Date of Award

2022

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Diane Hardej

Second Advisor

Louis Trombetta

Third Advisor

Joseph Cerreta

Abstract

Mancozeb is a fungicide used globally on a variety of crops. Studies on mancozeb attribute its toxicity to oxidative stress. There is debate if oxidative stress is caused by mancozeb’s metal components, manganese and zinc, its ethylenebis(dithiocarbamate) backbone, or both together. The ability of mancozeb to alter metal homeostasis and chelate copper has also been implicated in its toxicity. Manganese, zinc, copper, and iron are essential in the body such that deficiency results in disease. However, these metals in excess have toxic consequences. We sought to study the mancozeb’s ability to alter essential metal homeostasis, induce oxidative stress, and affect the glutathione defense system. To study the effects of the metal moieties and backbone separately, a mixture of manganese chloride and zinc chloride, and nabam (disodium ethylenebis(dithiocarbamate)) were used. Rats were treated via oral gavage for twenty-eight days with either PEG 400 (vehicle), nabam, manganese and zinc mixture, or mancozeb. Analysis of manganese, zinc, copper, and iron was done by using Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES). Mancozeb increased manganese in the gastrointestinal tract. Mancozeb and nabam increased copper in the kidneys and colon, and mancozeb decreased iron in the colon and feces. Nabam increased iron in the spleen and serum. Mancozeb did not produce oxidative stress via lipid peroxidation or protein carbonyls. Total glutathione, glutathione peroxidase and glutathione reductase activity were measured to assess glutathione defense activation. Total glutathione increased in the kidney, liver, and duodenum with mancozeb treatment. Mancozeb increased glutathione peroxidase activity in liver and glutathione reductase activity in liver and ileum. Nabam increased total glutathione and glutathione reductase activity in the liver and ileum. Histological examination of mancozeb and nabam exposed tissues showed focal alterations to crypt cells in the ileum and duodenum which suggest mild toxicity. It is concluded that mancozeb exposure alters metal homeostasis with varying degrees in the GI tract, liver, and kidney with the EBDC backbone playing a prominent role as similar results were observed with nabam exposure. It is further concluded that mancozeb exposure activates the glutathione defense system in kidney, liver, and duodenum suggesting a toxic response by this agent.

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