TOXICITY OF DIELDRIN FOR DOPAMINERGIC-NEURONS IN MESENCEPHALIC CULTURES

Dieldrin can be retained for decades in lipid-rich tissue and has been measured in some postmortem PD brains. Dieldrin has been reported to deplete brain monoamines in several species and has been shown to inhi bit mitochondrial respiration. To further investigate the possibility that it may be involved in the pathogenesis of parkinsonism, its toxic ity for dopaminergic (DA) neurons was assessed in a mesencephalic cell culture model. Primary neuronal cultures of mesencephalic neurons wer e prepared from fetal rats or fetal mice, grown for 1 week and incubat ed with Dieldrin (0.01-100 mu M) for 24 or 48 h. Toxicity for DA neuro ns was determined by measuring density of surviving tyrosine hydroxyla se immunoreactive (TH-ir) cells. Toxicity for gamma-aminobutyric acid (GABA)-ergic neurons was determined by measuring survival of glutamate decarboxylase (GAD)-ir neurons. General, nonselective cytotoxicity wa s determined by counting cells visualized by phase contrast microscopy or by DAPI-stained cells with fluorescence microscopy. Dieldrin expos ure for 24 h resulted in a dose-dependent decrease in survival of TH-I R cells (DA neurons) with a 50% decrease (EC50) produced by 12 mu M in rat mesencephalic cultures. Dieldrin also produced a dose-and time-de pendent decrease in mouse DA-ergic and GABA-ergic neurons in mouse mes encephalic cultures. GABA-ergic neurons were less sensitive to the tox in compared to DA-ergic neurons. Cellular uptake of H-3-DA was also af fected by lower concentrations of Dieldrin (EC50 = 7.98 mu M) than up- take of H-3-GABA (EC50 = 43 mu M) Thus, Dieldrin appears to be a relat ively selective DA-ergic neurotoxin in mesencephalic cultures. Dieldri n, which may be ubiquitous in the environment, is proposed as an agent which can initiate and promote dopaminergic neurodegeneration in susc eptible individuals. (C) 1998 Academic Press.