GLIAL CELL-SPECIFIC DIFFERENCES IN RESPONSE TO ALKYLATION DAMAGE

Oligodendrocytes are preferentially sensitive to the toxic, carcinogen ic, and teratogenic effects of methylnitrosourea (MNU). The mechanisms responsible for this enhanced sensitivity have not been fully elucida ted. One of the most vulnerable cellular targets for this chemical is mitochondrial DNA (mtDNA). To determine if differences in mtDNA damage and repair capacity exist among the different CNS glial cell types, t he effects of MNU exposure on oligodendroglia, astroglia, and microgli a cultured separately from neonatal rat brain were compared. Quantitat ive determinations of mtDNA initial break frequencies and repair effic iencies showed that whereas no cell type-specific differences in initi al mtDNA damage were detected, mtDNA repair in oligodendrocytes, oligo dendrocyte progenitors, and microglia was significantly reduced compar ed to that of astrocytes. In astrocytes, and all other cell types prev iously evaluated in our laboratory, >60% of N-methylpurines were remov ed from the mtDNA by 24 hr. In contrast, only 35% of lesions were remo ved from mtDNA of oligodendrocytes, oligodendrocyte progenitors, and m icroglia during the same time period. Mitochondrial perturbations by a variety of xenobiotics have been linked to apoptosis. In the present study, apoptosis, as determined by DNA laddering and ultrastructural a nalysis, was clearly induced by MNU treatment of cultured oligodendroc yte progenitors and microglia, but not in astroglia. These data demons trate a correlation between diminished mtDNA repair capacity and the i nduction of apoptosis. However, further experimentation is necessary t o determine if a causal relationship exists and contributes to the vul nerability of oligodendroglia following exposure to N-nitroso compound s in the environment or in chemotherapeutic regimen. (C) 1998 Wiley-Li ss, Inc.