| The developing nervous system has long been recognized as a primary target for environmental lead toxicity. To date, most efforts to understand the impact of lead on the brain have focused on neurons and astroglia as cellular targets for the metal. Little is known about the role of oligodendroglia, the myelin-forming cells in the central nervous system, in lead-induced neurotoxicity. The present study examines lead-induced deficits of myelinogenesis in the developing rat brain and oligodendroglial cell toxicity employing primary cultures of oligodendrocyte progenitor cells. Chronic dietary lead exposure decreased the cellular levels of myelin-specific galactolipids and their metabolic enzymes, as well as those of the myelin marker protein, 2′,3 ′-cyclic nucleotide 3′-phosphohydrolase, in rat pups exposed to lead in utero and subsequently through maternal milk from exposed mothers and in drinking water following weaning. In vitro, oligodendrocyte progenitors were found to be highly vulnerable to lead toxicity, whereas mature oligodendrocytes were relatively resistant. Lead acetate at a concentration as low as 1 μM retarded the developmental maturation of oligodendrocyte lineage cells, as evidenced by cell morphology and the emergence of stage-specific immunochemical markers. Furthermore, lead decreased the biosynthesis of galactolipids, as detected by metabolic radiolabeling with 3H-D-galactose and altered the developmental profile of galactolipid metabolic enzymes, consistent with the lead-induced delay of oligodendrocyte developmental maturation. It is noteworthy that while lead was capable of killing the cells in a dose-dependent manner, the metal inhibited the proliferation and differentiation of oligodendrocyte lineage cells, in vitro, at concentrations that did not decrease cell viability. These responses to lead exposure require the activation of protein kinase C. The results clearly indicate that in vitro cultured oligodendroglial progenitor cells are a significant target for lead toxicity. Chronic lead exposure may thus impact brain development by impairing timely myelinogenesis due to perturbation of the early developmental commitment of oligodendroglial progenitors, as well as loss of myelinating cells. It also appears that perturbation of galactolipid pathway during the developmental maturation of oligodendrocytes may represent a contributing mechanism for lead-induced neurotoxicity. |
