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

Jönsson, M.E., Jenny, M.J., Woodin, B.R., Hahn, M.E., and Stegeman, J.J.
Toxicological sciences : an official journal of the Society of Toxicology   100(1): 180-193 (Journal)
Registered Authors
Hahn, Mark E., Stegeman, John J.
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.
MeSH Terms
  • Animals
  • Aryl Hydrocarbon Hydroxylases/metabolism
  • Cell Cycle Proteins/genetics
  • Cell Cycle Proteins/metabolism*
  • Cell Proliferation/drug effects
  • Craniofacial Abnormalities/chemically induced
  • Craniofacial Abnormalities/metabolism
  • Cyclin E/metabolism
  • Cytochrome P-450 CYP1B1
  • Cytochrome P-450 Enzyme System/genetics
  • Cytochrome P-450 Enzyme System/metabolism*
  • Dose-Response Relationship, Drug
  • Edema/chemically induced
  • Edema/metabolism
  • Embryo, Nonmammalian/abnormalities
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/enzymology
  • Embryo, Nonmammalian/metabolism
  • Embryonic Development/drug effects
  • Environmental Pollutants/toxicity*
  • Gene Expression Regulation, Developmental/drug effects*
  • Gene Expression Regulation, Enzymologic/drug effects*
  • Heart Defects, Congenital/chemically induced
  • Heart Defects, Congenital/metabolism
  • Isoenzymes/metabolism
  • Oligonucleotides, Antisense/metabolism
  • Polychlorinated Biphenyls/toxicity*
  • Proliferating Cell Nuclear Antigen/metabolism
  • Receptors, Aryl Hydrocarbon/agonists*
  • Receptors, Aryl Hydrocarbon/genetics
  • Receptors, Aryl Hydrocarbon/metabolism
  • Time Factors
  • Transcriptional Activation
  • Zebrafish/abnormalities
  • Zebrafish/embryology
  • Zebrafish/metabolism*
  • Zebrafish Proteins/agonists*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
17686920 Full text @ Toxicol. Sci.
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 zebrafish (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 zebrafish. The four CYP1 genes differed in the time for maximal basal and induced expression, i.e., CYP1B1 peaked within 2 days post-fertilization (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 (0.3-100 nM) caused concentration-dependent CYP1 gene induction (EC(50): 1.4-2.7 nM, LOEC: 0.3-1 nM) and pericardial edema (EC(50): 4.4 nM, LOEC: 3 nM) 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 zebrafish 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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes