Benzo(a)pyrene [B(a)P] is a member of the polycyclic aromatic hydrocarbon (PAH) compounds. Potential? sources of B(a)P include combustion of coal, wood heating, cigarette smoking, and consumption of? contaminated food and water. Whereas the carcinogenicity of PAHs including B(a)P has been extensively? studied, much less is known about the neurotoxic effects of B(a)P. Maternal exposure to airborne PAHs? during pregnancy was associated with a reduction in head circumference in children that may correlate with? lower IQ and poorer cognitive functioning. In rats, gestational exposure to B(a)P induced decrements in birth? index, N-methyl-D-aspartate receptor mRNA expression, long-term potentiation, and fixed-ratio performance? learning behavior. Alterations in motor behavior, a measure of sensory, motor and associative function, has? been widely used as an early indicator of nervous system dysfunction. In that regard, studies show that? acute exposure to B(a)P and fluroranthene produces a variety of behavioral deficits that are specific to the? nervous system, including decreased motor activity, and responsiveness to sensory stimuli. The? neurochemical pathways mediating acute neurotoxic effects of B(a)P have not been elucidated but there are? indications that the dopaminergic system may be involved. Studies using radiolabeled B(a)P revealed that? B(a)P is capable of crossing the blood-brain barrier with the highest levels of radioactivity found in the? olfactory lobes, striatum and cerebellum. Intracranial injections of PAHs induced marked inhibition of tyrosine? hydroxylase in the striatum and hippocampus. Furthermore, a single dose of B(a)P produced decreases in? striatal concentrations of dopamine and noradrenaline. Given that oxidative stress plays a prominent role in? B(a)P carcinogenicity, the hypothesis is that B(a)P exposure will induce oxidative stress and lead to deficits? in dopaminergic function. The proposed Specific Aims are: 1) To determine if subacute inhalation exposure? to B(a)P will decrease locomotor activity in mice. 2) To determine if the presence of reactive metabolites of? B(a)P and markers of oxidative stress are localized to dopaminergic brain regions that are implicated in? motor function. 3) To assess the susceptibility of transgenic mice overexpressing the antioxidant enzymes? Cu.ZnSOD or catalase to B(a)P-induced deficits in dopaminergic markers. Studies will provide information? on the mechanism of the neurotoxic effects of B(a)P and strategies for intervention.
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