The long-term objective of the proposed research is to elucidate the mechanism by which chronic exposure to very low concentrations of inhalant anesthetics and other halogenated alkanes and alkenes leads to pathologies of neural development. Chronic exposure to low doses of inhalation anesthetics has been shown to cause alterations in synapse formation and a deficit of myelination in the central nervous system of developing animals. Although much effort has been devoted to defining the causes of acute hepatic toxicity following anesthesia, no systematic attempt has been made to define the causes of the neural pathologies observed in developing animals chronically exposed to subanesthetic doses of haloalkanes. The proposed project is intended specifically to determine whether trifluoroacetic acid (TFA), the product of the oxidative metabolism of widely used inhalation anesthetics, perturbs key metabolic pathways in glial cells. TFA is exceedingly caustic yet has been considered to be non-toxic simply because those who first investigated its potential toxicity found that high doses of TFA were required to kill laboratory animals. Preliminary studies performed in the laboratory of the PI suggest on the contrary that TFA may exert a profound effect on the metabolism of nucleotides and amino acids in glial cells. The experiments outlined below will specifically test whether TFA affects the rates of synthesis of DNA, proteins, glycoproteins, and fatty acids in cultured C6 glioma cells. The tendency of TFA to disrupt the ultrastructure of C6 cells and to hinder their proliferation will also be examined. If the existence of a lesion to the ultrastructure, intermediary metabolism, or proliferative potential of these glial cells is rigorously verified, progress will have been made toward understanding the mechanism of toxicity of halogenated alkanes and alkenes to the developing central nervous system.
