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.
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.
Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543, USA.
Maria E
ME
Jönsson
Matthew J
MJ
Jenny
Bruce R
BR
Woodin
Mark E
ME
Hahn
John J
JJ
Stegeman
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019465:Craniofacial Abnormalities / Q000139:chemically induced / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D015027:Zebrafish / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
C474372:AHR2 protein, zebrafish; D018797:Cell Cycle Proteins; D019927:Cyclin E; D004785:Environmental Pollutants; D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D000072317:Polychlorinated Dibenzodioxins; D018809:Proliferating Cell Nuclear Antigen; D018336:Receptors, Aryl Hydrocarbon; D029961:Zebrafish Proteins; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases; D065633:Cytochrome P-450 CYP1B1; C023035:3,4,5,3',4'-pentachlorobiphenyl