Developmental Neurotoxicity of Lead and Methyl Mercury Lead (PB) and methyl mercury (MM) are well known environmental contaminants. Exposure to these metals has been shown to affect developing brains to a greater extent. Children are more sensitive to Pb than adults whereas, both children and adults are sensitive to MM. A number of second messenger systems have been shown to play a key role in the development of the brain. However, the underlying mechanism of neurotoxicity of Pb or MM is not well understood. Our hypothesis is that developmental exposure to Pb or MM affect signal transduction process, possibly related to the modulation of nitric oxide as well as alterations in receptor-mediated phosphoinositide hydrolysis and protein kinase C. In order to test our hypothesis, we propose the following specific aims: a) Low levels of pb or MM exposure to rats during developmental results in alteration of second messenger system; and b) Conduct in vitro studies to determine the direct or indirect effects of Pb or MM on the second messenger systems. Experimental design include: a) Treat the sam perinatally with two doses of Pb (0.1% and 0.2%) or MM (0.01% and 0.02%) through drinking water from gestation day 6 up to weaning (postnatal day 20);b) Determine the neurochemical parameters such as nitric oxide synthase, inositol polyphosphate receptor binding activities, phosphoinositide (PI) hydrolysis, phospholipase C, protein kinase C and nitric oxide-mediated PI hydrolysis in hippocampus, cerebellum and frontal cortex at 2,5,10,15,20,25,30, and 60 postnatal days; c) Study the concentration- response of Pb or MM on the neurochemical parameters listed in b. In this study, nanomolar concentrations of metals will be used; d) Determine the concentrations of Pb and MM in blood and brain of rats in order to correlated in vivo and in vitro results. Two undergraduates and two graduate students will be involved in this research as student research participants. After an initial period of training, these students are expected to complete certain experiments on their own. The experiences gained in this research will motivate them to choose careers in biomedical Sciences.
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