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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Plasma vitellogenin concentrations, Reduction Vitellogenin accumulation into oocytes and oocyte growth/development, Reduction

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Androgen receptor agonism leading to reproductive dysfunction Directly Leads to Moderate Weak
Aromatase inhibition leading to reproductive dysfunction Directly Leads to Moderate Weak
Estrogen receptor antagonism leading to reproductive dysfunction Directly Leads to Moderate Weak
Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation Directly Leads to Moderate
Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcription Directly Leads to

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work


Weight of Evidence

Biological Plausibility

Vitellogenin synthesized in the liver and transported to the ovary via the circulation is the primary source of egg yolk proteins in fish (Tyler and Sumpter 1996; Arukwe and Goksøyr 2003). In many teleosts vitellogenesis can account for up to 95% of total egg size (Tyler and Sumpter 1996).

Empirical Support for Linkage

In some (Ankley et al. 2002; Ankley et al. 2003; Lalone et al. 2013), but not all (Ankley et al. 2005; Sun et al. 2007; Skolness et al. 2013) fish reproduction studies, reductions in plasma vitellogenin have been associated with visible decreases in yolk protein content in oocytes and overall reductions in ovarian stage.

Uncertainties or Inconsistencies

Not all fish reproduction studies showing reductions in plasma vitellogenin have caused visible decreases in yolk protein content in oocytes and overall reductions in ovarian stage. (Ankley et al. 2005; Sun et al. 2007; Skolness et al. 2013).

While plasma vitellogenin is well established as the only major source of vitellogenins to the oocyte, the extent to which a decrease will impact an ovary that has already developed vitellogenic staged oocytes is less certain. It would be assumed that the more rapid the turn-over of oocytes in the ovary, the tighter the linkage between these KEs. Thus, repeat spawning species with asynchronous oocyte development that spawn frequently would likely be more vulnerable than annual spawning species with synchronous oocyte development that had already reached late vitellogenic stages.

Quantitative Understanding of the Linkage

  • Rates of vitellogenin uptake as a function of ovarian follicle surface area have been estimated for rainbow trout, an annual spawning fish species, and may exceed 700 ng/mm2 follicle surface per hour (Tyler and Sumpter 1996).
  • Comparable data are lacking for repeat-spawning species and kinetic relationships between plasma concentrations and uptake rates within the ovary have not been defined.
  • A model based on a statistical relationship between plasma E2 concentrations, spawning interval, and cumulative fecundity has been developed to predict changes in cumulative fecundity from plasma VTG (Li et al. 2011b), but it does not incorporate a model of the kinetics of VTG uptake nor the influence of VTG uptake on oocyte growth.

Evidence Supporting Taxonomic Applicability

This KER is expected to be primarily applicable to oviparous vertebrates that synthesize vitellogenin in hepatic tissue which is ultimately incorporated into oocytes present in the ovary.


  • Tyler C, Sumpter J. 1996. Oocyte growth and development in teleosts. Reviews in Fish Biology and Fisheries 6: 287-318.
  • Arukwe A, Goksøyr A. 2003. Eggshell and egg yolk proteins in fish: hepatic proteins for the next generation: oogenetic, population, and evolutionary implications of endocrine disruption. Comparative Hepatology 2(4): 1-21.
  • Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, et al. 2003. Effects of the androgenic growth promoter 17--trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environmental Toxicology and Chemistry 22(6): 1350-1360.
  • Ankley GT, Kahl MD, Jensen KM, Hornung MW, Korte JJ, Makynen EA, et al. 2002. Evaluation of the aromatase inhibitor fadrozole in a short-term reproduction assay with the fathead minnow (Pimephales promelas). Toxicological Sciences 67: 121-130.
  • Ankley GT, Jensen KM, Durhan EJ, Makynen EA, Butterworth BC, Kahl MD, et al. 2005. Effects of two fungicides with multiple modes of action on reproductive endocrine function in the fathead minnow (Pimephales promelas). Toxicol Sci 86(2): 300-308.
  • Sun L, Zha J, Spear PA, Wang Z. 2007. Toxicity of the aromatase inhibitor letrozole to Japanese medaka (Oryzias latipes) eggs, larvae and breeding adults. Comp Biochem Physiol C Toxicol Pharmacol 145(4): 533-541.
  • Skolness SY, Blanksma CA, Cavallin JE, Churchill JJ, Durhan EJ, Jensen KM, et al. 2013. Propiconazole Inhibits Steroidogenesis and Reproduction in the Fathead Minnow (Pimephales promelas). Toxicological sciences : an official journal of the Society of Toxicology 132(2): 284-297.
  • Li Z, Villeneuve DL, Jensen KM, Ankley GT, Watanabe KH. 2011b. A computational model for asynchronous oocyte growth dynamics in a batch-spawning fish. Can J Fish Aquat Sci 68: 1528-1538.