Oocytes are vulnerable to alkylating agents like nitrogen mustard (NM), which can cause mitochondrial dysfunction associated with increased oxidative stress. Because mitochondria are maternally inherited, NM exposure affects oocyte mitochondrial physiology and compromises future progeny. Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux such cytotoxic substances; MDR-1 is expressed in oocyte plasma and mitochondrial membranes and protects against oxidative stress. Our objective was to investigate how loss of MDR-1 can modulate oocyte response to NM transgenerationally. Wild Type (WT) and Mdr1a mutant female mice were injected intraperitoneally with sterile saline (control) or 0.1 mg/kg NM. 48 hours post-injection, females were either sacrificed for F0 studies or mated with control males to yield F1 pups. After weaning, F1 females were sacrificed or mated to yield F2 pups. Germinal vesicle oocytes were assessed for mitochondrial membrane potential and reactive oxygen species (ROS) levels. NM exposed oocytes of both genotypes exhibited significantly higher ROS than controls in F0 and F1. NM F2 oocytes of neither genotype exhibited significantly higher ROS, though variation in Mdr1a mutants led to an upward trend. NM oocytes of both genotypes exhibited significantly disrupted mitochondrial membrane potential in F0. WT regained normalcy by F1 whereas Mdr1a mutants were unable to by F2. Our data suggest that Mdr1a mutants exhibit transgenerational mitochondrial dysfunction following toxic challenge that persists, implying that MDR-1 protects against toxicant-induced mitochondrial stress. Women without functional MDR-1 exposed to environmental toxicants could therefore be at risk for passing on compromised mitochondria to future offspring.

卵母细胞容易受到氮芥 (NM) 等烷化剂的影响，这会导致与氧化应激增加相关的线粒体功能障碍。由于线粒体是母系遗传的，NM 暴露会影响卵母细胞线粒体生理并损害未来的后代。多药耐药转运蛋白 (MDR) 是一种跨膜蛋白，可将此类细胞毒性物质排出体外；MDR-1 在卵母细胞血浆和线粒体膜中表达，可防止氧化应激。我们的目标是研究 MDR-1 的缺失如何跨代调节卵母细胞对 NM 的反应。野生型 (WT) 和Mdr1a用无菌盐水（对照）或 0.1 mg/kg NM 腹膜内注射突变雌性小鼠。注射后 48 小时，雌性被处死用于 F0 研究或与对照雄性交配以产生 F1 幼崽。断奶后，F1 雌性被处死或交配以产生 F2 幼崽。评估了生殖囊泡卵母细胞的线粒体膜电位和活性氧 (ROS) 水平。两种基因型的 NM 暴露卵母细胞在 F0 和 F1 中表现出比对照显着更高的 ROS。尽管Mdr1a突变体的变异导致上升趋势，但两种基因型的 NM F2 卵母细胞均未表现出显着更高的 ROS 。两种基因型的 NM 卵母细胞在 F0 中表现出显着破坏的线粒体膜电位。WT 通过 F1 恢复正常，而Mdr1a突变体无法通过 F2。我们的数据表明Mdr1a突变体在持续的毒性挑战后表现出跨代线粒体功能障碍，这意味着 MDR-1 可以防止毒物诱导的线粒体应激。因此，没有暴露于环境毒物的功能性 MDR-1 的女性可能会将受损的线粒体传递给未来的后代。