Sally Thompson

Project title: Modulation of Glutathione Associated with Methylmercury Exposure in Mice

Degree: PhD | Program: Environmental Toxicology (Tox) | Project type: Thesis/Dissertation
Completed in: 1996 | Faculty advisor: Terrance J. Kavanagh


The purpose of this dissertation was to examine the interaction between methylmercury and GSH, and to determine if methylmercury exposure altered GSH biosynthesis. In order to address these questions mice were exposed to methylmercury in the drinking water (0, 3 or 10 ppm) for a prolonged period of time (ranging from 4-12 weeks). Adult mice were evaluated for effects on the immune system, and for alterations in GSH status and biosynthesis in the liver, kidney and brain. In addition, pregnant mice were exposed prior to and throughout gestation, and fetuses were examined for congenital malformations and alterations in GSH status and biosynthesis.Exposure to methylmercury for 4 weeks resulted in alterations in thymocyte subset percentages, a decrease in GSH levels in splenocytes, and a decrease in intracellular calcium response in splenocytes. Exposure to methylmercury for 12 weeks resulted in up-regulation of glutamylcysteine ligase activity in the brain. This was accompanied by an increase in the protein levels of the enzyme, but there were no changes in GSH levels.Developmental exposure to methylmercury resulted in a decrease in the fecundity of the female mice, severe congenital malformations, decreased levels of albumin and $\alpha$-fetoprotein in the yolk sac and pronounced alterations in GSH homeostasis in the yolk sac and fetus. There was a decrease in the amount of reduced glutathione in the fetus and an increase in the amount of oxidized glutathione, resulting in an altered fetal redox status. There was no change in the activity of glutamylcysteine ligase in the fetus with exposure. In contrast, there was an increase in the total glutathione levels in the yolk sac at the low dose (3 ppm) but no change at the high dose (10 ppm). This was accompanied by a 2-fold increase in glutamylcysteine ligase activity, protein levels, and mRNA levels at both doses of methylmercury.In summary, mice chronically exposed to methylmercury had alterations in immune status, alterations in GSH biosynthesis in the adult brain, and alterations in GSH homeostasis and biosynthesis during fetal development. URI