ORCID

https://orcid.org/0000-0002-8744-9112

Date of Award

2022

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Louis D. Trombetta

Second Advisor

Joseph M. Cerreta

Third Advisor

Diane Hardej

Abstract

Mancozeb (MZ), an ethylene bis-dithiocarbamate complexed with the metals manganese and zinc, is a broad-spectrum fungicide used primarily on orchards and vineyards. Disulfiram (DS, Antabuse®), a diethyldithiocarbamate, is an FDA-approved drug used for alcohol aversion therapy. Both dithiocarbamates (DTCs) have shown neurological effects including motor impairment, muscle weakness, and hind-limb paralysis, although the mechanism of toxicity is not understood. The purpose of this study is to determine how these neurotoxic compounds are damaging striated muscle of rats. Adult, male Long-Evans rats were administered either 250mg/kg MZ or 750mg/kg DS via oral gavage 3x/week for four weeks. Animals were euthanized 24 hours after their final dose. Vastus medialis and right ventricular myocardium were collected and processed for transmission electron microscopy (TEM), analysis of metal levels, structural protein quantification, total antioxidant capacity, lipid peroxidation, and NOX2 levels. Tibialis cranialis was processed for scanning electron microscopy (SEM) to identify changes in the muscle fibers and their associated nerves. Both DTCs are causing toxicity to each muscle type, but their effects are occurring via different mechanisms. In skeletal muscle, morphological alterations from DTC treatment include myofibril splitting and degeneration, Z-disc streaming, flocculent mitochondria, dilated t-tubules, and nerve blebbing. Morphological changes in DS-treated rats were more severe and mimicked denervation atrophy. MZ and DS-treatment resulted in a significant decrease of NOX2 levels. MZ treatment resulted in a significant decrease in α-actinin.In myocardium, morphological alterations include myofibril splitting, swollen mitochondria, widened gap junction of the intercalated disc, and presence of multivesicular bodies. MZ treatment resulted in decreased manganese and increased zinc levels, and the morphological changes mimic dilated cardiomyopathy in humans. DS-treatment resulted in decreased manganese and increased copper levels, decreased desmin, increased α-actinin and dystrophin, and increased 4-HNE adducts. Based on these morphological and biochemical changes, it is apparent that dithiocarbamates induce myopathy, although the extent of their toxicity is musclespecific.

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