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Relationship: 2582
Title
Increased, Steroidogenic acute regulatory protein (StAR) leads to Increased, estrogens
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia | adjacent | High | Moderate | Cataia Ives (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Female | High |
Male | Low |
Life Stage Applicability
Term | Evidence |
---|---|
Adult, reproductively mature | High |
Key Event Relationship Description
Steroidogenic acute regulatory (StAR) protein (37-kDa) is synthesized with a mitochondrial leader sequence in response to the cell stimulation to produce steroid and plays a crucial role in steroidogenesis (Hanukoglu, 1992). Research had shown in human ovary StAR protein was produced in response to the Luteinizing Hormone (LH) surge (Kiriakidou et al., 1996). In particular, StAR protein involved in the transportation of the cholesterol (substrate for steroid hormone) from outer to inner mitochondrial membrane. This step is crucial and rate limiting in steroid biosynthesis. In the inner membrane of the mitochondria with the help of cleaved cholesterol pregnenolone is formed, which is the precursor to the different steroid hormones including estrogen (P. R. Manna et al., 2016). Effects of StAR protein on steroidal biosynthesis had been studied by number of researchers (Pulak R Manna et al., 2002; Pescador et al., 1996; Stocco, 2001).
Estradiol synthesis during menstrual cycle is governed via expression of StAR protein synthesis. Presence of StAR protein allows follicular production of androgens which allows the progesterone dominated microenvironment and help in sexual differentiation, growth, reproduction, development and metabolism. Kusakabe et al., had shown in trout fish (Salvelinus fontinalis) model that peak of StAR protein coincide with the menstrual hormone production peak (Kusakabe et al., 2002). Research had shown some toxic chemicals can caused alteration in steroidal regulation and resulted in the agonist effect on estrogen receptors (Lauretta et al., 2019).
Evidence Collection Strategy
Evidence Supporting this KER
Study on immature female rat model had shown rapid changes of the StAR protein level in the ovary during follicular development facilitate the production of estrogen (Ronen-Fuhrmann et al., 1998).
Fang et al., had studied StAR protein expression under the influence of amphiregulin protein in cultured primary human granulosa cells collected from female. Results of the study had shown that human chorionic gonadotropin (hCG) rapidly induces amphiregulin (AREG) expression in the culture cells. Treatment with amphiregulin increase StAR expression and progesterone production in the cells (Fang et al., 2016).
Biological Plausibility
StAR protein catalyzes the movement of cholesterol in the outer mitochondrial membrane to the inner membrane. There, cytochrome P450scc converts cholesterol to the steroid pregnenolone. Studies have shown (in mouse and rat model) some molecules (e.g. 25-hydroxycholesterol) can serve as a substrate for inducing the expression of StAR and influence the steroid production in different tissues. Other oxysterols molecules also capable of increasing STAR expression and pregnenolone synthesis in human endometrial stromal cells (P. R. Manna et al., 2016).
Empirical Evidence
Compound class |
Species |
Study type |
Dose |
KER findings |
Reference |
StAR Protein |
Trout fish (Salvelinus fontinalis) |
In situ hybridization, cloning of cDNAs, Northern blot analysis of mRNA |
Stressor concentration (0.5 ml/liter 2-phenoxyethanol) |
Increased in StAR transcripts in tissues exhibiting enhanced steroid production and increased circulating levels of 17β-estradiol and maturation inducing steroid ( 17α,20β -dihydroxy-4-pregnen-3-one). |
(Kusakabe et al., 2002) |
StAR Protein |
Hen (Single-comb white Leghorn) |
Northern blot analysis of mRNA collected from ovarian follicle granulosa cells |
MAP kinase inhibitor (U0126)-50 mM, Follicle stimulating hormone(FSH) -100 ng/ml, TGFa (50 ng/ml) |
Acute increase in progesterone production in response to LH treatment |
(Johnson et al., 2002) |
StAR Protein |
The mouse MA-10 Leydig tumor cell line |
Northern blot analysis of total RNA |
Fadrozole (100 µM) |
StAR Protein inhibition by antifungal drugs econazole and miconazole |
(Walsh et al., 2000) |
Uncertainties and Inconsistencies
Chang et al., had investigated the effects of antimullerian hormone (AMH) on estradiol production in primary culture of human granulosa-lutein (hGL) cells. In the control cell estradiol concentration was found 43.2–93.7 ng/mL. Whereas,treatment with AMH (10 ng/mL) significantly reduced the estradiol accumulation in the cells (Chang et al., 2013).
Known modulating factors
Arukwe had shown nonylphenol (15 µg/L) can induce the StAR protein in juvenile Atlantic salmon (Salmo salar) fish (Arukwe, 2005).
Quantitative Understanding of the Linkage
Pescador et al., had studied the StAR mRNA levels in the bovine corpus luteum. Result of the study had shown that expression of StAR mRNA was low in developing corpus luteum. In mid to late luteal phase the concentration increased 9- to 15-fold compared to the expression of StAR mRNA during developing stage. Results confirms that StAR mRNA and protein are tightly coupled in the corpus luteum cells and present at low levels during CL development and present elevated concentrations during the midluteal phase (Pescador et al., 1996).
Response-response Relationship
Not specified
Time-scale
Observed for hours
Known Feedforward/Feedback loops influencing this KER
Not specified
Domain of Applicability
Adult
References
Arukwe, A. (2005). Modulation of brain steroidogenesis by affecting transcriptional changes of steroidogenic acute regulatory (StAR) protein and cholesterol side chain cleavage (P450scc) in juvenile Atlantic salmon (Salmo salar) is a novel aspect of nonylphenol toxicity. Environ Sci Technol, 39(24), 9791-8. doi:10.1021/es0509937.
Chang, H. M., Klausen, C., & Leung, P. C. (2013). Antimullerian hormone inhibits follicle-stimulating hormone-induced adenylyl cyclase activation, aromatase expression, and estradiol production in human granulosa-lutein cells. Fertil Steril, 100(2), 585-92 e1. doi:S0015-0282(13)00515-3 [pii]10.1016/j.fertnstert.2013.04.019.
Fang, L., Yu, Y., Zhang, R., He, J., & Sun, Y. P. (2016). Amphiregulin mediates hCG-induced StAR expression and progesterone production in human granulosa cells. Sci Rep, 6, 24917. doi:srep24917 [pii]10.1038/srep24917.
Hanukoglu, I. (1992). Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis. The Journal of steroid biochemistry and molecular biology, 43(8), 779-804.
Johnson, A. L., Solovieva Ev Fau - Bridgham, J. T., & Bridgham, J. T. (2002). Relationship between steroidogenic acute regulatory protein expression and progesterone production in hen granulosa cells during follicle development. (0006-3363 (Print)).
Kiriakidou, M., Mcallister, J. M., Sugawara, T., & Strauss 3rd, J. (1996). Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. The Journal of Clinical Endocrinology & Metabolism, 81(11), 4122-4128.
Kusakabe, M., Todo, T., McQuillan, H. J., Goetz, F. W., & Young, G. (2002). Characterization and expression of steroidogenic acute regulatory protein and MLN64 cDNAs in trout. Endocrinology, 143(6), 2062-70. doi:10.1210/endo.143.6.8672.
Lauretta, R., Sansone, A., Sansone, M., Romanelli, F., & Appetecchia, M. (2019). Endocrine Disrupting Chemicals: Effects on Endocrine Glands. Front Endocrinol (Lausanne), 10, 178. doi:10.3389/fendo.2019.00178.
Manna, P. R., Dyson, M. T., Eubank, D. W., Clark, B. J., Lalli, E., Sassone-Corsi, P., et al. (2002). Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. Molecular Endocrinology, 16(1), 184-199.
Manna, P. R., Stetson, C. L., Slominski, A. T., & Pruitt, K. (2016). Role of the steroidogenic acute regulatory protein in health and disease. Endocrine, 51(1), 7-21. doi:10.1007/s12020-015-0715-610.1007/s12020-015-0715-6 [pii].
Men, Y., Fan, Y., Shen, Y., Lu, L., & Kallen, A. N. (2017). The Steroidogenic Acute Regulatory Protein (StAR) Is Regulated by the H19/let-7 Axis. Endocrinology, 158(2), 402-409. doi:10.1210/en.2016-1340.
Nimrod, A. (1981). On the synergistic action of androgen and FSH on progestin secretion by cultured rat granulosa cells: cellular and mitochondrial cholesterol metabolism. Molecular and cellular endocrinology, 21(1), 51-62.
Pescador, N., Soumano, K., Stocco, D. M., Price, C. A., & Murphy, B. D. (1996). Steroidogenic acute regulatory protein in bovine corpora lutea. Biology of reproduction, 55(2), 485-491.
Ronen-Fuhrmann, T., Timberg, R., King, S. R., Hales, K. H., Hales, D. B., Stocco, D. M., et al. (1998). Spatio-temporal expression patterns of steroidogenic acute regulatory protein (StAR) during follicular development in the rat ovary. Endocrinology, 139(1), 303-15. doi:10.1210/endo.139.1.5694.
Stocco, D. M. (2001). StAR protein and the regulation of steroid hormone biosynthesis. Annu Rev Physiol. , 63, 193-2013. doi:10.1146/annurev.physiol.63.1.193.
Walsh, L. P., Kuratko, C. N., & Stocco, D. M. (2000). Econazole and miconazole inhibit steroidogenesis and disrupt steroidogenic acute regulatory (StAR) protein expression post-transcriptionally. J Steroid Biochem Mol Biol, 75(4-5), 229-36. doi:S0960076000001709 [pii]10.1016/s0960-0760(00)00170-9.