RRC ID 15503
Author Howarth DL, Law SH, Law JM, Mondon JA, Kullman SW, Hinton DE.
Title Exposure to the synthetic FXR agonist GW4064 causes alterations in gene expression and sublethal hepatotoxicity in eleutheroembryo medaka (Oryzias latipes).
Journal Toxicol Appl Pharmacol
Abstract The small freshwater teleost, medaka (Oryzias latipes), has a history of usage in studies of chronic toxicity of liver and biliary system. Recent progress with this model has focused on defining the medaka hepatobiliary system. Here we investigate critical liver function and toxicity by examining the in vivo role and function of the farnesoid X receptor alpha (FXRalpha, NR1H4), a member of the nuclear receptor superfamily that plays an essential role in the regulation of bile acid homeostasis. Quantitative mRNA analysis of medaka FXRalpha demonstrates differential expression of two FXRalpha isoforms designated Fxralpha1 and Fxralpha2, in both free swimming medaka embryos with remaining yolk (eleutheroembryos, EEs) and adults. Activation of medaka Fxralpha in vivo with GW4064 (a strong FXRalpha agonist) resulted in modification of gene expression for defined FXRalpha gene targets including the bile salt export protein, small heterodimer partner, and cytochrome P450 7A1. Histological examination of medaka liver subsequent to GW4064 exposure demonstrated significant lipid accumulation, cellular and organelle alterations in both hepatocytes and biliary epithelial cells of the liver. This report of hepatobiliary injury following GW4064 exposure extends previous investigations of the intrahepatic biliary system in medaka, reveals sensitivity to toxicant exposure, and illustrates the need for added resolution in detection and interpretation of toxic responses in this vertebrate.
Volume 243(1)
Pages 111-21
Published 2010-2-15
DOI 10.1016/j.taap.2009.11.022
PII S0041-008X(09)00495-5
PMID 19963001
PMC PMC2853180
MeSH Animals Chemical and Drug Induced Liver Injury* Dose-Response Relationship, Drug Embryo, Nonmammalian / drug effects Embryo, Nonmammalian / physiology Female Gene Expression Regulation, Developmental / drug effects* Isoxazoles / pharmacology* Liver / drug effects Liver / pathology Liver / ultrastructure Male Oryzias / embryology* Protein Isoforms Receptors, Cytoplasmic and Nuclear / agonists* Yolk Sac
IF 3.347
Times Cited 30
Medaka database