Polychlorinated Biphenyl-Induced Neurotoxicity in Organotypic Cocultures of Developing Rat Ventral Mesencephalon and Striatum

Abstract

Polychlorinated biphenyls (PCBs) are persistent environmental contaminants that are highly toxic to the developing nervous system, particularly via their disruption of dopamine (DA) function. In order to characterize the effects of PCBs on the developing basal ganglia DA system, we utilized an organotypic coculture system of developing rat striatum and ventral mesencephalon (VM). Exposure of the cocultures to an environmentally relevant mixture of PCBs for 1, 3, 7, or 14 days reduced tissue DA concentrations and increased medium levels of DA, homovanillic acid, and 3,4-dihydroxyphenylacetic acid. PCB exposure also increased neuronal cell death in both the VM and the striatum and reduced the number of DA neurons in the VM. Decreases in both tyrosine hydroxylase and DA transporter protein expression were shown by Western blot analysis in PCB-exposed cocultures. There was also an increase in neuronal cell death, identified by Fluoro Jade B, prior to a reduction in the number of VM DA neurons; we hypothesize this increase to be partly due to a loss of gamma-aminobutyric acid (GABA) neurons. Indeed, Western blot analysis revealed up to a 50% reduction in both VM and striatal glutamic acid decarboxylase 65/67. Analysis of tissue PCB levels revealed that concentrations were at or below 10 ppm following all exposure paradigms. This coculture system provides an excellent model to examine the chronology of PCB-induced neurotoxic events in the developing basal ganglia. Our results suggest that PCB-induced neurotoxicity in the developing basal ganglia involves GABAergic neuronal dysfunction, in addition to PCBs' better-recognized effects on DA function. These findings have important implications for disease states such as Parkinson's disease and for developmental deficits associated with exposure to PCBs and toxicologically similar environmental contaminants.