ToxSci Advance Access originally published online on July 25, 2003
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Toxicological Sciences 76, 138-150 (2003)
Copyright © 2003 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Aryl Hydrocarbon Receptor 2 Mediates 2,3,7,8-Tetrachlorodibenzo-p-dioxin Developmental Toxicity in Zebrafish
,1
* Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53726;
Department of Toxicology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan;
Biology Department, Woods Hole Oceanographic Institute, Woods Hole, Massachusetts 02543;
School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705
In order to use the zebrafish as a model vertebrate to investigate the developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), it is essential to know whether one or both forms of the zebrafish aryl hydrocarbon receptor (AHR), zfAHR1 or zfAHR2, mediate toxicity. To determine the role of zfAHR2, an antisense morpholino approach was used to knock down translation of the protein. No effect of the zfahr2 morpholino (zfahr2-MO) was seen on normal development in embryos not treated with TCDD. Injection of embryos at the 1–2 cell stage with zfahr2-MO decreased TCDD-induced transcription of zfCYP1A mRNA until 96 h post fertilization (hpf), and immuno-histochemical detection of zfCYP1A protein in embryos at 72 hpf revealed a dramatic decrease in expression. The zfahr2-MO completely protected embryos from TCDD-induced edema and anemia and provided protection against TCDD-induced reductions in peripheral blood flow initially; however, a slight reduction in blood flow was observed at later times when the morpholino was no longer effective. Due to persistence of TCDD and decreasing effectiveness of the zfahr2-MO over time, the morpholino provided only transient protection against TCDD-induced inhibition of chondrogenesis of the lower jaw, and no protection against an effect of TCDD that was initiated late in development, blockade of swimbladder inflation. The zfahr2-MO did not protect embryos from TCDD-induced mortality but did produce a 48 h delay in its onset. Endpoints of TCDD developmental toxicity manifested in zfahr2 morphants at late stages of development, beyond 144 hpf, were clearly different from TCDD-exposed embryos injected with a control morpholino. Most strikingly, zfahr2 morphants exposed to TCDD never developed edema. Taken together, these results demonstrate that zfAHR2 mediates several endpoints of TCDD developmental toxicity in zebrafish.
Key Words: AHR2; CYP1A; TCDD; zebrafish; embryo; development; toxicity; ischemia; edema; anemia; antisense morpholino; cardiovascular; jaw malformation; 2,3,7,8-tetrachlorodibenzo-p-dioxin; Ah receptor.
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