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RP8 Ecotoxicology of Agrochemicals and Pharmaceuticals
(TIL-1117-671639) Dithiocarbamate developmental toxicity in zebrafish.
Tilton, F1, 2, 3, 4, La Du, J1, 2, 3, 4, Vue, M4, Alzaarban, N4, Tanguay, R1, 2, 3, 4, 1 Department of Environmental and Molecular Toxicology2 Environmental Health Sciences Center3 Marine and Freshwater Biomedical Sciences Center4 Oregon State University, Corvallis, OR, USA
ABSTRACT- We have demonstrated that dithiocarbamates (DTCs) from every subclass cause profound developmental toxicity involving the notochord and the surrounding tissue at environmentally relevant concentrations. Our current efforts are directed toward elucidating the mechanisms by which DTCs perturb vertebrate development. The hypothesis that metal chelation is the sole mode of developmental toxicity was tested. The membrane permeable copper chelator, neocuproine, mimicked the effects of DTCs albeit at much higher concentrations. No other metal chelator or metal caused this toxicity. Neocuproines effects were eliminated by co-treatment with copper. Moreover, copper and DTC co-treatments altered neither the developmental toxicity of DTCs nor the lethality of copper. This suggests a more complex mechanism of toxicity. The potential for DTCs to alter the redox balance within the developing embryo is currently under investigation. The thiol containing antioxidant, glutathione, will protect and recover monomethyl dithiocarbamate (MMDTC) effects but not DTCs with larger substituents. Several other thiol and non-thiol containing antioxidants were investigated with limited to no protection from the effect. There were no differences in populations of apoptotic cells between treated and control embryos during the period when the malformation becomes apparent (18 to 24 hours post fertilization). Utilizing whole mount in situ hybridization probes targeting developmentally important transcripts, similar alterations exist between DTCs, degradation products, and neocuproine exposures. Whole-mount immunohistochemistry of several neuronal cell types was also investigated to identify potential neuronal targets. Utilizing the Affymetrix zebrafish microarray, 154 genes at 18 hpf and 26 genes at 24 hpf were differentially regulated greater than 2-fold. Only 12 (18hpf) and 10 (24 hpf) genes passed the t-test and 3 genes were shared between the two time points. Genes associated with muscle development, immune function, and glutathione maintenance were well represented in the gene set. Supported by Northwest Health Foundation # 10257, NIEHS #ES00210, #ES03850, and #ES07060.
Key words: pesticide, development, zebrafish, microarray
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