This project will examine the role of toxicant-induced function changes in neuronal cells such as the ability to maintain calcium homeostasis. This process plays a critical regulatory role in cell-cell communication and signaling. A disruption in intracellular calcium can disrupt the calcium-mediated signal transduction processes resulting in a cascade of intracellular effects. Intracellular calcium has been examined in subcellular components of the nervous system following exposure to environmental agents such as inorganic lead and polychlorinated biphenyls. Using a primary cell culture system of cerebellar granule cells, this project has examined the effects of PCBs and other neurotoxicants on cellular calcium homeostasis in both a population of cells as well as individual cellular responses. The results suggests that selected neurotoxicants, which exhibited varied cytoxicity and are known to alter cellular calcium homeostasis, altered calcium sequestration in the cerebellum in distinct patterns directly related to each chemical. It has been suggested that the neurotoxicity associated with polychlorinated biphenyls is mediated by the ortho-substituted congener. This project compared the effects of two PCB congeners, with different chlorine substitutions, on calcium homeostasis in cerebellar granule cells. 2,2'-Dichlorobiphenyl (DCBP), a putative neurotoxic congener, increased intracellular calcium and inhibited calcium sequestration by intracellular organelles and calcium-pumps in synaptic plasma membrane. The position and the number of chlorine substitutions on a biphenyl ring may have a significant implication for predicting potential effects of PCB congeners in the nervous sysytem and perturbations in calcium homeostasis may play a significant role in the neuroactivity of PCBs. Alterations in calcium homeostasis will be studied with reference to the second messenger system and the subsequent cascade of effects upon the nervous system.
