Brain's DNA Repair Response to Neurotoxicants
Final rept. 1 Jul 2003-31 Dec 2006
UNIVERSITY OF SOUTH FLORIDA TAMPA
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Parkinsons Disease PD is associated with death of dopaminergic DA neurons in the substantia nigra SN of the brain. Military personnel abroad are at a greater risk of exposure to pesticides and toxins which may selectively damage DA neurons in the SN and increase the probability of development of Parkinsons disease PD later in life. The toxins of interest are mitochondrial poisons that create a bioenergetic crisis and generate toxic oxyradicals which damage macromolecules, including DNA. We hypothesized that regulation of the DNA repair response within certain neurons of the SN the pars compacta may be a critical determinant for their vulnerability to these neurotoxicants. We have measured regional differences in the brains capacity to increase repair of oxidized DNA indicated by oxyguanosine glycosylase OGG1 activity to three distinct chemical classes of neurotoxins MPTP, two mycotoxins, and an organochloriine pesticide. We have found that the temporal and spatial profile of OGG1 activity across brain regions elicited by each class of neurotoxicant is distinct and unique. Even though all 3 toxicants caused various degrees of depletion of striatal dopamine, the temporal profile of DA depletion and OGG1 activity in striatum was distinct for each toxicant. DNA repair gene expression in response to OTA and dieldrin revealed differences in VTA and SN compartments that may relate to differential vulnerability to oxidative stressors.
- Medicine and Medical Research