Polychlorinated biphenyls (PCBs) decrease basal ganglia dopamine (DA) function, including reductions in DA content and the number of tyrosine hydroxylase positive (TH+) neurons in the substantia nigra (SN) as well as inhibiting monoamine transporters. These data, however, have been gathered only in males and hence the effects of PCBs on DA function in the female are largely unknown. The need for these data become even more relevant because former capacitor workers exposed to extraordinarily high levels of PCBs show increased risk for mortality due to Parkinson's disease and a negative relationship between serum PCB concentrations and DA terminal densities only in women. Because of these epidemiological findings we hypothesize that ovarian hormones, including reductions induced by PCBs or following either menopause or ovariectomy (OVX), events known to reduce basal ganglia monoamine transporters and the number of TH+ neurons, will interact with, and exacerbate, similar PCB-induced changes in basal ganglia DA function, resulting in greater DA dysfunctions in hormonally-depleted females than incomparably- exposed males. These hypotheses will be tested in a series of experiments that will characterize the effects of PCB exposure in male and female rats and the consequences of PCB-induced changes in estrus cyclicity, OVX and ovarian hormone replacement on DA function, including inhibition of monoamine transporters, alterations in cytosolic and extra-neuronal DA and its metabolites, the number of TH+ SN neurons, and measures of oxidative stress and mitochondrial function. We will also measure serum and brain concentrations of PCBs to determine the role of gender in modifying PCB body burdens. The proposed experiments will provide information on the effects of PCB exposure on DA function in the female, a population that has been largely ignored in neurotoxicologicalstudies and will determine the consequences and mechanisms by which ovarian hormones, including their withdrawal, influence PCB- induced changes in DA function, oxidative stress and mitochondrial function. These experiments will set the stage for further study of the role of gender and ovarian hormones modifying the toxicity of other environmental and occupational dopamine neurotoxicants.
| Seegal, Richard F; Marek, Kenneth L; Seibyl, John P et al. (2010) Occupational exposure to PCBs reduces striatal dopamine transporter densities only in women: a beta-CIT imaging study. Neurobiol Dis 38:219-25 |
| Miller, V M; Lawrence, D A; Coccaro, G A et al. (2010) Sex effects of interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice. Brain Res 1318:11-22 |
| Miller, V M; Lawrence, D A; Mondal, T K et al. (2009) Reduced glutathione is highly expressed in white matter and neurons in the unperturbed mouse brain--implications for oxidative stress associated with neurodegeneration. Brain Res 1276:22-30 |
