Upstream eventReduction, Plasma 17beta-estradiol concentrations
Reduction, Vitellogenin synthesis in liver
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||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|
|Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation||directly leads to||Strong||Moderate|
|Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcription||directly leads to|
|fathead minnow||Pimephales promelas||Moderate||NCBI|
Life Stage Applicability
|Adult, reproductively mature||Not Specified|
How Does This Key Event Relationship Work
See Plausibility below.
Weight of Evidence
Vitellogenin synthesis in fish is localized in the liver and is well documented to be regulated by estrogens via interaction with estrogen receptors (Tyler et al. 1996; Tyler and Sumpter 1996; Arukwe and Goksøyr 2003). The vitellogenin gene contains estrogen repsonsive elements in its promoter region and site directed mutagenesis has shown these to be essential for estrogen-dependent expression of vitellogenin (Chang et al. 1992; Teo et al. 1998). Liver is not regarded as a major site of E2 synthesis (Norris 2007), therefore the majority of E2 in liver comes from the circulation.
- Estrogen regulates expression of the vitellogenin gene in the amphibian Xenopus laevis (Skipper and Hamilton, 1977).
Empirical Support for Linkage
- Empirical support for estrogen-dependent regulation of vitellogenin synthesis:
- Many studies have demonstrated that exposure of hepatocytes to estrogens in vitro or in vivo induce vitellogenin mRNA synthesis (e.g., see reviews by (Navas and Segner 2006; Iguchi et al. 2006)).
- In female fathead minnows exposed to 17β-trenbolone, significant reductions in plasma E2 concentrations preceded significant reductions in plasma VTG (Ekman et al. 2011).
- Intra-arterial injection of the estrogen 17α ethynyl estradiol into male rainbow trout causes vitellogenin induction with about a 12 h lag time before increasing from basal levels (Schultz et al. 2001).
- Specific empirical support for reductions in plasma E2 leading to reductions in hepatic vitellogenin synthesis:
- In a number of time-course experiments with aromatase inhibitors (e.g., fadrozole, prochloraz), 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).
- It was demonstrated in Danio rerio that in vivo exposure to the aromatase inhibitor letrozole significantly reduced the expression of mRNA transcripts coding for vtg1, vtg2, and erα, all of which are known to be regulated by estrogens (Sun et al. 2010). However, similar effects were not observed in primary cultured hepatocytes from Danio rerio, indicating that letrozole’s effects on vtg transcription were not direct.
Uncertainties or Inconsistencies
Based on the limited set of studies available to date, there are no known inconsistencies.
Quantitative Understanding of the Linkage
- At least two computational models that include functions which link circulating concentrations of E2 to VTG production by the liver have been published (Li et al. 2011a; Murphy et al. 2005; Murphy et al. 2009), although both models focus on predicting plasma VTG concentrations rather than transcription or translation within the liver. A significant positive correlation (r=0.87) between plasma E2 concentrations corresponding plasma VTG concentrations in female fathead minnows held under laboratory conditions has also been reported (Ankley et al. 2008).
- There are multiple isoforms of vitellogenin. The sensitivity and inducibility of each of those isoforms may vary somewhat. Consequently, response-response relationships may vary somewhat depending on the speicific isoform for which QPCR primers or antibodies were developed.
Evidence Supporting Taxonomic Applicability
Key enzymes needed to synthesize 17β-estradiol first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). However, non-oviparous vertebrates do not require vitellogenin. Consequently, this KER is applicable to oviparous vertebrates.
- 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.
- 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.
- 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.
- Chang TC, Nardulli AM, Lew D, and Shapiro, DJ. 1992. The role of estrogen response elements in expression of the Xenopus laevis vitellogenin B1 gene. Molecular Endocrinology 6:3, 346-354\
- Ekman DR, Villeneuve DL, Teng Q, Ralston-Hooper KJ, Martinovic-Weigelt D, Kahl MD, et al. 2011. Use of gene expression, biochemical and metabolite profiles to enhance exposure and effects assessment of the model androgen 17beta-trenbolone in fish. Environmental toxicology and chemistry / SETAC 30(2): 319-329.
- Iguchi T, Irie F, Urushitani H, Tooi O, Kawashima Y, Roberts M, et al. 2006. Availability of in vitro vitellogenin assay for screening of estrogenic and anti-estrogenic activities of environmental chemicals. Environ Sci 13(3): 161-183.
- 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.
- Navas JM, Segner H. 2006. Vitellogenin synthesis in primary cultures of fish liver cells as endpoint for in vitro screening of the (anti)estrogenic activity of chemical substances. Aquat Toxicol 80(1): 1-22.
- Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
- 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.
- Skipper JK, Hamilton TH. 1977. Regulation by estrogen of the vitellogenin gene. Proc Natl Acad Sci USA 74:2384-2388.
- 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.
- Sun L, Wen L, Shao X, Qian H, Jin Y, Liu W, et al. 2010. Screening of chemicals with anti-estrogenic activity using in vitro and in vivo vitellogenin induction responses in zebrafish (Danio rerio). Chemosphere 78(7): 793-799.
- Teo BY, Tan NS, Lim EH, Lam TJ, Ding JL. A novel piscine vitellogenin gene: structural and functional analyses of estrogen-inducible promoter. Mol Cell Endocrinol. 1998 Nov 25;146(1-2):103-20. PubMed PMID: 10022768.
- Tyler C, Sumpter J. 1996. Oocyte growth and development in teleosts. Reviews in Fish Biology and Fisheries 6: 287-318.
- Tyler C, van der Eerden B, Jobling S, Panter G, Sumpter J. 1996. Measurement of vitellogenin, a biomarker for exposure to oestrogenic chemicals, in a wide variety of cyprinid fish. Journal of Comparative Physiology and Biology 166: 418-426.
- 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.