API

Relationship: 5

Title

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Reduction, 17beta-estradiol synthesis by ovarian granulosa cells leads to Reduction, Plasma 17beta-estradiol concentrations

Upstream event

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Reduction, 17beta-estradiol synthesis by ovarian granulosa cells

Downstream event

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Reduction, Plasma 17beta-estradiol concentrations

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Strong NCBI
fathead minnow Pimephales promelas Moderate NCBI
Fundulus heteroclitus Fundulus heteroclitus Strong NCBI

Sex Applicability

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Sex Evidence
Female Strong

Life Stage Applicability

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Term Evidence
Adult, reproductively mature Strong

How Does This Key Event Relationship Work

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See plausibility, below.

Weight of Evidence

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Updated 03/20/2017.

Biological Plausibility

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While brain, interrenal, adipose, and breast tissue (in mammals) are capable of synthesizing estradiol, the gonads are generally considered the major source of circulating estrogens in vertebrates, including fish (Norris 2007). Consequently, if estradiol synthesis by ovarian granulosa cells is reduced, plasma E2 concentrations would be expected to decrease unless there are concurrent reductions in the rate of E2 catabolism. Synthesis in other tissues generally plays a paracrine role only, thus the contribution of other tissues to plasma E2 concentrations can generally be considered negligible.

 

Empirical Support for Linkage

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Include consideration of temporal concordance here

Fish

  • In multiple studies with aromatase inhibitors (e.g., fadrozole, prochloraz), significant reductions in ex vivo E2 production have been linked to, and shown to precede, reductions in circulating E2 concentrations (Villeneuve et al. 2009; Skolness et al. 2011). It is also notable that compensatory responses at the level of ex vivo steroid production (i.e., rate of E2 synthesis per unit mass of tissue) tend to precede recovery of plasma E2 concentrations following an initial insult (Villeneuve et al. 2009; Ankley et al. 2009a; Villeneuve et al. 2013).
  • Ex vivo E2 production by ovary tissue collected from female fish exposed to 30 or 300 μg ketoconazole/L showed significant decreases prior to significant effects on plasma estradiol being observed (Ankley et al. 2012).
  • Ekman et al. (2011) reported significant reductions in ex vivo E2 production and plasma E2 concentrations in female fathead minnows exposed to 0.05 ug/L 17ß-trenbolone. The effect on plasma E2 was observed at an earlier time point (24 h, versus 48 h for E2 production.
  • Rutherford et al. (2015) reported significant reductions in both E2 production and circulating E2 concentrations in female Fundulus heteroclitus exposed to 5alpha-dihydrotestosterone or 17alpha-methyltestosterone for 14 d. The effects were equipotent in the case of 17alpha-methyltestosterone, but in the case of 5alpha-dihyrotestosterone, the effect on plasma E2 could be detected at a lower dose (10 ug/L) than that at which a significant effect on E2 production was detected (100 ug/L).
  • In female Fundulus heteroclitus exposed to 17alpha-methyltestosterone for 7 or 14 d, both E2 production and plasma E2 were impacted at the same exposure concentrations (Sharpe et al. 2004). 

Mammals

  • MEHP /DEHP, mice, ex vivo DEHP (10 -100 μg/ml); MEHP (0.1 and 10 μg/ml) dose dependent reduction E2 production (Gupta et al., 2010)
  • DEHP, rat, in vivo 300-600 mg/kg/day, dose dependent reduction of E2 plasma levels (Xu et al., 2010)

Evidence for rodent and human models is summarized in Table 1.

 

Compound class

Species

Study type

Dose

E2 production/levels

Reference

Phthalates (DEHP)

rat

ex vivo

1500 mg/kg/day

Reduced/increased E2 production in ovary culture

(Laskey & Berman, 1993)

Phthalates (MEHP)

rat

in vitro

From 50 µM

Reduced E2 production (concentration and time dependent in Granulosa cell)

(Davis, Weaver, Gaines, & Heindel, 1994)

Phthalates (MEHP)

rat

in vitro

100-200µM

reduction E2 production (dose dependent)

(Lovekamp & Davis, 2001)

Phthalates (DEHP)

rat

in vivo

300-600 mg/kg/day

reduction E2 levels dose dependent

(Xu et al., 2010),

Phthalates (MEHP)

human

in vitro

IC(50)= 49- 138 µM (dependent on the stimulant)

reduction E2 production (dose dependent)

(Reinsberg, Wegener-Toper, van der Ven, van der Ven, & Klingmueller, 2009)

Phthalates (MEHP/DEHP)

mice

ex vivo

DEHP (10 -100 μg/ml); MEHP (0.1 and 10 μg/ml)

reduction E2 production (dose dependent)

(Gupta et al., 2010)


Table 1. Summary of the experimental data for decrease E2 production and decreased E2 levels. IC50- half maximal inhibitory concentration values reported if available, otherwise the concentration at which the effect was observed.

Uncertainties or Inconsistencies

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Based on the limited set of studies available to date, there are no known inconsistencies.

Quantitative Understanding of the Linkage

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At present we are unaware of any well established quantitative relationships between ex vivo E2 production (as an indirect measure of granulosa cell E2 synthesis) and plasma E2 concentrations.

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 (Breen et al. 2013; Shoemaker et al. 2010) and/or physiologically-based pharmacokinetic models of the hypothalamic-pituitary-gonadal axis (e.g., (Li et al. 2011a) that may be adaptable to support a quantitative understanding of this linkage.

• The Breen et al. 2013 model was developed based on in vivo time-course data for fathead minnow and incorporates prediction of compensatory responses resulting from feedback mechanisms operating as part of the hypothalamic-pituitary-gonadal axis.

• The Shoemaker et al. 2010 model is chimeric and includes signaling pathways and aspects of transcriptional regulation based on a mixture of fish-specific and mammalian sources.

• The Li et al. 2011 model is a PBPK-based model that was calibrated from data from fathead minnows, including controls and fish exposed to either 17alpha ethynylestradiol or 17beta trenbolone.

Evidence Supporting Taxonomic Applicability

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Key enzymes needed to synthesize 17β-estradiol first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). While some E2 synthesis can occur in other tissues, the ovary is recognized as the major source of 17β-estradiol synthesis in female vertebrates. Endocrine actions of ovarian E2 are facilitated through transport via the plasma. Consequently, this key event relationship is applicable to most female vertebrates.

References

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  • Ankley GT, Bencic DC, Cavallin JE, Jensen KM, Kahl MD, Makynen EA, et al. 2009a. Dynamic nature of alterations in the endocrine system of fathead minnows exposed to the fungicide prochloraz. Toxicological sciences : an official journal of the Society of Toxicology 112(2): 344-353.
  • 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. Molecular and cellular endocrinology 334(1-2): 14-20.
  • Davis, B J, R Weaver, L J Gaines, and J J Heindel. 1994. “Mono-(2-Ethylhexyl) Phthalate Suppresses Estradiol Production Independent of FSH-cAMP Stimulation in Rat Granulosa Cells.” Toxicology and Applied Pharmacology 128 (2) (October): 224–8. doi:10.1006/taap.1994.1201.
  • Ekman DR, Villeneuve DL, Teng Q, Ralston-Hooper KJ, Martinović-Weigelt D, Kahl MD, Jensen KM, Durhan EJ, Makynen EA, Ankley GT, Collette TW. Use of gene expression, biochemical and metabolite profiles to enhance exposure and effects assessment of the model androgen 17β-trenbolone in fish. Environ Toxicol Chem. 2011 Feb;30(2):319-29. doi: 10.1002/etc.406.
  • Gupta, Rupesh K, Jeffery M Singh, Tracie C Leslie, Sharon Meachum, Jodi a Flaws, and Humphrey H-C Yao. 2010. “Di-(2-Ethylhexyl) Phthalate and Mono-(2-Ethylhexyl) Phthalate Inhibit Growth and Reduce Estradiol Levels of Antral Follicles in Vitro.” Toxicology and Applied Pharmacology 242 (2) (January 15): 224–30. doi:10.1016/j.taap.2009.10.011.
  • Laskey, J.W., and E. Berman. 1993. “Steroidogenic Assessment Using Ovary Culture in Cycling Rats: Effects of Bis (2-Diethylhexyl) Phthalate on Ovarian Steroid Production.” Reproductive Toxicology 7 (1) (January): 25–33. doi:10.1016/0890-6238(93)90006-S.
  • Li Z, Kroll KJ, Jensen KM, Villeneuve DL, Ankley GT, Brian JV, et al. 2011a. A computational model of the hypothalamic: pituitary: gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17alpha-ethynylestradiol and 17beta-trenbolone. BMC systems biology 5: 63.
  • Lovekamp, T N, and B J Davis. 2001. “Mono-(2-Ethylhexyl) Phthalate Suppresses Aromatase Transcript Levels and Estradiol Production in Cultured Rat Granulosa Cells.” Toxicology and Applied Pharmacology 172 (3) (May 1): 217–24. doi:10.1006/taap.2001.9156.
  • Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
  • Reinsberg, Jochen, Petra Wegener-Toper, Katrin van der Ven, Hans van der Ven, and Dietrich Klingmueller. 2009. “Effect of Mono-(2-Ethylhexyl) Phthalate on Steroid Production of Human Granulosa Cells.” Toxicology and Applied Pharmacology 239 (1) (August 15): 116–23. doi:10.1016/j.taap.2009.05.022.
  • Rutherford R, Lister A, Hewitt LM, MacLatchy D. Effects of model aromatizable (17α-methyltestosterone) and non-aromatizable (5α-dihydrotestosterone) androgens on the adult mummichog (Fundulus heteroclitus) in a short-term reproductive endocrine bioassay. Comp Biochem Physiol C Toxicol Pharmacol. 2015 Apr;170:8-18.  doi: 10.1016/j.cbpc.2015.01.004.
  • Sharpe RL, MacLatchy DL, Courtenay SC, Van Der Kraak GJ. Effects of a model androgen (methyl testosterone) and a model anti-androgen (cyproterone acetate) on reproductive endocrine endpoints in a short-term adult mummichog (Fundulus heteroclitus) bioassay. Aquat Toxicol. 2004 Apr 28;67(3):203-15.
  • 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.
  • Skolness SY, Durhan EJ, Garcia-Reyero N, Jensen KM, Kahl MD, Makynen EA, et al. 2011. Effects of a short-term exposure to the fungicide prochloraz on endocrine function and gene expression in female fathead minnows (Pimephales promelas). Aquat Toxicol 103(3-4): 170-178.
  • Villeneuve DL, Breen M, Bencic DC, Cavallin JE, Jensen KM, Makynen EA, et al. 2013. Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition: I. Data Generation in a Small Fish Model. Toxicological sciences : an official journal of the Society of Toxicology.
  • Villeneuve DL, Mueller ND, Martinovic D, Makynen EA, Kahl MD, Jensen KM, et al. 2009. Direct effects, compensation, and recovery in female fathead minnows exposed to a model aromatase inhibitor. Environ Health Perspect 117(4): 624-631.
  • Xu, Chuan, Ji-An Chen, Zhiqun Qiu, Qing Zhao, Jiaohua Luo, Lan Yang, Hui Zeng, et al. 2010. “Ovotoxicity and PPAR-Mediated Aromatase Downregulation in Female Sprague-Dawley Rats Following Combined Oral Exposure to Benzo[a]pyrene and Di-(2-Ethylhexyl) Phthalate.” Toxicology Letters 199 (3) (December 15): 323–32. doi:10.1016/j.toxlet.2010.09.015.