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ToxSci Advance Access originally published online on August 8, 2007
Toxicological Sciences 2007 100(1):180-193; doi:10.1093/toxsci/kfm207
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Role of AHR2 in the Expression of Novel Cytochrome P450 1 Family Genes, Cell Cycle Genes, and Morphological Defects in Developing Zebra Fish Exposed to 3,3',4,4',5-Pentachlorobiphenyl or 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Maria E. Jönsson1,2, Matthew J. Jenny, Bruce R. Woodin, Mark E. Hahn and John J. Stegeman

Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543

2 To whom correspondence should be addressed. Fax: +46-18-51-88-43. E-mail: mjonsson{at}whoi.edu.

Received May 26, 2007; accepted August 1, 2007


  Abstract

Halogenated agonists for the aryl hydrocarbon receptor (AHR), such as 3,3',4,4',5-pentachlorobiphenyl (PCB126) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause developmental toxicity in fish. AHR dependence of these effects is known for TCDD but only presumed for PCB126, and the AHR-regulated genes involved are known only in part. We defined the role of AHR in regulation of four cytochrome P450 1 (CYP1) genes and the effect of PCB126 on cell cycle genes (i.e., PCNA and cyclin E) in zebra fish (Danio rerio) embryos. Basal and PCB126-induced expression of CYP1A, CYP1B1, CYP1C1, and CYP1C2 was examined over time as well as in relation to cell cycle gene expression and morphological effects of PCB126 in developing zebra fish. The four CYP1 genes differed in the time for maximal basal and induced expression, i.e., CYP1B1 peaked within 2 days postfertilization (dpf), the CYP1Cs around hatching (3 dpf), and CYP1A after hatching (14–21 dpf). These results indicate developmental periods when the CYP1s may play physiological roles. PCB126 (0.3–100nM) caused concentration-dependent CYP1 gene induction (EC50: 1.4–2.7nM, Lowest observed effect concentration [LOEC]: 0.3–1nM) and pericardial edema (EC50: 4.4nM, LOEC: 3nM) in 3-dpf embryos. Blockage of AHR2 translation significantly inhibited these effects of PCB126 and TCDD. PCNA gene expression was reduced by PCB126 in a concentration-dependent manner, suggesting that PCB126 could suppress cell proliferation. Our results indicate that the four CYP1 genes examined are regulated by AHR2 and that the effect of PCB126 on morphology in zebra fish embryos is AHR2 dependent. Moreover, the developmental patterns of expression and induction suggest that CYP1 enzymes could function in normal development and in developmental toxicity of PCB126 in fish embryos.

Key Words: cytochrome P450 1 (CYP1); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); embryotoxicity; aryl hydrocarbon receptor (AHR); PCNA.

1 Present address: Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, SE-752 36 Uppsala, Sweden


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