ToxSci Advance Access published online on February 25, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm027
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Polychlorinated Biphenyl-Induced Neurotoxicity in Organotypic Co-Cultures of Developing Rat Ventral Mesencephalon and Striatum
PCB-INDUCED NEUROTOXICITY IN CO-CULTURES
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* School of Public Health, University at Albany, Albany, NY 12222
Wadsworth Center, New York State Department of Health, Albany, NY 12201
1 Address Correspondence to: Richard F. Seegal, Wadsworth Center, New York State Dept. of Health, P.O. Box 509, Empire State Plaza, Albany, NY 12201. seegal{at}wadsworth.org, Phone: 518-473-4378, Fax: 518-486-1505
Received January 9, 2007; revision received February 7, 2007; accepted February 9, 2007
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Abstract |
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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 co-culture system of developing rat striatum and ventral mesencephalon (VM). Exposure of the co-cultures 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 (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC). PCB exposure also increased neuronal cell death in both the VM and striatum and reduced the number of DA neurons in the VM. Decreases in both tyrosine hydroxylase (TH) and DA transporter (DAT) protein expression were shown by Western blot analysis in PCB-exposed co-cultures. 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 GABAergic neurons. Indeed, Western blot analyses revealed up to a 50% reduction in both VM and striatal glutamic acid decarboxylase 65/67 (GAD 65/67). Analysis of tissue PCB levels revealed that concentrations were at or below 10 parts per million (ppm) following all exposure paradigms. This co-culture system provides an excellent model in which 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.
Key Words: PCBs; dopamine; GABA; substantia nigra; basal ganglia; development.