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Reduction, 17beta-estradiol synthesis by ovarian granulosa cells leads to Reduction, Plasma 17beta-estradiol concentrations
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female||adjacent||High||Elise Grignard (send email)||Open for citation & comment||EAGMST Under Review|
|Aromatase inhibition leading to reproductive dysfunction||adjacent||High||Moderate||Dan Villeneuve (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)||adjacent||High||Low||Dan Villeneuve (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation||adjacent||High||Moderate||Dalma Martinovic-Weigelt (send email)||Under Development: Contributions and Comments Welcome|
|Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcription||adjacent||Dalma Martinovic-Weigelt (send email)||Under Development: Contributions and Comments Welcome|
|Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR||adjacent||High||Moderate||Jon Doering (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
See plausibility, below.
Evidence Supporting this KER
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.
Uncertainties and Inconsistencies
Based on the limited set of studies available to date, there are no known inconsistencies.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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