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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Vitellogenin synthesis in liver, Reduction Plasma vitellogenin concentrations, Reduction

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Aromatase inhibition leading to reproductive dysfunction Directly Leads to Strong Moderate
Androgen receptor agonism leading to reproductive dysfunction Directly Leads to Strong Moderate
Estrogen receptor antagonism leading to reproductive dysfunction Directly Leads to Strong Moderate
Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation Directly Leads to Strong Strong
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

Liver is the major source of VTG protein production in fish (Tyler and Sumpter 1996; Arukwe and Goksøyr 2003). Protein production involves transcription and subsequent translation. The time-lag between decreases in transcription/translation and decreases in plasma VTG concentrations can be expected to be dependent on vitellogenin elimination half-lives.

Empirical Support for Linkage

  • In a number of time-course experiments with aromatase inhibitors, decreases in plasma estradiol concentrations precede decreases in plasma vitellogenin concentrations (Villeneuve et al. 2009; Skolness et al. 2011; Ankley et al. 2009b). Recovery of plasma E2 concentrations also precedes recovery of plasma VTG concentrations after cessation of exposure (Villeneuve et al. 2009; Ankley et al. 2009a; Villeneuve et al. 2013).
  • In experiments with strong estrogens, increases in vtg mRNA synthesis precede increases in plasma VTG concentration (Korte et al. 2000; Schmid et al. 2002).
  • Elimination half-lives for VTG protein have been determined for induced male fish, but to our knowledge, similar kinetic studies have not been done for reproductively mature females (Korte et al. 2000; Schultz et al. 2001).
  • In male sheepshead minnows injected with E2, induction of VTG mRNA precedes induction of plasma VTG (Bowman et al. 2000).
  • In male Cichlasoma dimerus exposed to octylphenol for 28 days and then held in clean water, decline in induced VTG mRNA concentrations precedes declines in induced plasma VTG concentrations (Genovese et al. 2012).

Uncertainties or Inconsistencies

There are no known inconsistencies between these KERs which are not readily explained on the basis of the expected dose, temporal, and incidence relationships between these two KERs. This applies across a significant body of literature in which these two KEs have been measured.

Quantitative Understanding of the Linkage

Due to temporal disconnects (lag) between induction of mRNA transcription and translation and significant changes in plasma concentrations as well as variable rates of uptake of VTG from plasma into oocytes, a precise quantitative relationship between VTG transcription/translation and circulating VTG concentrations has not been described. However, models and statistical relationships that define quantitative relationships between circulating E2 concentrations and circulating VTG concentrations have been developed (Li et al. 2011a; Murphy et al. 2005; Murphy et al. 2009; Ankley et al. 2008).

Evidence Supporting Taxonomic Applicability

This KER primarily applies to taxa that synthesize vitellogenin in the liver which is transported elsewhere in the body via plasma.


  • 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.
  • 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.
  • 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.
  • Ankley GT, Bencic D, Cavallin JE, Jensen KM, Kahl MD, Makynen EA, et al. 2009b. Dynamic nature of alterations in the endocrine system of fathead minnows exposed to the fungicide prochloraz. Toxicol Sci 112(2): 344-353.
  • 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.
  • 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.
  • Korte JJ, Kahl MD, Jensen KM, Mumtaz SP, Parks LG, LeBlanc GA, et al. 2000. Fathead minnow vitellogenin: complementary DNA sequence and messenger RNA and protein expression after 17B-estradiol treatment. Environmental Toxicology and Chemistry 19(4): 972-981.
  • Schmid T, Gonzalez-Valero J, Rufli H, Dietrich DR. 2002. Determination of vitellogenin kinetics in male fathead minnows (Pimephales promelas). Toxicol Lett 131(1-2): 65-74.
  • Schultz IR, Orner G, Merdink JL, Skillman A. 2001. Dose-response relationships and pharmacokinetics of vitellogenin in rainbow trout after intravascular administration of 17alpha-ethynylestradiol. Aquatic toxicology 51(3): 305-318.
  • Bowman CJ, Kroll KJ, Hemmer MJ, Folmar LC, Denslow ND. 2000. Estrogen-induced vitellogenin mRNA and protein in sheepshead minnow (Cyprinodon variegatus). General and comparative endocrinology 120(3): 300-313.
  • Genovese G, Regueira M, Piazza Y, Towle DW, Maggese MC, Lo Nostro F. 2012. Time-course recovery of estrogen-responsive genes of a cichlid fish exposed to waterborne octylphenol. Aquatic toxicology 114-115: 1-13.
  • 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.
  • Murphy CA, Rose KA, Rahman MS, Thomas P. 2009. Testing and applying a fish vitellogenesis model to evaluate laboratory and field biomarkers of endocrine disruption in Atlantic croaker (Micropogonias undulatus) exposed to hypoxia. Environmental toxicology and chemistry / SETAC 28(6): 1288-1303.
  • Murphy CA, Rose KA, Thomas P. 2005. Modeling vitellogenesis in female fish exposed to environmental stressors: predicting the effects of endocrine disturbance due to exposure to a PCB mixture and cadmium. Reproductive toxicology 19(3): 395-409.
  • Ankley GT, Miller DH, Jensen KM, Villeneuve DL, Martinovic D. 2008. Relationship of plasma sex steroid concentrations in female fathead minnows to reproductive success and population status. Aquatic toxicology 88(1): 69-74.