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Key Event Title
Reduction, Plasma 17beta-estradiol concentrations
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Aromatase (Cyp19a1) reduction leading to reproductive toxicity||KeyEvent||Elise Grignard (send email)||Open for citation & comment||EAGMST Under Review|
|Aromatase inhibition leading to reproductive dysfunction||KeyEvent||Dan Villeneuve (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Androgen receptor agonism leading to reproductive dysfunction||KeyEvent||Dan Villeneuve (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Prolyl hydroxylase inhibition||KeyEvent||Dalma Martinovic-Weigelt (send email)||Under Development: Contributions and Comments Welcome|
|Unknown MIE leading to reprodl||KeyEvent||Dalma Martinovic-Weigelt (send email)||Under Development: Contributions and Comments Welcome|
|TPO inhibition and impaired fertility||KeyEvent||June-Woo Park (send email)||Open for comment. Do not cite||Under Development|
|5α-reductase,female fish||KeyEvent||Young Jun Kim (send email)||Open for citation & comment||Under Development|
|AHR mediated epigenetic reproductive failure||KeyEvent||Jon Doering (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
Estradiol synthesized by the gonads is transported to other tissues via blood circulation. The gonads are generally considered to be the primary source of estrogens in systemic circulation.
How It Is Measured or Detected
Total concentrations of 17β-estradiol in plasma can be measured by radioimmunoassay (e.g., (Jensen et al. 2001)), enzyme-linked immunosorbent assay (available through many commercial vendors), or by analytical chemistry (e.g., LC/MS; Owen et al. 2014). Total steroid hormones are typically extracted from plasma or serum via liquid-liquid or solid phase extraction prior to analysis.
Given that there are numerous genes, like those coding for vertebrate vitellogenins, choriongenins, cyp19a1b, etc. which are known to be regulated by estrogen response elements, targeted qPCR or proteomic analysis of appropriate targets could also be used as an indirect measure of reduced circulating estrogen concentrations. However, further support for the specificity of the individual gene targets for estrogen-dependent regulation should be established in order to support their use.
A line of transgenic zebrafish employing green fluorescence protein under control of estrogen response elements could also be used to provide direct evidence of altered estrogen, with decreased GFP signal in estrogen responsive tissues like liver, ovary, pituitary, and brain indicating a reduction in circulating estrogens (Gorelick and Halpern 2011).
Domain of Applicability
Key enzymes needed to synthesize 17β-estradiol first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates.
- Jensen K, Korte J, Kahl M, Pasha M, Ankley G. 2001. Aspects of basic reproductive biology and endocrinology in the fathead minnow (Pimephales promelas). Comparative Biochemistry and Physiology Part C 128: 127-141.
- Baker ME. 2011. Origin and diversification of steroids: co-evolution of enzymes and nuclear receptors. Molecular and cellular endocrinology 334(1-2): 14-20.
- Owen LJ, Wu FC, Keevil BG. 2014. A rapid direct assay for the routine measurement of oestradiol and oestrone by liquid chromatography tandem mass spectrometry. Ann. Clin. Biochem. 51(pt 3):360-367.
- Gorelick DA, Halpern ME. Visualization of estrogen receptor transcriptional activation in zebrafish. Endocrinology. 2011 Jul;152(7):2690-703. doi: 10.1210/en.2010-1257. Epub 2011 May 3. PubMed PMID: 21540282