API

Relationship: 302

Title

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Reduction, Testosterone synthesis by ovarian theca cells leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells

Upstream event

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Reduction, Testosterone synthesis by ovarian theca cells

Downstream event

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Reduction, 17beta-estradiol synthesis by ovarian granulosa cells

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Directness Weight of Evidence Quantitative Understanding
Androgen receptor agonism leading to reproductive dysfunction directly leads to Strong Weak

Taxonomic Applicability

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Term Scientific Term Evidence Link
fathead minnow Pimephales promelas Moderate NCBI
Fundulus heteroclitus Fundulus heteroclitus Moderate NCBI

Sex Applicability

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Sex Evidence
Unspecific Not Specified

Life Stage Applicability

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Term Evidence
Adult, reproductively mature Moderate

How Does This Key Event Relationship Work

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Steroid biosynthesis pathway

Figure 1. Overview of steroid biosynthesis pathway.  Note, testosterone is converted to 17ß-estradiol through aromatization catalyzed by cyp19 (aromatase).

 

 

Weight of Evidence

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Biological Plausibility

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Theca cell-derived androgens (e.g., testosterone, androstenedione) are precursors for estrogen (e.g., 17β-estradiol, estrone) synthesis. Androgens secreted from the theca cells are aromatized to estrogens in the ovarian granulosa cells (Norris 2007; Senthilkumaran et al. 2004). Consequently, reductions in theca cell testosterone synthesis can be expected to reduce the rate of estradiol synthesis by the ovarian granulosa cells (Payne and Hales 2004; Miller 1988; Nagahama et al. 1993).

Empirical Support for Linkage

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  • Ex vivo T production by ovary tissue collected from female fathead minnows exposed in vivo to 33 or 472 ng 17β-trenbolone/L was significantly reduced after 24 or 48 h of exposure (Ekman et al. 2011). Reductions in ex vivo T production preceded significant reductions in ex vivo E2 production.
  • Ketoconazole is a fungicide thought to inhibit CYP11A and CYP17 (both involved in theca cell androgen production) with greater potency than it inhibits CYP19 (aromatase) (Villeneuve et al. 2007). Ex vivo E2 and T production were significantly reduced following exposure to 30 or 300 μg ketoconazole/L (Ankley et al. 2012).

Uncertainties or Inconsistencies

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No significant inconsistencies identified to date. However, the literature review on this topic has not been comprehensive.

Quantitative Understanding of the Linkage

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At present we are unaware of any well established quantitative relationships between ex vivo T production (as an indirect measure of theca cell T synthesis) and ex vivo E2 production (as an indirect measure of granulosa cell E2 synthesis). There are considerable data available which might support the development of such a relationship. Additionally, there are a number of existing mathematical/computational models of ovarian steroidogenesis that may be adaptable to support a quantitative understanding of this linkage (Breen et al. 2007; Shoemaker et al. 2010; Quignot and Bois 2013).

Evidence Supporting Taxonomic Applicability

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Enzymes required for testosterone and 17ß-estradiol synthesis are only found in vertebrates and amphioxus (Markov et al. 2009; Baker 2011). They are not present in invertebrates. Consequently, this KER is not applicable to invertebrates.  

References

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  • Ankley GT, Cavallin JE, Durhan EJ, Jensen KM, Kahl MD, Makynen EA, et al. 2012. A time-course analysis of effects of the steroidogenesis inhibitor ketoconazole on components of the hypothalamic-pituitary-gonadal axis of fathead minnows. Aquatic toxicology 114-115: 88-95.

  • Baker ME. 2011. Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors. Mol Cell Endocrinol 334: 14-20.
  • Breen MS, Villeneuve DL, Breen M, Ankley GT, Conolly RB. 2007. Mechanistic computational model of ovarian steroidogenesis to predict biochemical responses to endocrine active compounds. Annals of biomedical engineering 35(6): 970-981.
  • Ekman DR, Villeneuve DL, Teng Q, Ralston-Hooper KJ, Martinovic-Weigelt D, Kahl MD, et al. 2011. Use of gene expression, biochemical and metabolite profiles to enhance exposure and effects assessment of the model androgen 17beta-trenbolone in fish. Environmental toxicology and chemistry / SETAC 30(2): 319-329.
  • Markov GV, Tavares R, Dauphin-Villemant C, Demeneix BA, Baker ME, Laudet V. Independent elaboration of steroid hormone signaling pathways in metazoans. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11913-8. doi: 10.1073/pnas.0812138106.
  • Miller WL. 1988. Molecular biology of steroid hormone synthesis. Endocrine reviews 9(3): 295-318.
  • Nagahama Y, Yoshikumi M, Yamashita M, Sakai N, Tanaka M. 1993. Molecular endocrinology of oocyte growth and maturation in fish. Fish Physiology and Biochemistry 11: 3-14.
  • Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
  • Payne AH, Hales DB. 2004. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews 25(6): 947-970.
  • Quignot N, Bois FY. 2013. A computational model to predict rat ovarian steroid secretion from in vitro experiments with endocrine disruptors. PloS one 8(1): e53891.
  • Senthilkumaran B, Yoshikuni M, Nagahama Y. A shift in steroidogenesis occurring in ovarian follicles prior to oocyte maturation. Mol Cell Endocrinol. 2004 Feb 27;215(1-2):11-8.
  • Shoemaker JE, Gayen K, Garcia-Reyero N, Perkins EJ, Villeneuve DL, Liu L, et al. 2010. Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk. BMC systems biology 4: 89.
  • Villeneuve DL, Ankley GT, Makynen EA, Blake LS, Greene KJ, Higley EB, et al. 2007. Comparison of fathead minnow ovary explant and H295R cell-based steroidogenesis assays for identifying endocrine-active chemicals. Ecotoxicol Environ Saf 68(1): 20-32.