API

Relationship: 129

Title

?

Antagonism, Estrogen receptor leads to Reduction, Vitellogenin synthesis in liver

Upstream event

?

Antagonism, Estrogen receptor

Downstream event

?


Reduction, Vitellogenin synthesis in liver

Key Event Relationship Overview

?


AOPs Referencing Relationship

?

AOP Name Directness Weight of Evidence Quantitative Understanding
Estrogen receptor antagonism leading to reproductive dysfunction directly leads to Strong Weak

Taxonomic Applicability

?


Sex Applicability

?


Life Stage Applicability

?


How Does This Key Event Relationship Work

?


Weight of Evidence

?


Biological Plausibility

?

Vitellogenin synthesis in fish is localized in the liver and is well documented to be regulated by estrogens via interaction with estrogen receptors (Arukwe and Goksøyr 2003; Nelson and Habibi 2010; Tyler and Sumpter 1996; Tyler et al. 1996). During vitellogenic periods of the reproductive cycle, antagonism of the ER would be expected to reduce vitellogenin transcription and translation.

Empirical Support for Linkage

?

  • Eleven ER antagonists were shown to reduce in vitro E2-induced vitellogenin production by rainbow trout hepatocytes in a concentration-dependent manner (Petersen and Tollefsen 2012).
  • A review by Navas and Segner (Navas and Segner 2006) reports inhibition of E2-induced vitellogenin induction in primary fish liver cells to be useful for detecting anti-estrogens.
  • Methyl-piperidino-pyrazole (MPP), a synthetic mammalian ERα antagonist shown to antagonize activation of the tilapia ER, also reduced the ability of estradiol to stimulate vitellogenin production in tilapia injected with the compound in vivo (Davis et al. 2010).
  • A synthetic musk shown to act as a both a human and rainbow trout ERα antagonist inhibited E2-induced vitellogenin production in rainbow trout injected with the same compound (Simmons et al. 2010).
  • Tamoxifen inhibited vitellogenin induction in roach (Rutilus rutilus) liver explants exposed in vitro (Gerbron et al. 2010).
  • Hydroxytamoxifen inhibited vitellogenin induction in brown trout primary hepatocytes and rainbow trout and zebrafish liver cell lines (Christianson-Heiska and Isomaa 2008).
  • Nafoxidine and CI-628 inhibit estrogen-induced vitellogenin synthesis in roosters (Gschwendt 1975).

Uncertainties or Inconsistencies

?

  • Some uncertainty remains regarding which ER subtype(s) regulates vitellogenin gene expression in the liver of fish. In general, the literature suggests a close interplay between several ER subtypes in the regulation of vitellogenesis. Consequently, at present, the key event relationship is generalized to impacts on all ER subtypes, even though it remains possible that impacts on a particular sub-type may drive the effect on vitellogenin transcription and translation.
  • Griffin et al. reported that morpholino knock-downs of either esr1 (ERα) or esr2b (ERβb) prevented estradiol-mediated induction of vitellogenin expression in zebrafish (Griffin et al. 2013).
  • Using selective agonists agonists and antagonists for ERα and ERβ, it was concluded that ERβ was primarily responsible for inducing vitellogenin production in rainbow trout and that compounds exhibiting ERα selectivity would not be detected using a vitellogenin bioassay (Leanos-Castaneda and Van Der Kraak 2007). However, a subsequent study conducted in tilapia concluded that agonistic and antagonistic characteristics of mammalian, isoform-specific ER agonists and antagonists, cannot be reliably extrapolated to piscine ERs (Davis et al. 2010).
  • Based on RNA interference knock-down experiments Nelson and Habibi proposed a model in which all ER subtypes are involved in E2-mediated vitellogenesis, with ERβ isoforms stimulating expression of both vitellogenin and ERα gene expression, and ERα helping to drive vitellogenesis, particularly as it becomes more abundant following sensitization (Nelson and Habibi 2010).

Quantitative Understanding of the Linkage

?


At present, we are not aware of any studies that have defined the quantitative relationship between measures of ER antagonism and the magnitude or severity of impaired vitellogenin transcription or translation in liver.

Evidence Supporting Taxonomic Applicability

?


References

?


  • 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 2:1-21.
  • 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.
  • Petersen K, Tollefsen KE. 2012. Combined effects of oestrogen receptor antagonists on in vitro vitellogenesis. Aquatic toxicology 112-113:46-53.
  • 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. Aquatic toxicology 80:1-22.
  • Davis LK, Katsu Y, Iguchi T, Lerner DT, Hirano T, Grau EG. 2010. Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in mozambique tilapia. The Journal of steroid biochemistry and molecular biology 122:272-278.
  • Simmons DB, Marlatt VL, Trudeau VL, Sherry JP, Metcalfe CD. 2010. Interaction of galaxolide(r) with the human and trout estrogen receptor-alpha. The Science of the total environment 408:6158-6164.
  • Gerbron M, Geraudie P, Rotchell J, Minier C. 2010. A new in vitro screening bioassay for the ecotoxicological evaluation of the estrogenic responses of environmental chemicals using roach (rutilus rutilus) liver explant culture. Environmental toxicology 25:510-516.
  • Christianson-Heiska I, Isomaa B. 2008. The use of primary hepatocytes from brown trout (salmo trutta lacustris) and the fish cell lines rth-149 and zf-l for in vitro screening of (anti)estrogenic activity of wood extractives. Toxicology in vitro : an international journal published in association with BIBRA 22:589-597.
  • Gschwendt M. 1975. The effect of antiestrogens on egg yolk protein synthesis and estrogen-binding to chromatin in the rooster liver. Biochimica et biophysica acta 399:395-402.
  • Griffin LB, January KE, Ho KW, Cotter KA, Callard GV. 2013. Morpholino mediated knockdown of eralpha, erbetaa and erbetab mrnas in zebrafish (danio rerio) embryos reveals differential regulation of estrogen-inducible genes. Endocrinology.
  • Leanos-Castaneda O, Van Der Kraak G. 2007. Functional characterization of estrogen receptor subtypes, eralpha and erbeta, mediating vitellogenin production in the liver of rainbow trout. Toxicology and applied pharmacology 224:116-125.
  • Davis LK, Katsu Y, Iguchi T, Lerner DT, Hirano T, Grau EG. 2010. Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in mozambique tilapia. The Journal of steroid biochemistry and molecular biology 122:272-278.
  • Nelson ER, Habibi HR. 2010. Functional significance of nuclear estrogen receptor subtypes in the liver of goldfish. Endocrinology 151:1668-1676.