The response of glial fibrillary acidic protein (GFAP) and GFAPmRNA in the central nervous system as an index of neurotoxicant exposure

Previous studies showed that acute exposure (7-9 mg/kg) to Trimethyltin (TMT) induces increases in the concentration of a cytoskeletal protein, glial fibrillary acidic protein (GFAP). An acute study (7 mg/kg TMT s.c.) was performed in rats to replicate published effects on histopathological and behavioral measures. Twenty-one days after acute TMT or vehicle, brain tissues were assayed for GFAP and showed a significant increase in the hippocampus of the TMT-exposed animals. To evaluate the GFAP response during longer term exposures, GFAP concentrations along with behavioral and histopathologic changes were assessed in four groups of rats exposed to TMT in drinking water: 3 ppm TMT for 28 days followed by plain water for 14 days (Group 1); 9 ppm for 5 days and water for 17 days (Group 2); 3 ppm for 20 days, 9 ppm for 5 days and water for 2 days (Group 3); or 0 ppm for 42 days (control group). Group 1 showed significantly elevated GFAP levels in the hippocampus 14 days after the 28 day exposure period and Group 3 had significantly elevated GFAP in the cortex and hippocampus on day 27 of exposure. An effect of TMT exposure upon GFAP synthesis was shown by another group of rats exposed to TMT at 3 ppm for 28 days. Significant increases in GFAP mRNA preceded the increase in GFAP by a time range of between 1 and 11 days. This suggests de novo synthesis of GFAP as an important mechanism by which exposure to TMT increased concentrations of GFAP. These results support the following conclusions: that elevated concentrations of GFAP in the brain can indicate neurotoxicity (defined as behavioral and neuronal change) after subacute low level or after acute exposure to TMT; that measures of GFAP and GFAP mRNA were less sensitive than measures of behavior or neuronal morphometry; prior exposure to subclinical levels of TMT increased sensitivity to subsequent exposure.