Date of Award

2024

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Diane Hardej

Second Advisor

Louis Trombetta

Third Advisor

Joseph Cerreta

Abstract

Ziram is a broad spectrum fungicide that is used on a variety of crops. It has been shown to display a wide array of toxicological effects, however, there is still a scarcity of mechanistic data regarding how it facilitates those effects. One of its presumed mechanisms of toxicity is due to the production of oxidative stress. However, whether the production of oxidative stress is due to its dimethyldithiocarbamate backbone, its metal moiety, or a combination of both, is still unknown. Contributing to the production of oxidative stress is ziram’s ability to alter essential metal homeostasis through transchelation of other essential metals. To study the individual effects of the backbone structure and the metal moiety, sodium-dimethyldithiocarbamate and zinc chloride were used in conjunction with Ziram. This study sought to investigate the effects of ziram and its individual components with regards to altered metal homeostasis, and the downstream effects of this disturbance on the antioxidant defense system, along with the physiological parameters of the kidney and liver of exposed rats. Rats were orally dosed for 6-weeks with either PEG-400 (vehicle), ziram, sodium-dimethyldithiocarbamate, or zinc chloride. Metal analysis demonstrated increases in zinc and copper levels in the liver along with increases in zinc in the kidneys of animals treated with ziram only. Analysis of antioxidant parameters demonstrated increases in the glutathione defense system and total antioxidant levels in the liver and kidney of animals treated with ziram. Histopathological evaluation of ziram and sodium-dimethyldithiocarbamate treated tissue showed vacuolization and lipid deposition in the liver. In renal tissue, thickening of the basement membrane and vacuolization of tubular cells accompanied by increases in kidney injury marker-1 were seen in animals treated with ziram and sodium-dimethyldithiocarbamate. The kidneys of ziram and sodium-dimethyldithiocarbamate exposed animals demonstrated deleterious effects which is a novel finding, as kidney has not previously been shown to be a target organ of toxicity with these agents. It is concluded that the overall toxicological profile of ziram is mediated by an intrinsic property of the compound itself, rather than being attributed solely to any individual structural component.

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