Induction of cytochrome P450 1A is required for circulation failure and edema by 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish.
The mechanism of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is thought to result from changes in gene expression via the aryl hydrocarbon receptor (AHR). The induction of cytochrome P450 1A (CYP1A) in various organs is a cardinal effect of TCDD. However, whether CYP1A is involved in endpoints of TCDD toxicity is controversial. We investigated the role of CYP1A in TCDD-induced developmental toxicities using gene knock-down with morpholino antisense oligos. Exposure of zebrafish embryos to TCDD, at concentrations eliciting the hallmark endpoints of developmental toxicity, induced CYP1A in the heart and vascular endothelium throughout the body. This induction by TCDD was markedly inhibited by morpholinos to zebrafish arylhydrocarbon receptor 2 (zfAHR2-MO) and to zebrafish CYP1A (zfCYP1A-MO). The zfAHR2-MO but not the zfCYP1A-MO inhibited zfCYP1A mRNA expression, indicating the specificities of these morpholinos. Injection of either zfAHR2-MO or zfCYP1A-MO blocked the representative signs of TCDD developmental toxicity in zebrafish, pericardial edema and trunk circulation failure. The morpholinos appeared do not affect normal development in TCDD-untreated embryos. These results suggest a mediatory role of zfCYP1A induction through zfAHR2 activation in causing circulation failure by TCDD in zebrafish. This is the first molecular evidence demonstrating an essential requirement for CYP1A induction in TCDD-evoked developmental toxicities in any vertebrate species.
Teraoka
Hiroki
H
Department of Toxicology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan. hteraoka@rakuno.ac.jp
Dong
Wu
W
Tsujimoto
Yoshikazu
Y
Iwasa
Hiroyuki
H
Endoh
Daiji
D
Ueno
Naoto
N
Stegeman
John J
JJ
Peterson
Richard E
RE
Hiraga
Takeo
T
D000818:Animals; D001775:Blood Circulation / Q000187:drug effects*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000473:pathology; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004625:Embryo, Nonmammalian / Q000033:anatomy & histology / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010496:Pericardium / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology; D013723:Teratogens / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology* / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology
C474372:AHR2 protein, zebrafish; D016376:Oligonucleotides, Antisense; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D013723:Teratogens; D029961:Zebrafish Proteins; D003577:Cytochrome P-450 Enzyme System