13" title="Hoshino, 2005 #239">Hoshino et al, 2005</a>; <a href="#_ENREF_32" title="Saillenfait, 2009 #133">Saillenfait et al, 2009a</a>).</p></p><br><h4>butyl benzyl phthalate</h4><p><p>BBP has been shown to cause decreased male AGD in rats following intrauterine exposure to 500-1000 mg/kg bw/day (<a href="#_ENREF_8" title="Ema, 2002 #104">Ema & Miyawaki, 2002</a>; <a href="#_ENREF_10" title="Gray, 2000 #110">Gray et al, 2000</a>; <a href="#_ENREF_15" title="Hotchkiss, 2004 #40">Hotchkiss et al, 2004</a>; <a href="#_ENREF_30" title="Nagao, 2000 #128">Nagao et al, 2000</a>; <a href="#_ENREF_41" title="Tyl, 2004 #240">Tyl et al, 2004</a>).</p></p><br><h4>monobenzyl phthalate</h4><p><p>MBeP has been shown to cause decreased male AGD in rats following intrauterine exposure to 375 mg/kg bw/day (<a href="#_ENREF_9" title="Ema, 2003 #107">Ema et al, 2003</a>).</p></p><br><h4>di-n-heptyl phthalate</h4><p><p>DHPP has been shown to cause decreased male AGD in rats following intrauterine exposure to 1000 mg/kg bw/day (<a href="#_ENREF_36" title="Saillenfait, 2011 #135">Saillenfait et al, 2011</a>).</p></p><br><!-- end Evidence for Perturbation of This Event by Stressors --><h4>Domain of Applicability</h4><br><!-- loop to find taxonomic applicability under event --><div><strong>Taxonomic Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Term</th><th>Scientific Term</th><th>Evidence</th><th>Links</th></tr></thead><tbody><tr><td>human</td><td>Homo sapiens</td><td>Moderate</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a></td></tr><tr><td>rat</td><td>Rattus norvegicus</td><td>High</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" , target="_blank">NCBI</a></td></tr><tr><td>mouse</td><td>Mus musculus</td><td>High</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" , target="_blank">NCBI</a></td></tr></tbody></table></div></div><!-- end loop for taxons --><!-- life stages --><div><strong>Life Stage Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Life Stage</th><th>Evidence</th></tr></thead><tbody><tr><td>Foetal</td><td>High</td></tr></tbody></table></div></div><!-- end life stages --><!-- sex terms --><div><strong>Sex Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Sex</th><th>Evidence</th></tr></thead><tbody><tr><td>Male</td><td>High</td></tr></tbody></table></div></div><!-- end sex terms --><div><p>A short AGD in male offspring is a marker of insufficient androgen action during critical fetal developmental stages (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>; <a href="#_ENREF_49" title="Welsh, 2008 #23">Welsh et al, 2008</a>). A short AGD is thus a sign of undervirilization, which is also associated with a series of male reproductive disorders, including genital malformations and infertility in humans (<a href="#_ENREF_21" title="Juul, 2014 #3">Juul et al, 2014</a>; <a href="#_ENREF_44" title="Skakkebaek, 2001 #9">Skakkebaek et al, 2001</a>).</p><p>There are numerous human epidemiological studies showing associations with intrauterine exposure to anti-androgenic chemicals and short AGD in newborn boys alongside other reproductive disorders (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This underscores the human relevance of this AO. However, in reproductive toxicity studies and chemical risk assessment, rodents (rats and mice) are what is tested on. The list of chemicals inducing short male AGD in male rat offspring is extensive, as evidenced by the ‘stressor’ list and reviewed by (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).</p><br></div><!-- event text --><h4>Key Event Description</h4><p>The anogenital distance (AGD) refers to the distance between anus and the external genitalia. In rodents and humans, the male AGD is approximately twice the length as the female AGD (<a href="#_ENREF_39" title="Salazar-Martinez, 2004 #8">Salazar-Martinez et al, 2004</a>; <a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This sexual dimorphisms is a consequence of sex hormone-dependent development of secondary sexual characteristics (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). In males, it is believed that androgens (primarily DHT) activate AR-positive cells in non-myotic cells in the fetal perineum region to initiate differentiation of the perineal <em>levator ani</em> and <em>bulbocavernosus </em>(LABC) muscle complex (<a href="#_ENREF_18" title="Ipulan, 2014 #185">Ipulan et al, 2014</a>). This AR-dependent process occurs within a critical window of development, around gestational days 15-18 in rats (<a href="#_ENREF_26" title="MacLeod, 2010 #27">MacLeod et al, 2010</a>). In females, the absence of DHT prevents this masculinization effect from occurring.</p><p>The involvement of androgens in masculinization of the male fetus, including the perineum, has been known for a very long time (<a href="#_ENREF_20" title="Jost, 1953 #151">Jost, 1953</a>), and AGD has historically been used to, for instance, sex newborn kittens. It is now well established that the AGD in newborns is a proxy readout for the intrauterine sex hormone milieu the fetus was developing. Too low androgen levels in XY fetuses makes the male AGD shorter, whereas excess (ectopic) androgen levels in XX fetuses makes the female AGD longer, in humans and rodents (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).</p><br><h4>How it is Measured or Detected</h4><p>The AGD is a morphometric measurement carried out by trained technicians (rodents) or medical staff (humans).</p><p>In rodent studies AGD is assessed as the distance between the genital papilla and the anus, and measured using a stereomicroscope with a micrometer eyepiece. The AGD index (AGDi) is often calculated by dividing AGD by the cube root of the body weight. It is important in statistical analysis to use litter as the statistical unit. This is done when more than one pup from each litter is examined. Statistical analyses is adjusted using litter as an independent, random and nested factor. AGD are analysed using body weight as covariate as recommended in Guidance Document 151 (<a href="#_ENREF_37" title="OECD, 2013 #30">OECD, 2013</a>).</p><p> </p><br><h4>Regulatory Significance of the AO</h4><p>In regulatory toxicology, the AGD is mandatory inclusions in OECD test guidelines used to test for developmental and reproductive toxicity of chemicals. Guidelines include ‘TG 443 extended one-generation study’, ‘TG 421/422 reproductive toxicity screening studies’ and ‘TG 414 developmental toxicity study’.</p><br><h4>References</h4><p><a name="_ENREF_1">Aydoğan Ahbab M, Barlas N (2015) Influence of in utero di-n-hexyl phthalate and dicyclohexyl phthalate on fetal testicular development in rats. <em>Toxicol Lett</em> <strong>233:</strong> 125-137</a></p><p><a name="_ENREF_2">Boberg J, Axelstad M, Svingen T, Mandrup K, Christiansen S, Vinggaard AM, Hass U (2016) Multiple endocrine disrupting effects in rats perinatally exposed to butylparaben. <em>Toxicol Sci</em> <strong>152:</strong> 244-256</a></p><p><a name="_ENREF_3">Boberg J, Metzdorff S, Wortziger R, Axelstad M, Brokken L, Vinggaard AM, Dalgaard M, Nellemann C (2008) Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats. <em>Toxicology</em> <strong>250:</strong> 75-81</a></p><p><a name="_ENREF_4">Bowman CJ, Barlow NJ, Turner KJ, Wallace DG, Foster PM (2003) Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. <em>Toxicol Sci</em> <strong>74:</strong> 393-406</a></p><p><a name="_ENREF_5">Christiansen S, Boberg J, Axelstad M, Dalgaard M, Vinggaard AM, Metzdorff SB, Hass U (2010) Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats. <em>Reprod Toxicol</em> <strong>30:</strong> 313-321</a></p><p><a name="_ENREF_6">Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, Hass U (2009) Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. <em>Environ Health Perspect</em> <strong>117:</strong> 1839-1846</a></p><p><a name="_ENREF_7">Draskau MK, Boberg J, Taxvig C, Pedersen M, Frandsen HL, Christiansen S, Svingen T (2019) In vitro and in vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole. <em>Environ Pollut</em> <strong>255:</strong> 113309</a></p><p><a name="_ENREF_8">Ema M, Miyawaki E (2002) Effects on development of the reproductive system in male offspring of rats given butyl benzyl phthalate during late pregnancy. <em>Reprod Toxicol</em> <strong>16:</strong> 71-76</a></p><p><a name="_ENREF_9">Ema M, Miyawaki E, Hirose A, Kamata E (2003) Decreased anogenital distance and increased incidence of undescended testes in fetuses of rats given monobenzyl phthalate, a major metabolite of butyl benzyl phthalate. <em>Reprod Toxicol</em> <strong>17:</strong> 407-412</a></p><p><a name="_ENREF_10">Foster PM, Harris MW (2005) Changes in androgen-mediated reproductive development in male rat offspring following exposure to a single oral dose of flutamide at different gestational ages. <em>Toxicol Sci</em> <strong>85:</strong> 1024-1032</a></p><p><a name="_ENREF_11">Gray LE, Jr., Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L (2000) Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. <em>Toxicol Sci</em> <strong>58:</strong> 350-365</a></p><p><a name="_ENREF_12">Gray LEJ, Ostby JS, Kelce WR (1994) Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat. <em>Toxicol Appl Pharmacol</em> <strong>129:</strong> 46-52</a></p><p><a name="_ENREF_13">Hass U, Boberg J, Christiansen S, Jacobsen PR, Vinggaard AM, Taxvig C, Poulsen ME, Herrmann SS, Jensen BH, Petersen A, Clemmensen LH, Axelstad M (2012) Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides. <em>Reprod Toxicol</em> <strong>34:</strong> 261-274</a></p><p><a name="_ENREF_14">Hass U, Scholze M, Christiansen S, Dalgaard M, Vinggaard AM, Axelstad M, Metzdorff SB, Kortenkamp A (2007) Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. <em>Environ Health Perspect</em> <strong>115 Suppl. 1:</strong> 122-128</a></p><p><a name="_ENREF_15">Hoshino N, Iwai M, Okazaki Y (2005) A two-generation reproductive toxicity study of dicyclohexyl phthalate in rats. <em>J Toxicol Sci</em> <strong>30 Spec No:</strong> 79-96</a></p><p><a name="_ENREF_16">Hotchkiss AK, Parks-Saldutti LG, Ostby JS, Lambright C, Furr J, Vandenbergh JG, Gray LEJ (2004) A mixture of the "antiandrogens" linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. <em>Biol Reprod</em> <strong>71:</strong> 1852-1861</a></p><p><a name="_ENREF_17">Howdeshell KL, Furr J, Lambright CR, Rider CV, Wilson VS, Gray LE, Jr. (2007) Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. <em>Toxicol Sci</em> <strong>99:</strong> 190-202</a></p><p><a name="_ENREF_18">Ipulan LA, Suzuki K, Sakamoto Y, Murashima A, Imai Y, Omori A, Nakagata N, Nishinakamura R, Valasek P, Yamada G (2014) Nonmyocytic androgen receptor regulates the sexually dimorphic development of the embryonic bulbocavernosus muscle. <em>Endocrinology</em> <strong>155:</strong> 2467-2479</a></p><p><a name="_ENREF_19">Jarfelt K, Dalgaard M, Hass U, Borch J, Jacobsen H, Ladefoged O (2005) Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. <em>Reprod Toxicol</em> <strong>19:</strong> 505-515</a></p><p><a name="_ENREF_20">Jost A (1953) Problems of fetal endocrinology: The gonadal and hypophyseal hormones. <em>Recent Prog Horm Res</em> <strong>8:</strong> 379-418</a></p><p><a name="_ENREF_21">Juul A, Almstrup K, Andersson AM, Jensen TK, Jorgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebaek NE (2014) Possible fetal determinants of male infertility. <em>Nat Rev Endocrinol</em> <strong>10:</strong> 553-562</a></p><p><a name="_ENREF_22">Kita DH, Meyer KB, Venturelli AC, Adams R, Machado DL, Morais RN, Swan SH, Gennings C, Martino-Andrade AJ (2016) Manipulation of pre and postnatal androgen environments and anogenital distance in rats. <em>Toxicology</em> <strong>368-369:</strong> 152-161</a></p><p><a name="_ENREF_23">Laier P, Metzdorff SB, Borch J, Hagen ML, Hass U, Christiansen S, Axelstad M, Kledal T, Dalgaard M, McKinnell C, Brokken LJ, Vinggaard AM (2006) Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz. <em>Toxicol Appl Pharmacol</em> <strong>213:</strong> 2</a></p><p><a name="_ENREF_24">Li M, Qiu L, Zhang Y, Hua Y, Tu S, He Y, Wen S, Wang Q, Wei G (2013) Dose-related effect by maternal exposure to di-(2-ethylhexyl) phthalate plasticizer on inducing hypospadiac male rats. <em>Environ Toxicol Pharmacol</em> <strong>35:</strong> 55-60</a></p><p><a name="_ENREF_25">Lin H, Lian QQ, Hu GX, Jin Y, Zhang Y, Hardy DO, Chen GR, Lu ZQ, Sottas CM, Hardy MP, Ge RS (2009) In utero and lactational exposures to diethylhexyl-phthalate affect two populations of Leydig cells in male Long-Evans rats. <em>Biol Reprod</em> <strong>80:</strong> 882-888</a></p><p><a name="_ENREF_26">Loeffler IK, Peterson RE (1999) Interactive effects of TCDD and p,p'-DDE on male reproductive tract development in in utero and lactationally exposed rats. <em>Toxicol Appl Pharmacol</em> <strong>154:</strong> 28-39</a></p><p><a name="_ENREF_27">MacLeod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, Drake AJ, van den Driesche S (2010) Androgen action in the masculinization programming window and development of male reproductive organs. <em>Int J Androl</em> <strong>33:</strong> 279-287</a></p><p><a name="_ENREF_28">Matsuura I, Saitoh T, Ashina M, Wako Y, Iwata H, Toyota N, Ishizuka Y, Namiki M, Hoshino N, Tsuchitani M (2005) Evaluation of a two-generation reproduction toxicity study adding endpoints to detect endocrine disrupting activity using vinclozolin. <em>J Toxicol Sci</em> <strong>30 Spec No:</strong> 163-168</a></p><p><a name="_ENREF_29">McIntyre BS, Barlow NJ, Foster PM (2001) Androgen-mediated development in male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues. <em>Toxicol Sci</em> <strong>62:</strong> 236-249</a></p><p><a name="_ENREF_30">McIntyre BS, Barlow NJ, Sar M, Wallace DG, Foster PM (2002) Effects of in utero linuron exposure on rat Wolffian duct development. <em>Reprod Toxicol</em> <strong>16:</strong> 131-139</a></p><p><a name="_ENREF_31">Melching-Kollmuss S, Fussell KC, Schneider S, Buesen R, Groeters S, Strauss V, van Ravenzwaay B (2017) Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz. <em>Arch Toxicol</em> <strong>91:</strong> 143-162</a></p><p><a name="_ENREF_32">Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE (2001) Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate. <em>Environ Health Perspect</em> <strong>109:</strong> 229-237</a></p><p><a name="_ENREF_33">Mylchreest E, Sar M, Cattley RC, Foster PM (1999) Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. <em>Toxicol Appl Pharmacol</em> <strong>156:</strong> 81-95</a></p><p><a name="_ENREF_34">Nagao T, Ohta R, Marumo H, Shindo T, Yoshimura S, Ono H (2000) Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study. <em>Reprod Toxicol</em> <strong>14:</strong> 513-532</a></p><p><a name="_ENREF_35">Nardelli TC, Albert O, Lalancette C, Culty M, Hales BF, Robaire B (2017) In utero and lactational exposure study in rats to identify replacements for di(2-ethylhexyl) phthalate. <em>Sci Rep</em> <strong>7:</strong> 3862</a></p><p><a name="_ENREF_36">Noriega NC, Ostby J, Lambright C, Wilson VS, Gray LE, Jr. (2005) Late gestational exposure to the fungicide prochloraz delays the onset of parturition and causes reproductive malformations in male but not female rat offspring. <em>Biol Reprod</em> <strong>72:</strong> 1324-1335</a></p><p><a name="_ENREF_37">OECD. (2013) Guidance document in support of the test guideline on the extended one generation reproductive toxicity study No. 151.</a></p><p><a name="_ENREF_38">Ostby J, Kelce WR, Lambright C, Wolf CJ, Mann P, Gray CLJ (1999) The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-receptor antagonist in vivo and in vitro. <em>Toxicol Ind Health</em> <strong>15:</strong> 80-93</a></p><p><a name="_ENREF_39">Saillenfait AM, Gallissot F, Sabaté JP (2009a) Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats. <em>J Appl Toxicol</em> <strong>29:</strong> 510-521</a></p><p><a name="_ENREF_40">Saillenfait AM, Roudot AC, Gallissot F, Sabaté JP (2011) Prenatal developmental toxicity studies on di-n-heptyl and di-n-octyl phthalates in Sprague-Dawley rats. <em>Reprod Toxicol</em> <strong>32:</strong> 268-276</a></p><p><a name="_ENREF_41">Saillenfait AM, Sabaté JP, Gallissot F (2009b) Effects of in utero exposure to di-n-hexyl phthalate on the reproductive development of the male rat. <em>Reprod Toxicol</em> <strong>28:</strong> 468-476</a></p><p><a name="_ENREF_42">Salazar-Martinez E, Romano-Riquer P, Yanez-Marquez E, Longnecker MP, Hernandez-Avila M (2004) Anogenital distance in human male and female newborns: a descriptive, cross-sectional study. <em>Environ Health</em> <strong>3:</strong> 8</a></p><p><a name="_ENREF_43">Schneider S, Kaufmann W, Strauss V, van Ravenzwaay B (2011) Vinclozolin: a feasibility and sensitivity study of the ILSI-HESI F1-extended one-generation rat reproduction protocol. <em>Regulatory Toxicology and Pharmacology</em> <strong>59:</strong> 91-100</a></p><p><a name="_ENREF_44">Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T (2019) Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. <em>Arch Toxicol</em> <strong>93:</strong> 253-272</a></p><p><a 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<strong>68:</strong> 174-183</a></p><p><a name="_ENREF_49">Tyl RW, Myers CB, Marr MC, Fail PA, Seely JC, Brine DR, Barter RA, Butala JH (2004) Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. <em>Reprod Toxicol</em> <strong>18:</strong> 241-264</a></p><p><a name="_ENREF_50">Van den Driesche S, Kolovos P, Platts S, Drake AJ, Sharpe RM (2012) Inter-relationship between testicular dysgenesis and Leydig cell function in the masculinization programming window in the rat. <em>PloS one</em> <strong>7:</strong> e30111</a></p><p><a name="_ENREF_51">Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. <em>J Clin Invest</em> <strong>118:</strong> 1479-1490</a></p><p><a name="_ENREF_52">Welsh M, Saunders PT, Sharpe RM (2007) The critical time window for androgen-dependent development of the Wolffian duct in the rat. <em>Endocrinology</em> <strong>148:</strong> 3185-3195</a></p><p><a name="_ENREF_53">Wolf CJ, LeBlanc GA, Gray LE, Jr. (2004) Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat. <em>Toxicol Sci</em> <strong>78:</strong> 135-143</a></p><p><a name="_ENREF_54">Wolf CJJ, Lambright C, Mann P, Price M, Cooper RL, Ostby J, Gray CLJ (1999) Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. <em>Toxicol Ind Health</em> <strong>15:</strong> 94-118</a></p><p><a name="_ENREF_55">Zhang L, Dong L, Ding S, Qiao P, Wang C, Zhang M, Zhang L, Du Q, Li Y, Tang N, Chang B (2014) Effects of n-butylparaben on steroidogenesis and spermatogenesis through changed E₂ levels in male rat offspring. <em>Environ Toxicol Pharmacol</em> <strong>37:</strong> 705-717</a></p><br><!-- end event text --></div><h2>Appendix 2</h2><h2>List of Key Event Relationships in the AOP</h2><!-- Evidence for relationship links section, this lists the relationships and then supports them --><div id="evidence_supporting_links"><hr><h3>List of Adjacent Key Event Relationships</h3><div><h4><a href="/relationships/1880">Relationship: 1880: 5α-reductase, inhibition leads to Decrease, DHT level</a></h4><h4>AOPs Referencing Relationship</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP Name</th><th>Adjacency</th><th>Weight of Evidence</th><th>Quantitative Understanding</th></tr></thead><tbody><tr><th><a href="/aops/289">Inhibition of 5α-reductase leading to impaired fecundity in female fish</a></th><th>adjacent</th><th>High </th><th>High</th></tr><tr><th><a href="/aops/305">5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th><th>adjacent</th><th>High </th><th>High</th></tr></tbody></table></div><!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed --><!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>--><!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>--><!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>--><!--<h3>Domain of Applicability</h3>--><!--<!%== aop_rel.relationship.taxon_evidence %>--><!--<!% end %>--><!--<!% end %>--></div><br><div><h4><a href="/relationships/1935">Relationship: 1935: Decrease, DHT level leads to Decrease, AR activation</a></h4><h4>AOPs Referencing Relationship</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP Name</th><th>Adjacency</th><th>Weight of Evidence</th><th>Quantitative Understanding</th></tr></thead><tbody><tr><th><a href="/aops/288">Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)</a></th><th>adjacent</th><th>High </th><th>High</th></tr><tr><th><a href="/aops/307">Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th><th>adjacent</th><th>High </th><th>Moderate</th></tr><tr><th><a href="/aops/305">5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th><th>adjacent</th><th>High </th><th>Moderate</th></tr></tbody></table></div><!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed --><!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>--><!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>--><!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>--><!--<h3>Domain of Applicability</h3>--><!--<!%== aop_rel.relationship.taxon_evidence %>--><!--<!% end %>--><!--<!% end %>--></div><br><div><h4><a href="/relationships/2128">Relationship: 2128: Decrease, AR activation leads to decrease, transcription of genes by AR </a></h4><h4>AOPs Referencing Relationship</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP Name</th><th>Adjacency</th><th>Weight of Evidence</th><th>Quantitative Understanding</th></tr></thead><tbody><tr><th><a href="/aops/305">5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th><th>adjacent</th><th>Moderate </th><th>Low</th></tr><tr><th><a href="/aops/306">Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th><th>adjacent</th><th>High </th><th>Moderate</th></tr></tbody></table></div><h4>Evidence Supporting Applicability of this Relationship</h4><br><!-- loop to find taxonomic applicability under relationship --><div><strong>Taxonomic Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Term</th><th>Scientific Term</th><th>Evidence</th><th>Links</th></tr></thead><tbody><tr><td>human</td><td>Homo sapiens</td><td>High</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a></td></tr><tr><td>mouse</td><td>Mus musculus</td><td>High</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" , target="_blank">NCBI</a></td></tr><tr><td>human and other cells in culture</td><td>human and other cells in culture</td><td>High</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" , target="_blank">NCBI</a></td></tr><tr><td>rat</td><td>Rattus norvegicus</td><td>High</td><td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" , target="_blank">NCBI</a></td></tr></tbody></table></div></div><!-- end loop for taxons --><!-- loop to find life stages under relationship --><div><strong>Life Stage Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Life Stage</th><th>Evidence</th></tr></thead><tbody><tr><td>During development and at adulthood</td><td>High</td></tr></tbody></table></div></div><!-- end loop for life stages --><!-- sex terms --><div><strong>Sex Applicability</strong><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>Sex</th><th>Evidence</th></tr></thead><tbody><tr><td>Male</td><td>High</td></tr><tr><td>Female</td><td>High</td></tr></tbody></table></div></div><!-- end sex terms --><!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed --><!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>--><!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>--><!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>--><!--<h3>Domain of Applicability</h3>--><!--<!%== aop_rel.relationship.taxon_evidence %>--><!--<!% end %>--><!--<!% end %>--></div><br><div><h4><a href="/relationships/2129">Relationship: 2129: decrease, transcription of genes by AR leads to short male AGD</a></h4><h4>AOPs Referencing Relationship</h4><div class="panel panel-default"><table class="table table-bordered table-striped"><thead><tr><th>AOP Name</th><th>Adjacency</th><th>Weight of Evidence</th><th>Quantitative Understanding</th></tr></thead><tbody><tr><th><a href="/aops/305">5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th><th>adjacent</th><th>Moderate </th><th>Low</th></tr><tr><th><a href="/aops/306">Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring</a></th><th>adjacent</th><th>Moderate </th><th>Low</th></tr></tbody></table></div><!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed --><!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>--><!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>--><!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>--><!--<h3>Domain of Applicability</h3>--><!--<!%== aop_rel.relationship.taxon_evidence %>--><!--<!% end %>--><!--<!% end %>--></div><br></div><!-- end relationship loop --></div></div></div></div><footer class="footer"><div class="navbar navbar-fixed-bottom navbar-inverse"><div class="container"><ul class="nav navbar-nav"><li ><a href="/info_pages/2">Help</a></a></li><li ><a href="/info_pages/3">About</a></a></li><li ><a href="/info_pages/4">FAQ</a></a></li><li ><a href="/info_pages/5">Downloads</a></a></li><li><a href="/metrics_summary">Metrics </a></li></ul></div></div><br /><br /><br 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