This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Decrease, Steroidogenic acute regulatory protein (STAR) leads to Reduction, Cholesterol transport in mitochondria
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|
Life Stage Applicability
Key Event Relationship Description
Steroidogenic acute regulatory protein (StAR) mediates the cholesterol transport from the outer to the inner mitochondrial membrane, where it undergoes side chain cleavage by cytochrome P-450 enzyme (P450scc) that yields the steroid precursor, pregnenolone (Besman et al. 1989). The cholesterol transfer within the mitochondria is the rate-limiting step in the production of steroid hormones. Therefore reduced amount/activity of the StAR impairs the cholesterol delivery that is necessary for the hormone biosynthesis.
Evidence Collection Strategy
Evidence Supporting this KER
The first step in steroidogenesis takes place within mitochondria. StAR facilitates the movement of cholesterol from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM) for steroidogenesis [reviewed in (Miller and Auchus 2011)]. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cells in the adrenal cortex.
Uncertainties and Inconsistencies
Some steroidogenesis is independent of StAR; when nonsteroidogenic cells are transfected with the P450scc system, they convert cholesterol to pregnenolone at about 14% of the StAR-induced rate (Lin et al. 1995). The mechanism of StAR-independent steroidogenesis is unclear (Miller and Auchus 2011). Johnson et al proposed the involvment of sterol regulatory element–binding protein (SREBP) in phthalate mediated disruption of steroidogenesis. Their study showed lipid metabolism pathways transcriptionally regulated by SREBP were inhibited in the rat but induced in the mouse, and this differential species response corresponded with repression of the steroidogenic pathway. In rats exposed to 100 or 500 mg/kg DBP from gestational days (GD) 16 to 20, a correlation was observed between GD20 testis steroidogenic inhibition and reductions of testis cholesterol synthesis endpoints including testis total cholesterol levels (Johnson et al. 2011).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Rat see Table 1.
Barlow, Norman J, Suzanne L Phillips, Duncan G Wallace, Madhabananda Sar, Kevin W Gaido, and Paul M D Foster. 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) (June): 431–41. doi:10.1093/toxsci/kfg087.
Besman, M J, K Yanagibashi, T D Lee, M Kawamura, P F Hall, and J E Shively. 1989. “Identification of Des-(Gly-Ile)-Endozepine as an Effector of Corticotropin-Dependent Adrenal Steroidogenesis: Stimulation of Cholesterol Delivery Is Mediated by the Peripheral Benzodiazepine Receptor.” Proceedings of the National Academy of Sciences of the United States of America 86 (13) (July): 4897–901.
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.
Johnson, Kamin J, Erin N McDowell, Megan P Viereck, and Jessie Q Xia. 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) (April): 460–74. doi:10.1093/toxsci/kfr020.
Lin, D, T Sugawara, J F Strauss, B J Clark, D M Stocco, P Saenger, A Rogol, and W L Miller. 1995. “Role of Steroidogenic Acute Regulatory Protein in Adrenal and Gonadal Steroidogenesis.” Science (New York, N.Y.) 267 (5205) (March 24): 1828–31.
Miller, Walter L, and Richard J Auchus. 2011. “The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders.” Endocrine Reviews 32 (1) (February): 81–151. doi:10.1210/er.2010-0013.
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.
Svechnikov, Konstantin, Irina Svechnikova, and Olle Söder. 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) (August): 485–90. doi:10.1016/j.reprotox.2008.05.057.
Thompson, Christopher J, Susan M Ross, and Kevin W Gaido. 2004. “Di(n-Butyl) Phthalate Impairs Cholesterol Transport and Steroidogenesis in the Fetal Rat Testis through a Rapid and Reversible Mechanism.” Endocrinology 145 (3) (March): 1227–37. doi:10.1210/en.2003-1475.
Thompson, Christopher J, Susan M Ross, Janan Hensley, Kejun Liu, Susanna C Heinze, S Stanley Young, and Kevin W Gaido. 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) (November): 908–17. doi:10.1095/biolreprod.105.042382.