Volatile organic compound effects on brain and behavior

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Abstract Up to one million individuals stationed at Camp Lejeune, NC may have been poisoned by exposure to volatile organic compounds (VOCs) that had leached into the base drinking water from 1953 – 1987. The VA is now covering the health costs for Camp Lejeune veterans, civilian staff, and the resident families stationed at the base during that time for a variety of health conditions, including Parkinson's Disease (PD). Still, two of the main contaminants implicated in the toxic effects, trichloroethylene (TCE) and tetrachloroethylene (PCE), have yet to be shown to cause PD at the levels within 100-fold of those documented to have existed in the drinking water. TCE can cause PD at very high levels when given sub-chronically to rodents, and PCE has only been suggested to elicit PD in the animal models when it is combined with TCE. Neither the duration nor the dose of TCE or PCE used in past studies approximated the Camp Lejeune average exposure estimates. Therefore, the goal of this pilot project is to document the basic parameters necessary for chronic TCE (with and without PCE) exposure to cause behavioral and biological signs of PD neurotoxicity when delivered chronically in the water supply. Our working hypothesis is that chronic TCE+PCE ingestion through drinking water leads to behavioral changes indicative of underlying neuroinflammation in the substantia nigra pars compacta (SNPC) of the brain that, with continued ingestion, eventually leads to neurodegeneration of the SNPC dopamine (DA) neurons (i.e. development of PD). The testing of this hypothesis will occur by assessing function and neuropathology in exposed rats through 2 aims. Aim 1 will focus upon determining the possible contribution of drinking water TCE to PD pathology. An established toxic sub-chronic daily gavage TCE dose will be extended over a 6 month period in the drinking water to determine if the total cumulative exposure predicts the induction of PD or if daily high concentrations are necessary for TCE to induce PD. Following a similar experimental design, Aim 2 will determine if the addition of PCE to TCE-contaminated drinking water potentiates the induction of PD. Functional assessments, via behavioral testing, will occur during and following TCE or TCE+PCE exposure. At each time-point, rats will be assessed for motor coordination and sensorimotor reactivity. Upon completion of the last post- exposure behavioral test, all rats will have their brains harvested for subsequent brain assessments. The brains will be assessed for DA and DA-metabolite levels in the striatum and neuroinflammation/neuropathology in the SNPC. These post-mortem analyses, combined with the repeated behavioral testing over time, will provide the first evidence if chronic drinking water contamination by TCE or TCE+PCE are sufficient to cause a PD-like motor impairments or outright PD.