Methylmercury Antagonizes the Survival-Promoting Activity of Insulin-like Growth Factor on Developing Cerebellar Granule Neurons

Abstract

Methylmercury (MeHg), a widely distributed environmental toxicant, has a profound effect on the developing central nervous system. Human exposure to MeHgin uterohas led to severe neurological abnormalities in children, including cognitive and motor dysfunction. The abnormalities appear to result from death of neurons and altered cytoarchitecture in the developing CNS. Death of cerebellar granule neurons occurs following both adult andin uteroexposure to MeHg, indicating the vulnerability of these cells to the toxic action of MeHg. The studies reported here use purified cultures of developing mouse cerebellar granule neurons to evaluate whether MeHg directly acts on these developing neurons to inhibit their survival. These experiments show that, in purified cultures of cerebellar granule neurons maintained in medium containing insulin-like growth factor I (IGF-I) as the only added trophic factor, low micromolar concentrations of MeHg inhibit granule neuron survival. The reduction in survival produced by MeHg can be partially reversed by increasing the concentration of IGF-I, suggesting an antagonism between MeHg and IGF-I. Inhibition of phosphoinositide 3-kinase (PI3-K), an intracellular mediator of IGF-I's survival promoting action, can synergistically enhance MeHg's effect on survival. Further studies indicate that MeHg's inhibition of survival involves apoptotic death of granule neurons. This apoptosis appears to require activation of gene transcription and may involve an increase in expression of the immediate early transcription factor c-Jun. These studies suggest that MeHg can act on developing granule neurons to increase the expression of c-Jun and antagonize IGF-I's survival promoting activity.