Graduate Thesis Or Dissertation

 

Developmental ramifications of dithiocarbamate pesticide exposure in zebrafish Public Deposited

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/hx11xj53m

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  • Dithiocarbamates are widely used agricultural pesticides, industrial chemicals and effluent additives. DTCs and their related compounds have historical and current relevance in clinical and experimental medicine. DTC developmental toxicity is well established, but poorly understood. Dithiocarbamates according to the U.S. EPA have a mechanism of action involving, "the inhibition of metal-dependent and sulfhydryl enzyme systems in fungi, bacteria, plants, as well as mammals." We hypothesized that by using the zebrafish development model we could better define the mechanism of action of DTCs and for the first time establish a molecular understanding of DTC developmental toxicity in vertebrates. We have established that all types of dithiocarbamate pesticides and some degradation products have the potential to elicit a common toxic effect on development resulting in a distorted notochord and a significant impact to the body axis. We provide evidence to support the hypothesis that metal chelation is not the primary mechanism of action by which DTCs impact the developing vertebrate. By manipulating the exposure window of zebrafish we hypothesized that somitogenesis was the targeted developmental process. We tested this by using the Affymetrix microarray to observe gene expression induced by the N-methyl dithiocarbamate, metam sodium (NaM). Throughout this process it is clear that genes related to muscle development are perturbed. These gene signatures are consistent with the morphological changes observed in larval and adult animals and that somitogenesis is the developmental target. Novel findings include the targeting of many redox sensitive targets and a possible role for the TGF3 signaling pathway. Thiol status is a critical modifying factor in DTC developmental toxicity but this toxicity does not result from dramatic cell death. It is possible this outcome is reached by DTCs and its primary degradation products through several pathways. Taken together we can hypothesize that the development mechanism of action of DTCs involves the depletion, oxidation, or adduct formation of critical thiols in the somites of developing vertebrates. It is likely copper plays some role but it is not the target. The proximate toxicant is likely a DTC mixture of parent and degradation products acting to alter the redox thiol state of the animal.
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