Ledoux S P, Shen C C, Grishko V I, Fields P A, Gard A L, Wilson G L
Department of Structural and Cellular Biology, University of South Alabama, Mobile 36688, USA.
Glia. 1998 Nov;24(3):304-12.
Oligodendrocytes are preferentially sensitive to the toxic, carcinogenic, and teratogenic effects of methylnitrosourea (MNU). The mechanisms responsible for this enhanced sensitivity have not been fully elucidated. 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, the effects of MNU exposure on oligodendroglia, astroglia, and microglia cultured separately from neonatal rat brain were compared. Quantitative determinations of mtDNA initial break frequencies and repair efficiencies showed that whereas no cell type-specific differences in initial mtDNA damage were detected, mtDNA repair in oligodendrocytes, oligodendrocyte progenitors, and microglia was significantly reduced compared to that of astrocytes. In astrocytes, and all other cell types previously evaluated in our laboratory, >60% of N-methylpurines were removed from the mtDNA by 24 hr. In contrast, only 35% of lesions were removed from mtDNA of oligodendrocytes, oligodendrocyte progenitors, and microglia 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 analysis, was clearly induced by MNU treatment of cultured oligodendrocyte progenitors and microglia, but not in astroglia. These data demonstrate a correlation between diminished mtDNA repair capacity and the induction of apoptosis. However, further experimentation is necessary to determine if a causal relationship exists and contributes to the vulnerability of oligodendroglia following exposure to N-nitroso compounds in the environment or in chemotherapeutic regimen.
少突胶质细胞对甲基亚硝基脲（MNU）的毒性、致癌性和致畸性作用尤为敏感。导致这种增强敏感性的机制尚未完全阐明。这种化学物质最易损伤的细胞靶点之一是线粒体DNA（mtDNA）。为了确定不同中枢神经系统神经胶质细胞类型之间在mtDNA损伤和修复能力上是否存在差异，比较了MNU暴露对从新生大鼠脑中分离培养的少突胶质细胞、星形胶质细胞和小胶质细胞的影响。mtDNA初始断裂频率和修复效率的定量测定表明，虽然未检测到初始mtDNA损伤存在细胞类型特异性差异，但与星形胶质细胞相比，少突胶质细胞、少突胶质前体细胞和小胶质细胞中的mtDNA修复明显减少。在星形胶质细胞以及我们实验室之前评估过的所有其他细胞类型中，到24小时时，>60%的N-甲基嘌呤从mtDNA中被去除。相比之下，在同一时间段内，少突胶质细胞、少突胶质前体细胞和小胶质细胞的mtDNA中仅35%的损伤被去除。多种外源性物质引起的线粒体扰动与细胞凋亡有关。在本研究中，通过DNA梯状条带分析和超微结构分析确定，MNU处理培养的少突胶质前体细胞和小胶质细胞可明显诱导细胞凋亡，但对星形胶质细胞则无此作用。这些数据表明mtDNA修复能力降低与细胞凋亡诱导之间存在相关性。然而，有必要进一步实验以确定是否存在因果关系，并导致少突胶质细胞在暴露于环境或化疗方案中的N-亚硝基化合物后变得脆弱。
