<p>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>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>
<br>
</div>
<!-- event text -->
<h4>Key Event Description</h4>
<p><b>Biological state</b>
<h4>Key Event Description</h4>
<p><b>Biological state</b>
</p><p>Testosterone is a steroid hormone from the androgen group and is found in humans and other vertebrates.
</p><p><b>Biological compartments</b>
</p><p>In humans and other mammals, testosterone is secreted primarily by the testicles of males and, to a lesser extent, the ovaries of females and other steroidogenic tissues (e.g., brain, adipose). It either acts locally /or is transported to other tissues via blood circulation. Testosterone synthesis takes place within the mitochondria of Leydig cells, the testosterone-producing cells of the testis. It is produced upon stimulation of these cells by Luteinizing hormone (LH) that is secreted in pulses into the peripheral circulation by the pituitary gland in response to Gonadotropin-releasing hormone (GnRH) from the hypothalamus. Testosterone and its aromatized product, estradiol, feed back to the hypothalamus and pituitary gland to suppress transiently LH and thus testosterone production. In response to reduced testosterone levels, GnRH and LH are produced. This negative feedback cycle results in pulsatile secretion of LH followed by pulsatile production of testosterone (Ellis, Desjardins, and Fraser 1983), (Chandrashekar and Bartke 1998).
</p><p><b>General role in biology</b>
</p><p>Testosterone is the principal male sex hormone and an anabolic steroid. Male sexual differentiation depends on testosterone (T), dihydrotestosterone (DHT), and the expression of androgen receptors by target cells (Manson and Carr 2003). During the development secretion of androgens by Leydig cells is essential for masculinization of the foetus (Nef 2000).
The foetal Leydig cells develop in utero. These cells become competent to produce testosterone in rat by gestational day (GD) 15.5, with increasing production thereafter. Peak steroidogenic activity is reached just prior to birth, on GD19 (Chen, Ge, and Zirkin 2009). Testosterone secreted by foetal Leydig cells is required for the differentiation of the male urogenital system late in gestation (Huhtaniemi and Pelliniemi 1992). Foetal Leydig cells also play a role in the scrotal descent of the testis through their synthesis of insulin-like growth factor 3 (Insl3), for review see (Nef 2000).
</p><p>In humans, the first morphological sign of testicular differentiation is the formation of testicular cords, which can be seen between 6 and 7 weeks of gestation. Steroid-secreting Leydig cells can be seen in the testis at 8 weeks of gestation. At this period, the concentration of androgens in the testicular tissue and blood starts to rise, peaking at 14-16 weeks of gestation. This increase comes with an increase in the number of Leydig cells for review see (Rouiller-Fabre et al. 2009).
</p><p>Adult Leydig cells, which are distinct from the foetal Leydig cells, form during puberty and supply the testosterone required for the onset of spermatogenesis, among other functions. Distinct stages of adult Leydig cell development have been identified and characterized. The stem Leydig cells are undifferentiated cells that are capable of indefinite self-renewal but also of differentiation to steroidogenic cells. These cells give rise to progenitor Leydig cells, which proliferate, continue to differentiate, and give rise to the immature Leydig cells. Immature Leydig cells synthesize high levels of testosterone metabolites and develop into terminally differentiated adult Leydig cells, which produce high levels of testosterone. With aging, both serum and testicular testosterone concentrations progressively decline, for review see (Nef 2000).
</p><p>Androgens play a crucial role in the development and maintenance of male reproductive and sexual functions.
Low levels of circulating androgens can cause disturbances in male sexual development, resulting in congenital
abnormalities of the male reproductive tract. Later in life, this may cause reduced fertility, sexual dysfunction,
decreased muscle formation and bone mineralisation, disturbances of fat metabolism, and cognitive
dysfunction. Testosterone levels decrease as a process of ageing: signs and symptoms caused by this decline
can be considered a normal part of ageing.
</p>
<br>
<h4>How it is Measured or Detected</h4>
<p>OECD TG 456 <a rel="nofollow" target="_blank" class="external autonumber" href="http://www.oecd-ilibrary.org/environment/test-no-456-h295r-steroidogenesis-assay_9789264122642-en">[1]</a> is the validated test guideline for an in vitro screen for chemical effects on steroidogenesis, specifically the production of 17ß-estradiol (E2) and testosterone (T).
<h4>How it is Measured or Detected</h4>
<p>OECD TG 456 <a rel="nofollow" target="_blank" class="external autonumber" href="http://www.oecd-ilibrary.org/environment/test-no-456-h295r-steroidogenesis-assay_9789264122642-en">[1]</a> is the validated test guideline for an in vitro screen for chemical effects on steroidogenesis, specifically the production of 17ß-estradiol (E2) and testosterone (T).
The testosterone syntheis can be measured in vitro cultured Leydig cells. The methods for culturing Leydig cells can be found in the Database Service on Alternative Methods to animal experimentation (DB-ALM):
Testicular Organ and Tissue Culture Systems <a rel="nofollow" target="_blank" class="external autonumber" href="http://ecvam-dbalm.jrc.ec.europa.eu/beta/index.cfm/methodsAndProtocols/index?id_met=515">[3]</a>.
</p><p>Testosterone synthesis in vitro cultured cells can be measured indirectly by testosterone radioimmunoassay or analytical methods such as LC-MS.
</p>
<br>
<h4>References</h4>
<p>Chandrashekar, V, and A Bartke. 1998. “The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats.” Endocrinology 139 (3) (March): 1067–74. doi:10.1210/endo.139.3.5816.
<h4>References</h4>
<p>Chandrashekar, V, and A Bartke. 1998. “The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats.” Endocrinology 139 (3) (March): 1067–74. doi:10.1210/endo.139.3.5816.
</p><p>Ellis, G B, C Desjardins, and H M Fraser. 1983. “Control of Pulsatile LH Release in Male Rats.” Neuroendocrinology 37 (3) (September): 177–83.
Huhtaniemi, I, and L J Pelliniemi. 1992. “Fetal Leydig Cells: Cellular Origin, Morphology, Life Span, and Special Functional Features.” Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 201 (2) (November): 125–40.
</p><p>Manson, Jeanne M, and Michael C Carr. 2003. “Molecular Epidemiology of Hypospadias: Review of Genetic and Environmental Risk Factors.” Birth Defects Research. Part A, Clinical and Molecular Teratology 67 (10) (October): 825–36. doi:10.1002/bdra.10084.
</p><p>Nef, S. 2000. “Hormones in Male Sexual Development.” Genes & Development 14 (24) (December 15): 3075–3086. doi:10.1101/gad.843800.
</p><p>Rouiller-Fabre, Virginie, Vincent Muczynski, Romain Lambrot, Charlotte Lécureuil, Hervé Coffigny, Catherine Pairault, Delphine Moison, et al. 2009. “Ontogenesis of Testicular Function in Humans.” Folia Histochemica et Cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society 47 (5) (January): S19–24. doi:10.2478/v10042-009-0065-4.
<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>
</tr>
<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>
</tr>
<tr>
<td><a href="/aops/496">Aop:496 - Androgen receptor agonism leading to reproduction dysfunction （in zebrafish）</a></td>
<td>KeyEvent</td>
</tr>
<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>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
</div>
<!-- end loop for taxons -->
<!-- life stages -->
<div>
</div>
<!-- end life stages -->
<!-- sex terms -->
<div>
</div>
<!-- end sex terms -->
<div>
<p>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>
<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>Testosterone (T) is a steroid hormone from the androgen group. T serves as a substrate for two metabolic pathways that produce antagonistic sex steroids.</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><strong>Biological compartments</strong></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>Testosterone is synthesized by the gonads and other steroidogenic tissues (e.g., brain, adipose), acts locally and/or is transported to other tissues via blood circulation. Leydig cells are the testosterone-producing cells of the testis.</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>
<br>
<h4>How it is Measured or Detected</h4>
<p>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>
<br>
<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>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>
<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>Murashima, A., Kishigami, S., Thomson, A., & Yamada, G. (2015). Androgens and mammalian male reproductive tract development. Biochimica et Biophysica Acta, 1849(2), 163–170. doi:10.1016/j.bbagrm.2014.05.020</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>
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</div>
<div>
<div>
<h4><a href="/events/520">Event: 520: Decreased sperm quantity or quality in the adult, Decreased fertility </a><br></h4>
<h5>Short Name: Decreased sperm quantity or quality in the adult, Decreased fertility </h5>
<td><a href="/aops/7">Aop:7 - Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female</a></td>
<td>AdverseOutcome</td>
</tr>
<tr>
<td><a href="/aops/51">Aop:51 - PPARα activation leading to impaired fertility in adult male rodents </a></td>
<td>AdverseOutcome</td>
</tr>
<tr>
<td><a href="/aops/18">Aop:18 - PPARα activation in utero leading to impaired fertility in males</a></td>
<td>AdverseOutcome</td>
</tr>
<tr>
<td><a href="/aops/64">Aop:64 - Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility</a></td>
<td>AdverseOutcome</td>
</tr>
<tr>
<td><a href="/aops/348">Aop:348 - Inhibition of 11β-Hydroxysteroid Dehydrogenase leading to decreased population trajectory </a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/349">Aop:349 - Inhibition of 11β-hydroxylase leading to decresed population trajectory </a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/396">Aop:396 - Deposition of ionizing energy leads to population decline via impaired meiosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/398">Aop:398 - Inhibition of ALDH1A (RALDH) leading to impaired fertility via disrupted meiotic initiation of fetal oogonia of the ovary</a></td>
<td>AdverseOutcome</td>
</tr>
<tr>
<td><a href="/aops/492">Aop:492 - Glutathione conjugation leading to reproductive dysfunction via oxidative stress</a></td>
<td>AdverseOutcome</td>
</tr>
<tr>
<td><a href="/aops/345">Aop:345 - Androgen receptor (AR) antagonism leading to decreased fertility in females</a></td>
<p><strong>Plausible domain of applicability</strong></p>
<p><strong><em>Taxonomic applicability</em>: </strong>The impaired fertility may also have relevance for fish, mammals, amphibians, reptiles, birds and and invertebrates with sexual reproduction.</p>
<p><strong><em>Life stage applicability</em></strong>: The impaired fertility can be measured at juveniles and adults.</p>
<p><em><strong>Sex applicability</strong></em>: The impaired fertility can be measured in both male and female species. </p>
</div>
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<div>
</div>
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<div>
</div>
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<div>
</div>
<!-- event text -->
<h4>Key Event Description</h4>
<p><strong>Biological state</strong></p>
<h4>Key Event Description</h4>
<p><strong>Biological state</strong></p>
<p>capability to produce offspring</p>
<p><strong>Biological compartments</strong></p>
<p>System</p>
<p><strong>General role in biology</strong></p>
<p>Fertility is the capacity to conceive or induce conception. Impairment of fertility represents disorders of male or female reproductive functions or capacity.</p>
<br>
<h4>How it is Measured or Detected</h4>
<p>As a measure, fertility rate, is the number of offspring born per mating pair, individual or population.</p>
<br>
<h4>How it is Measured or Detected</h4>
<p>As a measure, fertility rate, is the number of offspring born per mating pair, individual or population.</p>
<h4>Regulatory Significance of the AO</h4>
<p>Under REACH, information on reproductive toxicity is required for chemicals with an annual production/importation volume of 10 metric tonnes or more. Standard information requirements include a screening study on reproduction toxicity (OECD TG 421/422) at Annex VIII (10-100 t.p.a), a prenatal developmental toxicity study (OECD 414) on a first species at Annex IX (100-1000 t.p.a), and from March 2015 the OECD 443(Extended One-Generation Reproductive Toxicity Study) is reproductive toxicity requirement instead of the two generation reproductive toxicity study (OECD TG 416). If not conducted already at Annex IX, a prenatal developmental toxicity study on a second species at Annex X (≥ 1000 t.p.a.).</p>
<h4>Regulatory Significance of the AO</h4>
<p>Under REACH, information on reproductive toxicity is required for chemicals with an annual production/importation volume of 10 metric tonnes or more. Standard information requirements include a screening study on reproduction toxicity (OECD TG 421/422) at Annex VIII (10-100 t.p.a), a prenatal developmental toxicity study (OECD 414) on a first species at Annex IX (100-1000 t.p.a), and from March 2015 the OECD 443(Extended One-Generation Reproductive Toxicity Study) is reproductive toxicity requirement instead of the two generation reproductive toxicity study (OECD TG 416). If not conducted already at Annex IX, a prenatal developmental toxicity study on a second species at Annex X (≥ 1000 t.p.a.).</p>
<p>Under the Biocidal Products Regulation (BPR), information is also required on reproductive toxicity for active substances as part of core data set and additional data set (EU 2012, ECHA 2013). As a core data set, prenatal developmental toxicity study (EU TM B.31) in rabbits as a first species and a two-generation reproduction toxicity study (EU TM B.31) are required. OECD TG 443 (Extended One-Generation Reproductive Toxicity Study) shall be considered as an alternative approach to the multi-generation study.) According to the Classification, Labelling and Packaging (CLP) regulation (EC, 200; Annex I: 3.7.1.1): a) “reproductive toxicity” includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring; b) “effects on fertility” includes adverse effects on sexual function and fertility; and c) “developmental toxicity” includes adverse effects on development of the offspring.</p>
<br>
<h4>References</h4>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px">OECD (2001), <em>Test No. 416: Two-Generation Reproduction Toxicity</em>, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, <a href="https://doi.org/10.1787/9789264070868-en">https://doi.org/10.1787/9789264070868-en</a>.</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px">OECD (2018), <em>Test No. 443: Extended One-Generation Reproductive Toxicity Study</em>, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, <a href="https://doi.org/10.1787/9789264185371-en">https://doi.org/10.1787/9789264185371-en</a>.</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px">OECD (2018), <em>Test No. 414: Prenatal Developmental Toxicity Study</em>, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, <a href="https://doi.org/10.1787/9789264070820-en">https://doi.org/10.1787/9789264070820-en</a>.</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px">OECD (2018), "Reproduction/Developmental Toxicity Screening Test (OECD TG 421) and Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD TG 422)", in <em>Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption</em>, OECD Publishing, Paris, <a href="https://doi.org/10.1787/9789264304741-25-en">https://doi.org/10.1787/9789264304741-25-en</a>.</span></span></p>
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</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/1645">Relationship: 1645: GR Agonist, Activation leads to Increased apoptosis, decreased Leydig Cells </a></h4>
<div id="evidence_supporting_links">
<h3>List of Adjacent Key Event Relationships</h3>
<div>
<h4><a href="/relationships/1645">Relationship: 1645: GR Agonist, Activation leads to Decreased Leydig Cells </a></h4>
<!-- loop to find life stages under relationship -->
<div>
</div>
<!-- end loop for life stages -->
<!-- sex terms -->
<div>
</div>
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<p>Ses Table 1.</p>
<h4>Key Event Relationship Description</h4>
<p>Impairment of testosterone production in testes directly impacts on testosterone levels.</p>
<!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed -->
<h4>Evidence Supporting this KER</h4>
<strong>Biological Plausibility</strong>
<p>Within the testes, steroid synthesis takes place within the mitochondria of Leydig cells. Testosterone production by Leydig cells is primarily under the control of LH. LH indirectly stimulates the transfer of cholesterol into the mitochondrial matrix to cholesterol side-chain cleavage cytochrome P450 (P450scc, CYP11A), which converts cholesterol to pregnenolone. Pregnenolone diffuses to the smooth endoplasmic reticulum where it is further metabolized to testosterone via the actions of 3β-hydroxysteroid dehydrogenase Δ5-Δ4-isomerase (3β-HSD), 17α-hydroxylase/C17-20 lyase (P450c17, CYP17), and 17β-hydroxysteroid dehydrogenase type III (17HSD3). For review see (Payne & Hales, 2013). Therefore, inhibition or impairment of the testosterone production directly impacts on the levels of testosterone.</p>
<h4>Key Event Relationship Description</h4>
<div>
<p>Impairment of testosterone production in testes directly impacts on testosterone levels.</p>
</div>
<h4>Evidence Supporting this KER</h4>
<strong>Biological Plausibility</strong>
<p>Within the testes, steroid synthesis takes place within the mitochondria of Leydig cells. Testosterone production by Leydig cells is primarily under the control of LH. LH indirectly stimulates the transfer of cholesterol into the mitochondrial matrix to cholesterol side-chain cleavage cytochrome P450 (P450scc, CYP11A), which converts cholesterol to pregnenolone. Pregnenolone diffuses to the smooth endoplasmic reticulum where it is further metabolized to testosterone via the actions of 3β-hydroxysteroid dehydrogenase Δ5-Δ4-isomerase (3β-HSD), 17α-hydroxylase/C17-20 lyase (P450c17, CYP17), and 17β-hydroxysteroid dehydrogenase type III (17HSD3). For review see (Payne & Hales, 2013). Therefore, inhibition or impairment of the testosterone production directly impacts on the levels of testosterone.</p>
<strong>Empirical Evidence</strong>
<p>There is evidence from experimental work that demonstrates a coordinated, dose-dependent reduction in the production of testosterone and consecutive reduction of testosterone levels in foetal testes and in serum, see Table 1.</p>
<strong>Empirical Evidence</strong>
<p>There is evidence from experimental work that demonstrates a coordinated, dose-dependent reduction in the production of testosterone and consecutive reduction of testosterone levels in foetal testes and in serum, see Table 1.</p>
<p>testicular testosterone production, reduction (ex vivo)</p>
</td>
<td>
<p>testicular testosterone levels, reduction, no change plasma testosterone</p>
</td>
<td>
<p>testosterone levels at GD 21 in male rat fetuses exposed to 0, 10, 30, 100, or 300 mg /kg bw/day from GD 7 to GD 21 testicular testosterone production ex vivo</p>
</td>
<td>
<p>(Borch, Metzdorff, Vinggaard, Brokken, & Dalgaard, 2006)</p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DBP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL =50 mg/kg/day</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>testicular testosterone levels, reduction,</p>
</td>
<td>
<p>Testicular testosterone was reduced >50 mg/kg/day</p>
<p>Akingbemi, B. T. 2001. “Modulation of Rat Leydig Cell Steroidogenic Function by Di(2-Ethylhexyl)Phthalate.” Biology of Reproduction 65 (4) (October 1): 1252–1259. doi:10.1095/biolreprod65.4.1252.</p>
<h4>References</h4>
<p>Akingbemi, B. T. 2001. “Modulation of Rat Leydig Cell Steroidogenic Function by Di(2-Ethylhexyl)Phthalate.” Biology of Reproduction 65 (4) (October 1): 1252–1259. doi:10.1095/biolreprod65.4.1252.</p>
<p>Borch, Julie, Ole Ladefoged, Ulla Hass, and Anne Marie Vinggaard. 2004. “Steroidogenesis in Fetal Male Rats Is Reduced by DEHP and DINP, but Endocrine Effects of DEHP Are Not Modulated by DEHA in Fetal, Prepubertal and Adult Male Rats.” Reproductive Toxicology (Elmsford, N.Y.) 18 (1): 53–61. doi:10.1016/j.reprotox.2003.10.011.</p>
<p>Borch, Julie, Stine Broeng Metzdorff, Anne Marie Vinggaard, Leon Brokken, and Majken Dalgaard. 2006. “Mechanisms Underlying the Anti-Androgenic Effects of Diethylhexyl Phthalate in Fetal Rat Testis.” Toxicology 223 (1-2) (June 1): 144–55. doi:10.1016/j.tox.2006.03.015.</p>
<p>Culty, Martine, Raphael Thuillier, Wenping Li, Yan Wang, Daniel B Martinez-Arguelles, Carolina Gesteira Benjamin, Kostantinos M Triantafilou, Barry R Zirkin, and Vassilios Papadopoulos. 2008. “In Utero Exposure to Di-(2-Ethylhexyl) Phthalate Exerts Both Short-Term and Long-Lasting Suppressive Effects on Testosterone Production in the Rat.” Biology of Reproduction 78 (6) (June): 1018–28. doi:10.1095/biolreprod.107.065649.</p>
<p>Hannas, Bethany R, Christy S Lambright, Johnathan Furr, Nicola Evans, Paul M D Foster, Earl L Gray, and Vickie S Wilson. 2012. “Genomic Biomarkers of Phthalate-Induced Male Reproductive Developmental Toxicity: A Targeted RT-PCR Array Approach for Defining Relative Potency.” Toxicological Sciences : An Official Journal of the Society of Toxicology 125 (2) (February): 544–57. doi:10.1093/toxsci/kfr315.</p>
<p>Parks, L. G. 2000. “The Plasticizer Diethylhexyl Phthalate Induces Malformations by Decreasing Fetal Testosterone Synthesis during Sexual Differentiation in the Male Rat.” Toxicological Sciences 58 (2) (December 1): 339–349. doi:10.1093/toxsci/58.2.339.</p>
<p>Shultz, V. D. 2001. “Altered Gene Profiles in Fetal Rat Testes after in Utero Exposure to Di(n-Butyl) Phthalate.” Toxicological Sciences 64 (2) (December 1): 233–242. doi:10.1093/toxsci/64.2.233.</p>
<p>Wilson, Vickie S., Christy Lambright, Johnathan Furr, Joseph Ostby, Carmen Wood, Gary Held, and L.Earl Gray. 2004. “Phthalate Ester-Induced Gubernacular Lesions Are Associated with Reduced insl3 Gene Expression in the Fetal Rat Testis.” Toxicology Letters 146 (3) (February): 207–215. doi:10.1016/j.toxlet.2003.09.012.</p>
</div>
<br>
<div>
<h4><a href="/relationships/1649">Relationship: 1649: Reduction, testosterone level leads to Decreased sperm quantity or quality in the adult, Decreased fertility </a></h4>
<div>
<h4><a href="/relationships/3225">Relationship: 3225: Decrease, testosterone levels leads to Decreased sperm quantity or quality in the adult, Decreased fertility </a></h4>
<h4><a href="/relationships/1650">Relationship: 1650: Decreased sperm quantity or quality in the adult, Decreased fertility leads to impaired, Fertility</a></h4>