Aberrant ligand-induced activation of G protein-coupled estrogen receptor 1 (GPER) results in developmental malformations during vertebrate embryogenesis

Toxicol Sci. 2012 Jan;125(1):262-73. doi: 10.1093/toxsci/kfr269. Epub 2011 Oct 9.

Abstract

G protein-coupled estrogen receptor 1 (GPER) is a G protein-coupled receptor (GPCR) unrelated to nuclear estrogen receptors but strongly activated by 17β-estradiol in both mammals and fish. To date, the distribution and functional characterization of GPER within reproductive and nonreproductive vertebrate organs have been restricted to juvenile and adult animals. In contrast, virtually nothing is known about the spatiotemporal distribution and function of GPER during vertebrate embryogenesis. Using zebrafish as an animal model, we investigated the potential functional role and expression of GPER during embryogenesis. Based on real-time PCR and whole-mount in situ hybridization, gper was expressed as early as 1 h postfertilization (hpf) and exhibited strong stage-dependent expression patterns during embryogenesis. At 26 and 38 hpf, gper mRNA was broadly distributed throughout the body, whereas from 50 to 98 hpf, gper expression was increasingly localized to the heart, brain, neuromasts, craniofacial region, and somite boundaries of developing zebrafish. Continuous exposure to a selective GPER agonist (G-1)-but not continuous exposure to a selective GPER antagonist (G-15)-from 5 to 96 hpf, or within three developmental windows ranging from 10 to 72 hpf, resulted in adverse concentration-dependent effects on survival, gross morphology, and somite formation within the trunk of developing zebrafish embryos. Importantly, based on co-exposure studies, G-15 blocked severe G-1-induced developmental toxicity, suggesting that G-1 toxicity is mediated via aberrant activation of GPER. Overall, our findings suggest that xenobiotic-induced GPER activation represents a potentially novel and understudied mechanism of toxicity for environmentally relevant chemicals that affect vertebrate embryogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / chemically induced
  • Abnormalities, Multiple / metabolism*
  • Animals
  • Benzodioxoles / pharmacology
  • Calcium / metabolism
  • Cyclopentanes / pharmacology
  • Dose-Response Relationship, Drug
  • Embryo, Nonmammalian / abnormalities*
  • Embryo, Nonmammalian / drug effects
  • Embryo, Nonmammalian / metabolism
  • Embryonic Development / drug effects*
  • Female
  • In Situ Hybridization
  • Ligands
  • Male
  • Muscles / abnormalities
  • Muscles / drug effects
  • Muscles / metabolism
  • Quinolines / pharmacology
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Somites / abnormalities
  • Somites / drug effects
  • Somites / metabolism
  • Zebrafish / abnormalities*
  • Zebrafish / embryology
  • Zebrafish Proteins / agonists*
  • Zebrafish Proteins / antagonists & inhibitors*

Substances

  • 1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone
  • 4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline
  • Benzodioxoles
  • Cyclopentanes
  • Ligands
  • Quinolines
  • Receptors, G-Protein-Coupled
  • Zebrafish Proteins
  • gper1 protein, zebrafish
  • Calcium