Dissertation

Polychlorinated biphenyls dysregulate calcium homeostasis and dopamine transporters: Consequences on dopamine regulation

Bemis, Jeffrey C

2004

Overview

Polychlorinated biphenyls (PCBs) and methylmercury (MeHg) are two well-known neurotoxicants which persist in the environment and are commonly found in food destined for human consumption. Children whose mothers regularly consume such contaminated foods, both before and during pregnancy, demonstrate developmental and behavioral deficits associated with PCB and/or MeHg body burdens. Experiments performed in our laboratory demonstrated that combined exposure to PCBs and MeHg results in synergistic reductions in rat brain striatal tissue dopamine (DA) content and elevations in extracellular DA concentrations. Experiments in rat cerebellar granule cells revealed that exposure to PCBs+MeHg resulted in both dose- and time-dependent synergistic and antagonistic elevations in intracellular calcium concentrations. In order to improve our understanding of how these two toxicants may induce these effects, I used rat striatal synaptosomes to examine the potential consequences which PCB-induced increases in intracellular calcium and/or inhibition of dopamine transporters can have on DA. PCBs altered both synaptosomal tissue DA content and media DA concentrations, and intrasynaptosomal calcium. Manipulation of synaptosomal calcium by incubation in nominal calcium free medium or chelation of intracellular calcium, inhibited the ability of PCBs to reduce tissue DA content but did not affect PCB-mediated elevations in media DA concentrations. Because PCBs are known to inhibit monoamine transporter function, the consequences of this inhibition on the neurochemical effects observed following exposure of synaptosomes to PCBs was investigated. PCB-mediated inhibition of the dopamine transporter (DAT) was significantly correlated with both reductions in tissue DA and elevations in media DA concentrations. Inhibition of the vesicular monoamine transporter only correlated with an increase in tissue+media dihydroxyphenylacetic acid concentrations. Thus, PCB-induced alterations in tissue DA appear to be partly calcium-dependent and both tissue and media DA alterations appear to be partially mediated by the ability of PCBs to inhibit the uptake of DA by DAT. These studies provide a more complete understanding of the mechanistic pathways through which PCBs alter neurochemical function. Improving our understanding of how PCBs alter specific DA nerve terminal processes will provide insight into how PCBs may interact with other environmental contaminants to alter neurotransmitter function, and ultimately influence behavior.

• Publisher: ProQuest Dissertations & Theses
• Subject: Neurology / Neurosciences / Toxicology
• ISBN: 9780496732609, 0496732609