API

Relationship: 436

Title

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Decrease, Steroidogenic acute regulatory protein (STAR) leads to Reduction, Cholesterol transport in mitochondria

Upstream event

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Decrease, Steroidogenic acute regulatory protein (STAR)

Downstream event

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Reduction, Cholesterol transport in mitochondria

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Directness Weight of Evidence Quantitative Understanding
PPARα activation in utero leading to impaired fertility in males directly leads to Moderate

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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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.

Weight of Evidence

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Biological Plausibility

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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.

Empirical Support for Linkage

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Down-regulation of StAR and impaired steroidogenesis was reported upon exposure to phthalates i.a. (Barlow et al. 2003), (Borch et al. 2006), for details see Table 1.

     

KE: StAR, decrease

KE: Cholesterol transport, decrease

   

Compound

Species

Effect level

   

Details

References

Phthalate (DBP)

rat

LOEL=500 mg/kg/day

mRNA StAR decrease (by ~34%)

reduced Leydig cell lipid content

 

(Barlow et al. 2003)

Phthalate (DBP)

rat

LOEL=500 mg/kg/day (GD12-19)

 

decrease uptake of cholesterol Leydig cell mitochondria

decreased testosterone, decreased expression of scavenger receptor B1, P450(SCC), steroidogenic acute regulatory protein, and cytochrome p450c17

(Thompson, Ross, and Gaido 2004)

Phthalate (DBP)

rat

LOEL=500 mg/kg

mRNA and protein StAR decrease

 

1 dose, Time course analysis (0,5,1,2,3,6,12,18, 24h killed at GD), decreased testosterone in foetal testis

(Thompson et al. 2005)

Phthalate (DEHP)

rat

LOEL=300 mg/ kg/day

 

mRNA StAR decrease

 

dose-dependently reduced StAR, TSOP mRNA (GD 21 testes), also on protein levels in Leydig cells

 

(Borch et al. 2006)

Phthalate (DBP)

rat

LOEL=500 mg/kg/day, (GD12 to 21)

mRNA StAR decrease

 

Testes examined GD 16, 19, and 21, cytochrome P450 side chain cleavage, cytochrome P450c17, decrease.

Testicular testosterone and androstenedione decreased (GD 19 and 21)

(Shultz 2001)

Phthalate (MEHP)

rat

LOEC=250 μM

protein StAR decrease (immature and adult Leydig cells)

cholesterol transport, decrease (into the mitochondria of immature and adult Leydig cells

decreased testosterone by approximately 60%, in vitro ( immature and adult Leydig cells)

(Svechnikov, Svechnikova, and Söder 2008)

Phthalate (DBP)

rat

LOEL=500 mg/kg/day

mRNA StAR decrease

 

GD 12 -20, examinations on GD20

(Johnson et al. 2011)

Table 1 Summary table of empirical support for this KER. LOEC-lowest effect concentration, LOEL- lowest observed effect level, Dibutyl phthalate (DBP), Di-2-ethylhexyl phthalate (DEHP), mono(2-ethylhexyl) phthalate (MEHP).

Uncertainties or Inconsistencies

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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).

Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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Rat see Table 1.

References

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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.