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Reduction, Cholesterol transport in mitochondria leads to Reduction, Testosterone synthesis in Leydig cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|PPARα activation in utero leading to impaired fertility in males||adjacent||Moderate||Arthur Author (send email)||Open for citation & comment||EAGMST Under Review|
|PPARα activation leading to impaired fertility in adult male rodents||adjacent||Moderate||Evgeniia Kazymova (send email)||Not under active development||Under Development|
Life Stage Applicability
Key Event Relationship Description
Production of steroid hormones depends on the availability of cholesterol in the mitochondrial matrix. A decreased amount of cholesterol inside the mitochondria (e. g by decreased expression of enzymes that transport cholesterol like StAR or TSOP) means diminished substrate for hormone (testosterone) production in testes.
Evidence Supporting this KER
Steroid hormones play a critical role in sexual development, homeostasis, stress-responses, carbohydrate metabolism, tumor growth, and reproduction. These hormones are primarily produced in specialized steroidogenic tissues and are synthesized from a common precursor, cholesterol. Mitochondria are a key control point for the regulation of steroid hormone biosynthesis. The first and rate-limiting step in steroidogenesis is the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, a process dependent on the action of StAR (Stocco, 2001) and the subsequent transport across the inner mitochondrial space into the steroidogenic pathway, which is executed by TSPO (Hauet et al., 2005). Testosterone production by Leydig cells is primarily under the control of luteinizing hormone (LH). Stimulation of the Leydig cells results in the activation of StAR transcription and translation, which facilitates 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). Decreased expression of genes that are responsible for cholesterol transport and steroidogenic enzyme activities in the Leydig cell leads to decreased testosterone production.
Uncertainties and Inconsistencies
Thompson et al investigated time course effects of phthalate on steroidogenesis gene expression and testosterone concentration. The study showed diminished concentration testosterone concentration in the foetal testis by 50% within 1h of treatment with phthalate (DBP). Surprisingly, the diminution in testosterone concentration preceded any alteration in expression of genes in the steroidogenesis pathway. Star mRNA was significantly diminished 2 h after DBP exposure, but Cyp11a1, Cyp17a1, and Scarb1 did not show a significant decrease in expression until 6 h after DBP exposure (Thompson et al., 2005). In utero exposure of rats to PFOA 20 mg/kg did not cause any effect on fetal testosterone (Boberg et.al. 2008) although in mice (adult) the decrease level of testosterone was observed. Testosterone production may also be diminished due to reduction/inhibition of other genes involved in steroidogenesis (e.g. P450scc, Cyp17a1) (Thompson et al., 2004), (Boberg et al., 2008), (Chauvigné et al., 2009), (Chauvigné et al., 2011).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
See Table 1.
Barlow, N. J., Phillips, S. L., Wallace, D. G., Sar, M., Gaido, K. W., & Foster, P. M. D. (2003). Quantitative changes in gene expression in fetal rat testes following exposure to di(n-butyl) phthalate. Toxicological Sciences : An Official Journal of the Society of Toxicology, 73(2), 431–41. doi:10.1093/toxsci/kfg087
Boberg, J., Metzdorff, S., Wortziger, R., Axelstad, M., Brokken, L., Vinggaard, A. M., … Nellemann, C. (2008). Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats. Toxicology, 250(2-3), 75–81. doi:10.1016/j.tox.2008.05.020
Borch, J., Ladefoged, O., Hass, U., & Vinggaard, A. M. (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
Borch, J., Metzdorff, S. B., Vinggaard, A. M., Brokken, L., & Dalgaard, M. (2006). Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis. Toxicology, 223(1-2), 144–55. doi:10.1016/j.tox.2006.03.015
Chauvigné, F., Plummer, S., Lesné, L., Cravedi, J.-P., Dejucq-Rainsford, N., Fostier, A., & Jégou, B. (2011). Mono-(2-ethylhexyl) phthalate directly alters the expression of Leydig cell genes and CYP17 lyase activity in cultured rat fetal testis. PloS One, 6(11), e27172. doi:10.1371/journal.pone.0027172
Furr, J. R., Lambright, C. S., Wilson, V. S., Foster, P. M., & Gray, L. E. (2014). A short-term in vivo screen using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to predict disruption of sexual differentiation. Toxicological Sciences : An Official Journal of the Society of Toxicology, 140(2), 403–24. doi:10.1093/toxsci/kfu081
Gazouli, M. (2002). Effect of Peroxisome Proliferators on Leydig Cell Peripheral-Type Benzodiazepine Receptor Gene Expression, Hormone-Stimulated Cholesterol Transport, and Steroidogenesis: Role of the Peroxisome Proliferator-Activator Receptor . Endocrinology, 143(7), 2571–2583. doi:10.1210/en.143.7.2571
Hauet, T., Yao, Z.-X., Bose, H. S., Wall, C. T., Han, Z., Li, W., … Papadopoulos, V. (2005). Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into leydig cell mitochondria. Molecular Endocrinology (Baltimore, Md.), 19(2), 540–54. doi:10.1210/me.2004-0307
Johnson, K. J., McDowell, E. N., Viereck, M. P., & Xia, J. Q. (2011). Species-specific dibutyl phthalate fetal testis endocrine disruption correlates with inhibition of SREBP2-dependent gene expression pathways. Toxicological Sciences : An Official Journal of the Society of Toxicology, 120(2), 460–74. doi:10.1093/toxsci/kfr020
Lehmann, K. P., Phillips, S., Sar, M., Foster, P. M. D., & Gaido, K. W. (2004). Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate. Toxicological Sciences : An Official Journal of the Society of Toxicology, 81(1), 60–8. doi:10.1093/toxsci/kfh169
Li, Y., Ramdhan, D. H., Naito, H., Yamagishi, N., Ito, Y., Hayashi, Y., … Nakajima, T. (2011). Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα. Toxicology Letters, 205(3), 265–72. doi:10.1016/j.toxlet.2011.06.015 Miller, W. L. (2007). Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochimica et Biophysica Acta, 1771(6), 663–76. doi:10.1016/j.bbalip.2007.02.012
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), 339–349. doi:10.1093/toxsci/58.2.339
Payne, A. H., & Hales, D. B. (2013). Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones. Endocrine Reviews. Stocco, D. M. (2001). StAR protein and the regulation of steroid hormone biosynthesis. Annual Review of Physiology, 63, 193–213. doi:10.1146/annurev.physiol.63.1.193
Svechnikov, K., Svechnikova, I., & Söder, O. (2008). Inhibitory effects of mono-ethylhexyl phthalate on steroidogenesis in immature and adult rat Leydig cells in vitro. Reproductive Toxicology (Elmsford, N.Y.), 25(4), 485–90. doi:10.1016/j.reprotox.2008.05.057
Thompson, C. J., Ross, S. M., & Gaido, K. W. (2004). Di(n-butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism. Endocrinology, 145(3), 1227–37. doi:10.1210/en.2003-1475
Thompson, C. J., Ross, S. M., Hensley, J., Liu, K., Heinze, S. C., Young, S. S., & Gaido, K. W. (2005). Differential steroidogenic gene expression in the fetal adrenal gland versus the testis and rapid and dynamic response of the fetal testis to di(n-butyl) phthalate. Biology of Reproduction, 73(5), 908–17. doi:10.1095/biolreprod.105.042382
Wilson, V. S., Lambright, C., Furr, J., Ostby, J., Wood, C., Held, G., & Gray, L. E. (2004). Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis. Toxicology Letters, 146(3), 207–15.