Effects of Methylmercury on the Developing Brain

Abstract

In an attempt to elucidate the mechanisms of methylmercury (MeHg) action on the developing brain, MeHg effects on neuronal migration and on proliferative neuroepithelial germinal cells within the ventricular zone of telencephalic vesicles were investigated in C57BL/6J mice. 3H-thymidine autoradiographic studies following acute and chronic MeHg intoxication in embryonic mice showed that heavily labeled neurons (generated on E-16) within specified regions of the cerebral cortex of prenatally intoxicated offspring were distributed irregularly throughout layers II and III, whereas those in controls were tightly clustered within the upper part of layer II. These findings support the hypothesis that prenatal MeHg poisoning results in anomalous cytoarchitectonic patterning of the cerebral cortex, and provide a possible morphological basis for some of the neurobehavioral abnormalities that may follow sublethal prenatal MeHg intoxication. Whether the irregular distribution of labeled neurons was due to the effects of MeHg on the dividing neuroepithelial germinal cells, on the process of neuronal migration, or on the final positioning of postmigratory neurons within the cerebral cortex remained unclear. Ultrastructural studies of telencephalic vesicles during acute phases of MeHg intoxication revealed the presence of acute degenerative changes within ventricular cells, characterized by spongy change and vacuolization of the cytoplasmic matrix and by loss of microtubules. 3H-thymidine autoradiography demonstrated features suggestive of disturbed interkinetic nuclear migration. Also noted were reduction of the mitotic indices of neuroepithelial germinal cells at the ventricular surface at 4 to 12 hours and early-phase mitotic arrest. These findings suggest that MeHg exerts significant effects on proliferating neuroepithelial germinal cells during the acute phases of MeHg poisoning, and may eventually affect the architectonic makeup of the cortical plate as the brain matures. Additional studies in our laboratory demonstrated 1) a failure of histotypic re-organization of dissociated embryonic cerebral cortical cells in rotation-mediated re-aggregation culture, 2) disturbances in neural cell adhesion molecule expression in PC12 cells, 3) modifications in the density of excitatory neurotransmitter L-glutamate receptors, 4) marked disturbances in the glutamate uptake mechanism of fetal astrocytes in vitro, and 5) reductions in cholinoceptive muscarinic receptor (M1 and M2) binding in selected regions of the cerebrum. Thus, MeHg may affect the developing brain through diverse pathogenetic pathways. Possible effects of mercurial compounds on the interaction between certain serine proteases and protease inhibitors during brain development are also discussed.