|Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1999: ¥2,600,000 (Direct Cost: ¥2,600,000)
The present study was conducted in order to study the molecular mechanisms of the impairment in hippocampal functions following the administration of trimethyltin (TMT). TMT is a byproduct of certain plastics, and closely related to well known endocrine disruptors, tributyltin and triphenyltin. TMT was found to induce a profound loss of CA3 pyramidal cells as well as a moderate loss of CA1 cells, starting 4-5 days after dosing. This neuronal death was preceded by an early and transient elevation of plasma corticosterone, which was partially blocked by the pretreatment of interleukin-1 receptor antagonist. Behaviorally, TMT intoxication was characterized by an early and transient development of seizures, followed by a persistent aggression and learning impairments. It is thus suggested that TMT induced an early activation of hypothalamo-pituitary-adrenal axis, presumably preceded by the involvement of immuno-active cytokines, which may trigger the neuronal death via glucocorticoid (GC) receptors in the hippocampus.
Further study was designed with use of a combination of adrenalectomy and administration of type I and II specific GC-receptor agonists. The suppression of an early elevation of plasma corticosterone by means of metyrapone adinistration resulted in the rescue of CA1 cell death, but not of CA3 cells, and subsequently, at least a partial improvement of learning impairments., Dexamethasone, a type II GC receptor agonist, but not aldosterone, a type I receptor agonist, blocks both the neuronal and behavioral impairment in TMT rats. The involvement of cytokines such as IL-1α and -1β were also examined. Supplemental treatment with corticosterone or dexamethasone cancelled adrenalectomy-induced enhancement of IL-1α and-1β expression, suggesting that TMT-induced OL-1α and-1β production was regulated via type II GC receptors.