<td>Under development: Not open for comment. Do not cite</td>
<td>Under Development: Contributions and Comments Welcome</td>
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<td>1.29</td>
<td>Under Development</td>
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<h2>Abstract</h2>
<p>During sexual differentiation and gonadal development in utero or in ovo, androgenic tissues develop, in part, under the control of testosterone (Viger et al. 2005). Reduction of circulating testosterone during this crucial time of development can result in malformed reproductive tracts in males. Exposure to drugs (e.g., statins) or other compounds may cause male reproductive tract abnormalities by inhibiting HMG-CoA reductase, which is the rate-limiting enzyme in the production of cholesteron, the precursor of testosterone.</p>
<h2>Abstract</h2>
<hr>
<p>During sexual differentiation and gonadal development in utero or in ovo, androgenic tissues develop, in part, under the control of testosterone (Viger et al. 2005). Reduction of circulating testosterone during this crucial time of development can result in malformed reproductive tracts in males. Exposure to drugs (e.g., statins) or other compounds may cause male reproductive tract abnormalities by inhibiting HMG-CoA reductase, which is the rate-limiting enzyme in the production of cholesteron, the precursor of testosterone.
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<h2>Overall Assessment of the AOP</h2>
<p>This AOP was developed primarily from one study of exposure of rats in utero to simvastatin (as well as a phthalate ester; Beverley et al., 2015) and biological plausibility. It currently should be considered putative and untested.
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<p>This AOP was developed primarily from one study of exposure of rats in utero to simvastatin (as well as a phthalate ester; Beverley et al., 2015) and biological plausibility. It currently should be considered putative and untested.</p>
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<h2>References</h2>
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<p>Beverly, B. E. J., et al. (2014). "Simvastatin and Dipentyl Phthalate Lower Ex Vivo Testicular Testosterone Production and Exhibit Additive Effects on Testicular Testosterone and Gene Expression Via Distinct Mechanistic Pathways in the Fetal Rat." Toxicological Sciences.
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<p>Beverly, B. E. J., et al. (2014). "Simvastatin and Dipentyl Phthalate Lower Ex Vivo Testicular Testosterone Production and Exhibit Additive Effects on Testicular Testosterone and Gene Expression Via Distinct Mechanistic Pathways in the Fetal Rat." Toxicological Sciences.</p>
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<h4>How it is Measured or Detected</h4>
<p>The activity of HMG-CoA reductase inhibition may be measured by a commercially available kit which measures a decrease in absorbance at 340 nm, which represents the oxidation of NADPH by the catalytic subunit of HMGR in the presence of the substrate HMG-CoA. Sterol Regulatory element-binding factor 1 (SREBF) is the transcription factor controlling downstream regulation of HMG-CoA reductase. The ToxCast assay ATG_SREBF1_CIS_up is one method of measuring transcriptional control of HMG-CoA reductase.
<h4>How it is Measured or Detected</h4>
<p>The activity of HMG-CoA reductase inhibition may be measured by a commercially available kit which measures a decrease in absorbance at 340 nm, which represents the oxidation of NADPH by the catalytic subunit of HMGR in the presence of the substrate HMG-CoA. Sterol Regulatory element-binding factor 1 (SREBF) is the transcription factor controlling downstream regulation of HMG-CoA reductase. The ToxCast assay ATG_SREBF1_CIS_up is one method of measuring transcriptional control of HMG-CoA reductase.
<p>Taxonomic Applicability: Cholesterol is synthesized in plants but acts as a precursor for different products than in animals (Sonawane et al. 2016). Within the animal kingdom most deuterostomes (including vertebrata, cyclostomata, cephalochordate, and echinodermata, but not chordata) possess the genes necessary for cholesterol biosynthesis. However, most protostomes (including arthropoda and nematomorpha) have lost these genes (Zhang et al., 2019). Thus far vertebrates are the primary consideration for this KE.</p>
<p>Lifestage Applicability: Cholesterol can be measured in organisms at all life stages. However, the size of young organisms may limit the ability to collect plasma for cholesterol analysis. Whole-body measurements or pooled samples may be more feasible.</p>
<p>Sex Applicability: Cholesterol measurements are applicable for all sexes</p>
<h4>Key Event Description</h4>
<p>Most cholesterol synthesis in vertebrates occurs within the endoplasmic reticulum of hepatic cells. First, acetyl-CoA is converted to HMG-CoA via HMG-CoA synthase. Next, HMG-CoA is converted to mevalonate via HMG-CoA reductase. Several other steps follow, but conversion of HMG-CoA to mevalonate is the rate-limiting step of cholesterol synthesis (Cerqueira et al. 2016; Risley 2002). Consequently, Statin drugs inhibit HMG-CoA reductase to reduce cholesterol (Pahan 2006).</p>
<p>Cholesterol synthesis may also occur to a limited extent in steroidogenic cells where it’s used to produce steroid hormones (Azhar et al., 2007)</p>
<p>Once cholesterol is produced in the liver, it’s transported in the plasma. Hydrophobic lipids like cholesterol, cholesteryl ester (a cholesterol molecule bound to a fatty acid), and triglycerides are transported via lipoprotein complexes. There are different groups of lipoproteins which use different proteins and ratios of lipids including high-density lipoprotein (HDL), low-density (LDL), and very low-density (VLDL).</p>
<p>Commerical assay kits are available for measuring cholesterol using either colorimetric or fluorometric detection. Total cholesterol assay kits often include cholesteryl esters in the measurement (<a href="https://www.cellbiolabs.com/total-cholesterol-assay-kit">Cell Bio Labs</a>, <a href="https://www.thermofisher.com/order/catalog/product/A12216#/A12216">ThermoFisher</a>). Additional kits are availalbe for measuring the cholesterol in the different lipoprotein complexes (<a href="https://www.cellbiolabs.com/hdl-and-ldlvldl-cholesterol-assay-kit">Cell Bio Labs</a>). </p>
<p>Oil Red O staining can be used for organisms such as zebrafish larvae that are clear, however it stains triglycerides and lipids not just cholesterol (Zhou et al., 2015). </p>
<p>Plasma cholesterol is a common clinical measurement in humans and the Abell-Kendall technique is the standard chemical determination method (Cox et al. 1990), although there are a wide variety of viable methods.</p>
<h4>References</h4>
<p>Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) “Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (<em>Danio rerio</em>)”, <em>Comparative Biochemistry and Physiology, Part B, </em>Vol. 199, Elsevier, pp. 87-96. http://dx.doi.org/10.1016/j.cbpb.2015.11.009</p>
<p>Azhar, S., E. Reaven (2007) “Regulation of Leydig cell cholesterol metabolism”, in A.H. Payne, M.P. Hardy (eds.) <em>The Leydig Cell in Health and Disease, </em>Humana Press. https://doi.org/10.1007/978-1-59745-453-7</p>
<p>Cox RA, García-Palmieri MR. Cholesterol, Triglycerides, and Associated Lipoproteins. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 31. Available from: https://www.ncbi.nlm.nih.gov/books/NBK351/</p>
<p>Dai, W. et al. (2015) "High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs", <em>Nutrition and Metabolism</em>, Vol. 12(42), Springer Nature. DOI 10.1186/s12986-015-0036-z </p>
<p>Du, Z.Y. et al. (2008) “Hypolipidaemic effect of fenofibrate and fasting in the herbivorous grass carp (<em>Ctenopharyngodon idella) </em>fed a high-fat diet”, <em>British Journal of Nutrition, </em>Vol. 100, Cambridge University Press, pp. 1200-1212. doi:10.1017/S0007114508986840</p>
<p>Guo, X. et al. (2015) “Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (<em>Ctenopharyngodon idellal </em>Val.) fed with the high non-protein energy diets”, <em>Fish Physiology and Biochemistry, </em>Vol. 41, Springer, pp. 331-343. doi: 10.1007/s10695-014-9986-8</p>
<p>Cerqueira, N. M., Oliveira, E. F., Gesto, D. S., Santos-Martins, D., Moreira, C., Moorthy, H. N., ... & Fernandes, P. A. (2016). Cholesterol biosynthesis: a mechanistic overview. <em>Biochemistry</em>, <em>55</em>(39), 5483-5506.</p>
<p>Prindiville, J.S. et al. (2011) “The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout”, <em>Toxicology and Applied Pharmacology, </em>Vol. 251, Elsevier, pp. 201-238. doi:10.1016/j.taap.2010.12.013</p>
<p>Pahan, K. (2006). Lipid-lowering drugs. <em>Cellular and molecular life sciences CMLS</em>, <em>63</em>(10), 1165-1178.</p>
<p>Risley, J. M. (2002). Cholesterol biosynthesis: Lanosterol to cholesterol. <em>Journal of chemical education</em>, <em>79</em>(3), 377.</p>
<p>Velasco-Santamaría, Y.M. et al. (2011) “Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (<em>Danio rerio</em>)”, <em>Aquatic Toxicology, </em>Vol. 105, Elsevier, pp. 107-118. doi:10.1016/j.aquatox.2011.05.018</p>
<p>Zhang, T. et al. (2019) “Evolution of the cholesterol biosynthesis pathway in animals”, <em>Molecular Biology and Evolution, </em>Vol. 36(11), Oxford University Press, pp. 2548-2556. doi:10.1093/molbev/msz167</p>
<p>Zhou, J. et al. (2015) "Rapid analysis of hypolipidemic drugs in a live zebrafish assay", <em>Journal of Pharmacological and Toxicological Methods, </em>Vol. 72, Elsevier, pp. 47-52. http://dx.doi.org/10.1016/j.vascn.2014.12.002</p>
<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/526">Aop:526 - Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) leads to Impaired, Spermatogenesis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/124">Aop:124 - HMG-CoA reductase inhibition leading to decreased fertility</a></td>
<td>KeyEvent</td>
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<tr>
<td><a href="/aops/18">Aop:18 - PPARα activation in utero leading to impaired fertility in males</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/51">Aop:51 - PPARα activation leading to impaired fertility in adult male rodents </a></td>
<td>KeyEvent</td>
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<tr>
<td><a href="/aops/496">Aop:496 - Androgen receptor agonism leading to reproduction dysfunction （in zebrafish）</a></td>
<td>KeyEvent</td>
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<tr>
<td><a href="/aops/64">Aop:64 - Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/120">Aop:120 - Inhibition of 5α-reductase leading to Leydig cell tumors (in rat)</a></td>
<td>KeyEvent</td>
</tr>
<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>
<p style="text-align:justify">This KE is applicable to mammals since the role of testosterone and its synthesis are conserved (Vitousek et al., 2018). Both sexes need, and produce, testosterone and its role is observed throughout different life stages, from development to adulthood (Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022). Therefore, this KE is also applicable to both males and females as well as throughout these life stages. Also of note, key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, it is acknowledged that this KE most likely has a much broader domain of applicability extending to non-mammalian vertebrates. AOP developers are encouraged to add additional relevant knowledge to expand on the applicability beyond mammals to other vertebrates.</p>
<p style="text-align:justify">Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates, including humans.</p>
<h4>Key Event Description</h4>
<p style="text-align:justify"><span style="font-size:11pt">Testosterone is an endogenous steroid hormone and a potent androgen. Androgens act by binding androgen receptors in androgen-responsive tissues <span style="color:black">(Murashima et al., 2015)</span>. Testosterone and other androgens such as dihydrotestosterone (DHT) are important for reproductive development and masculinization of the fetus. <span style="font-family:Aptos,sans-serif">Androgens are also important for bone, brain, muscle and skin health <span style="color:black">(Alemany, 2022)</span>. Just like other steroid hormones, testosterone is produced through a process known as steroidogenesis which is controlled by enzymes converting cholesterol into all of the downstream steroid hormones.</span> In steroidogenesis, androstenedione or androstenediol is converted to testosterone by the enzymes 17β-hydroxysteroid dehydrogenase (HSD) or 3β-HSD, respectively. Testosterone can then be converted to the more potent androgen, DHT, by 5α-reductase, or aromatized by aromatase (CYP19A1) into estrogens. <span style="font-family:Aptos,sans-serif"><span style="font-family:"Verdana",sans-serif">Testosterone secreted in blood circulation can be found free but more frequently is found bound to SHBG or albumin (Trost & Mulhall, 2016). </span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Verdana",sans-serif">Testosterone is produced mainly by the ovaries (in females ), testes (in males), and to a lesser degree in the adrenal glands. During fetal development testosterone plays a crucial role in the differentiation of male reproductive tissues and the overall male phenotype. In adulthood, testosterone synthesis is controlled by the Hypothalamus-Pituitary-Gonadal (HPG) axis. GnRH is released from the hypothalamus inducing LH pulses secreted by the anterior pituitary. This LH surge leads to increased testosterone production. If testosterone reaches low levels, this axis is once again stimulated to provoke more testosterone synthesis. This feedback loop is essential for maintenance of appropriate testosterone levels (Chandrashekar & Bartke, 1998; Ellis et al., 1983; Rey, 2021).</span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt">Disruption of any of the aforementioned processes may result in reduced testosterone levels, such as inhibition of steroidogenic enzyme activity thereby inhibiting production of testosterone. </span></p>
<p><strong>General role in biology</strong></p>
<p>Androgens, the main male sex steroids, are the critical factors responsible for the development of the male phenotype during embryogenesis and for the achievement of sexual maturation at puberty. In adulthood, androgens remain essential for the maintenance of male reproductive function and behaviour. Apart from their effects on reproduction, androgens affect a wide variety of non-reproductive tissues such as skin, bone, muscle, and brain (Heemers, Verhoeven, & Swinnen, 2006). Androgens, principally T and 5α-dihydrotestosterone (DHT), exert most of their effects by interacting with a specific receptor, the androgen receptor (AR), for review see (Murashima, Kishigami, Thomson, & Yamada, 2015). On the one hand, testosterone can be reduced by 5α-reductase to produce 5α dihydrotestosterone (DHT). On the other hand, testosterone can be aromatized to generate estrogens. Testosterone effects can also be classified by the age of usual occurrence, postnatal effects in both males and females are mostly dependent on the levels and duration of circulating free testosterone.</p>
<h4>How it is Measured or Detected</h4>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Verdana",sans-serif">Quantification of testosterone levels can be performed by various means (e.g. serum levels in vivo, cell culture medium levels in vitro, tissue ex vivo or in vitro). Traditional immunoassay methods (ELISA or RIA), and advanced instrumental techniques (e.g. LC-MS/MS) or liquid scintillation spectrometry (after radiolabeling) can be used (Shiraishi et al., 2008).</span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Aptos,sans-serif"><span style="font-family:"Verdana",sans-serif">The H295R Steroidogenesis assay (OECD TG 456) is used to measure mainly the production of estradiol and testosterone. This is a validated OECD test guideline using adrenal H295R cells and hormone levels are then measured in the cell medium (OECD 2011). H295R adrenocortical carcinoma cells produce all the main enzymes and hormones of the steroidogenic pathway. Therefore, exposure to different stressors allows for broad analysis of their impact on steroidogenesis by measuring hormones in culture medium by LC-MS/MS. H295 assay was designed measure disruption to testosterone or estradiol levels but can now also be used to measure additional steroid hormones such as progesterone or pregnenolone. The U.S. EPA’s ToxCast program developed a high throughput method for the H295R assay which can measure a total of 11 hormones from the steroidogenesis pathway (Haggard et al., 2018). The H295R can be considered an indirect measurement as it provides information on a disruption of overall steroidogenesis that would result in a change of testosterone levels but not the underlying mechanism. </span></span></span></p>
<p style="text-align:justify">Testosterone can be measured by immunoassays and by isotope-dilution gas chromatography-mass spectrometry in serum (Taieb et al., 2003), (Paduch et al., 2014). Testosterone levels are measured i.a. in: Fish Lifecycle Toxicity Test (FLCTT) (US EPA OPPTS 850.1500), Male pubertal assay (PP Male Assay) (US EPA OPPTS 890.1500), OECD TG 441: Hershberger Bioassay in Rats (H Assay).</p>
<h4>References</h4>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Alemany, M. (2022). The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health. <em>International Journal of Molecular Sciences</em>, <em>23</em>(19), 11952. https://doi.org/10.3390/ijms231911952</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Baker, M.E. (2011). Insights from the structure of estrogen receptor into the evolution of estrogens: implications for endocrine disruption. <em>Biochem Pharmacol</em>, 82(1), 1-8.</span></span> <span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"><a href="https://doi.org/10.1016/j.bcp.2011.03.008" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/j.bcp.2011.03.008</a></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Chandrashekar, V., & Bartke, A. (1998). The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats*. <em>Endocrinology</em>, <em>139</em>(3), 1067–1074. https://doi.org/10.1210/endo.139.3.5816</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Ellis, G. B., Desjardins, C., & Fraser, H. M. (1983). Control of Pulsatile LH Release in Male Rats. <em>Neuroendocrinology</em>, <em>37</em>(3), 177–183. https://doi.org/10.1159/000123540</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Haggard, D. E., Karmaus, A. L., Martin, M. T., Judson, R. S., Setzer, R. W., & Paul Friedman, K. (2018). High-Throughput H295R Steroidogenesis Assay: Utility as an Alternative and a Statistical Approach to Characterize Effects on Steroidogenesis. <em>Toxicological Sciences</em>, <em>162</em>(2), 509–534. https://doi.org/10.1093/toxsci/kfx274</span></span></p>
<p>Heemers, H. V, Verhoeven, G., & Swinnen, J. V. (2006). Androgen activation of the sterol regulatory element-binding protein pathway: Current insights. Molecular Endocrinology (Baltimore, Md.), 20(10), 2265–77. doi:10.1210/me.2005-0479</p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Luetjens, C. M., & Weinbauer, G. F. (2012). Testosterone: biosynthesis, transport, metabolism and (non-genomic) actions. In <em>Testosterone</em> (pp. 15–32). Cambridge University Press. https://doi.org/10.1017/CBO9781139003353.003</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Murashima, A., Kishigami, S., Thomson, A., & Yamada, G. (2015). Androgens and mammalian male reproductive tract development. <em>Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms</em>, <em>1849</em>(2), 163–170. https://doi.org/10.1016/j.bbagrm.2014.05.020</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Naamneh Elzenaty, R., du Toit, T., & Flück, C. E. (2022). Basics of androgen synthesis and action. <em>Best Practice & Research Clinical Endocrinology & Metabolism</em>, <em>36</em>(4), 101665. https://doi.org/10.1016/j.beem.2022.101665</span></span></p>
<p>Paduch, D. A., Brannigan, R. E., Fuchs, E. F., Kim, E. D., Marmar, J. L., & Sandlow, J. I. (2014). The laboratory diagnosis of testosterone deficiency. Urology, 83(5), 980–8. doi:10.1016/j.urology.2013.12.024</p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Rey, R. A. (2021). The Role of Androgen Signaling in Male Sexual Development at Puberty. <em>Endocrinology</em>, <em>162</em>(2). https://doi.org/10.1210/endocr/bqaa215</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Shiraishi, S., Lee, P. W. N., Leung, A., Goh, V. H. H., Swerdloff, R. S., & Wang, C. (2008). Simultaneous Measurement of Serum Testosterone and Dihydrotestosterone by Liquid Chromatography–Tandem Mass Spectrometry. <em>Clinical Chemistry</em>, <em>54</em>(11), 1855–1863. https://doi.org/10.1373/clinchem.2008.103846</span></span></p>
<p>Taieb, J., Mathian, B., Millot, F., Patricot, M.-C., Mathieu, E., Queyrel, N., … Boudou, P. (2003). Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clinical Chemistry, 49(8), 1381–95.</p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Trost, L. W., & Mulhall, J. P. (2016). Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials. <em>The Journal of Sexual Medicine</em>, <em>13</em>(7), 1029–1046. https://doi.org/10.1016/j.jsxm.2016.04.068</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Vitousek, M. N., Johnson, M. A., Donald, J. W., Francis, C. D., Fuxjager, M. J., Goymann, W., Hau, M., Husak, J. F., Kircher, B. K., Knapp, R., Martin, L. B., Miller, E. T., Schoenle, L. A., Uehling, J. J., & Williams, T. D. (2018). HormoneBase, a population-level database of steroid hormone levels across vertebrates. <em>Scientific Data</em>, <em>5</em>(1), 180097. https://doi.org/10.1038/sdata.2018.97</span></span></p>
<h4><a href="/events/809">Event: 809: malformed, Male reproductive tract</a></h4>
<h5>Short Name: malformed, Male reproductive tract</h5>