ORCID

https://orcid.org/0009-0007-3799-0078

Date of Award

2024

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Louis D Trombetta

Second Advisor

Joseph Cerreta

Third Advisor

Sue Ford

Abstract

The herbicide glyphosate and the fungicide mancozeb are globally applied on a variety of agricultural crops. Residues of both pesticides are frequently detected in food and water. Combined exposure to both compounds is therefore possible. Glyphosate and mancozeb have been separately investigated in previous studies and were shown to induce neurotoxicity. The current study investigates the cytotoxicity of different glyphosate and mancozeb combinations including mixture of mancozeb + glyphosate, combination of mancozeb followed by glyphosate and combination of glyphosate followed by mancozeb and compares neurotoxicity seen with the combinations to that of glyphosate or mancozeb using mouse neuroblastoma Neuro-2a cells. Significant decreases in cell viability were observed with glyphosate (500-10,000 µM), mancozeb (4-10 µM) and with glyphosate (100 µM) and mancozeb (6 µM) combinations. Glyphosate and mancozeb combinations resulted in greater decrease in cells viability than that induced by the same concentration of glyphosate when tested alone. Light microscopy observations were consistent with cell viability data. Scanning electron microscopy (SEM) observations showed more prominent morphological alterations in glyphosate and mancozeb combination groups compared to either glyphosate or mancozeb including, neuretic processes disruptions, loss of retraction fibers, blebbing and distorted plasmalemma. Metal analysis was done using Inductively Coupled Plasma-Optical emission spectroscopy (ICP-OES). Mancozeb and combinations of glyphosate and mancozeb resulted in intracellular elevations in copper, manganese and zinc levels. Intracellular metal levels elevations caused by combination treatments were induced at a glyphosate concentration that didn’t affect metal levels when glyphosate was tested alone. Mancozeb and combinations of glyphosate and mancozeb induced a decrease in GSH/GSSG ratio. Combinations of glyphosate and mancozeb induced a greater decrease in GSH/GSSG ratio than that exerted by glyphosate alone. Antioxidant post-treatment with butylated hydroxytoluene did not alleviate cytotoxicity of either mancozeb or glyphosate + mancozeb mixture. These findings concluded that mancozeb and combinations of glyphosate and mancozeb cause cytotoxicity in Neuro-2a cells through inducing intracellular metal levels elevations leading to redox balance disruptions and oxidative stress. It is further concluded that glyphosate and mancozeb combinations induce greater cytotoxicity, more intracellular metal elevations and redox balance disruptions in Neuro-2a cells than glyphosate alone.

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