title: Trimethyltin exposure in the rat induces delayed changes in brain-derived neurotrophic factor, fos and heat shock protein 70.
abstract: Trimethyltin chloride (TMT) treatment in adult rats leads to limbic brain lesions that are detectable with classical neuropathological techniques 3 days after exposure. In particular, the hippocampal cells of the CA3c region are affected. The temporal and regional characteristics of TMT toxicity as reflected in changes of activity-dependent factors were studied in adult male Sprague-Dawley rats using quantitative in situ hybridization and immunohistochemistry. No significant alterations in the BDNF mRNA were detected in hippocampus and cerebral cortex 1 and 4 h after 8 mg TMT/kg. Three days after TMT, a significant increase in BDNF mRNA was detected in CA1, and increases in BDNF mRNA were also seen in cortical layers. An increase in BDNF hybridization signal was seen over scattered neurons within and outside CA3c at 3 days. Four h after 8 mg TMT/kg, BDNF immunoreactivity was reduced in the pyramidal cells of the CA3c and CA1 regions as well as in the dentate gyrus. No significant change in BDNF immunoreactivity was seen in hippocampus or cerebral cortex 3 days after TMT. BDNF interacts with the high-affinity receptor tyrosine kinase B (trkB). No immediate alteration in trkB mRNA was seen in hippocampus or cerebral cortex after 8 mg TMT/kg, while at 3 days trkB mRNA was significantly reduced in the CA3c pyramidal cell layer. No changes could be detected in neurotrophin-3 mRNA at either 1, 4 h or 3 days after TMT. Three days after 8 mg TMT/kg, a major induction of hsp70 mRNA occurred in a subset of neurons in the CA3c region, concomitant with an increased expression of c-fos mRNA as well as Fos protein in the hilar region of hippocampus. Hence, an early and transient decrease in BDNF appears to occur after TMT exposure, which is succeeded at 3 days by increases in BDNF, c-fos and hsp 70 mRNAs, concomitant with a decrease in trkB mRNA in regions known to be vulnerable to TMT. These results demonstrate that TMT causes a delayed, spatially restricted increase in activity-dependent gene expression, making TMT-induced disturbances an interesting model of neurodegenerative events.
authors.affiliation: Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Andersson
authors.forename: C
authors.initials: C
authors.lastname: Wetmore
authors.forename: E
authors.initials: E
authors.lastname: Lindqvist
authors.forename: J
authors.initials: J
authors.lastname: Luthman
authors.forename: L
authors.initials: L
authors.lastname: Olson
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020801:Receptor, Ciliary Neurotrophic Factor; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D014298:Trimethyltin Compounds / Q000633:toxicity*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D014298:Trimethyltin Compounds; C046488:trimethyltin; D020794:Receptor Protein-Tyrosine Kinases; D020812:Receptor, trkC