Pilot Project: 1 Effect of B(a)P Exposure on Dopaminergic Mechanisms

Meharry Medical College, Nashville TN

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Abstract

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