Role of zebrafish cytochrome P450 CYP1C genes in the reduced mesencephalic vein blood flow caused by activation of AHR2

Journal Article · Wed Jun 15 04:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.03.025· OSTI ID:21587766

Kubota, Akira ^[1]; Stegeman, John J; Woodin, Bruce R ^[2]; Iwanaga, Toshihiko ^[3]; Harano, Ryo ^[1]; Peterson, Richard E ^[4]; Hiraga, Takeo; Teraoka, Hiroki ^[1]

---

1. Department of Toxicology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501 (Japan)
2. Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States)
3. Department of Functional Morphology, Laboratory of Histology and Cytology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638 (Japan)
4. School of Pharmacy, University of Wisconsin, Madison, WI 53705 (United States)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). We previously reported a sensitive and useful endpoint of TCDD developmental toxicity in zebrafish, namely a decrease in blood flow in the dorsal midbrain, but downstream genes involved in the effect are not known. The present study addressed the role of zebrafish cytochrome P450 1C (CYP1C) genes in association with a decrease in mesencephalic vein (MsV) blood flow. The CYP1C subfamily was recently discovered in fish and includes the paralogues CYP1C1 and CYP1C2, both of which are induced via AHR2 in zebrafish embryos. We used morpholino antisense oligonucleotides (MO or morpholino) to block initiation of translation of the target genes. TCDD-induced mRNA expression of CYP1Cs and a decrease in MsV blood flow were both blocked by gene knockdown of AHR2. Gene knockdown of CYP1C1 by two different morpholinos and CYP1C2 by two different morpholinos, but not by their 5 nucleotide-mismatch controls, was effective in blocking reduced MsV blood flow caused by TCDD. The same CYP1C-MOs prevented reduction of blood flow in the MsV caused by {beta}-naphthoflavone (BNF), representing another class of AHR agonists. Whole-mount in situ hybridization revealed that mRNA expression of CYP1C1 and CYP1C2 was induced by TCDD most strongly in branchiogenic primordia and pectoral fin buds. In situ hybridization using head transverse sections showed that TCDD increased the expression of both CYP1Cs in endothelial cells of blood vessels, including the MsV. These results indicate a potential role of CYP1C1 and CYP1C2 in the local circulation failure induced by AHR2 activation in the dorsal midbrain of the zebrafish embryo. - Research Highlights: > We examine the roles of zebrafish CYP1C1 and CYP1C2 in TCDD developmental toxicity. > TCDD induces mRNA expression of both CYP1Cs in the mesencephalic vein. > Knockdown of each CYP1C prevents mesencephalic circulation failure by TCDD. > Induced CYP1Cs are involved in reduction of mesencephalic vein blood flow by TCDD.

• OSTI ID: 21587766
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 253; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANIMALS
BIOTECHNOLOGY
BLOOD FLOW
BLOOD VESSELS
BODY
CARDIOVASCULAR SYSTEM
DIOXIN
DNA
EMBRYOS
GENES
GENETIC ENGINEERING
HETEROCYCLIC COMPOUNDS
IN-SITU HYBRIDIZATION
MESSENGER-RNA
NUCLEIC ACID HYBRIDIZATION
NUCLEIC ACIDS
NUCLEOTIDES
OLIGONUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
RNA
TOXICITY
VEINS
VERTEBRATES