Ovarian Biology Laboratory, Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.
J Ovarian Res. 2021 May 10;14(1):65. doi: 10.1186/s13048-021-00817-w.
Cisplatin is a platinum-based chemotherapeutic that damages genomic DNA leading to cell death. It also damages mitochondrial DNA and induces high levels of mitochondrial reactive oxygen species (mtROS), further sensitising cells to apoptosis. Notably, immature oocytes are particularly vulnerable to cisplatin treatment, a common side effect of which is depletion of the primordial follicle reserve, leading to infertility and early menopause. Cisplatin is known to damage the DNA of oocytes, but the possibility that cisplatin also compromises oocyte survival and quality by damaging mitochondria, has not been investigated. To begin to address this question, neonatal mice were treated with saline or cisplatin (2 mg/kg or 4 mg/kg) and the short and long-term impacts on mitochondria in oocytes were characterised.
At 6 and 24 h after treatment, mitochondrial localisation, mass and ATP content in immature oocytes were similar between groups. However, TMRM staining intensity, a marker of mitochondrial membrane potential, was decreased in immature oocytes from cisplatin treated mice compared to saline treated controls, consistent with the induction of apoptosis. When mice were super ovulated 5 weeks after exposure, the number of mature oocytes harvested from cisplatin treated mice was significantly lower than controls. Mitochondrial localisation, mass, membrane potential and ATP levels showed no differences between groups.
These findings suggest that mitochondrial dysfunction may contribute to the depletion of the ovarian reserve caused by cisplatin, but long-term impacts on mitochondria may be minimal as those immature oocytes that survive cisplatin treatment develop into mature oocytes with normal mitochondrial parameters.
顺铂是一种铂类化疗药物，可损伤基因组 DNA 导致细胞死亡。它还会损伤线粒体 DNA 并诱导高水平的线粒体活性氧（mtROS），进一步使细胞对细胞凋亡敏感。值得注意的是，未成熟卵母细胞特别容易受到顺铂治疗的影响，其常见的副作用是原始卵泡储备耗尽，导致不孕和早绝经。顺铂已知会损伤卵母细胞的 DNA，但顺铂是否通过损伤线粒体而影响卵母细胞的存活和质量，尚未得到研究。为了开始解决这个问题，用生理盐水或顺铂（2mg/kg 或 4mg/kg）处理新生小鼠，并对卵母细胞中线粒体的短期和长期影响进行了表征。
在治疗后 6 小时和 24 小时，未成熟卵母细胞中的线粒体定位、质量和 ATP 含量在各组之间相似。然而，与生理盐水处理的对照组相比，来自顺铂处理的小鼠的未成熟卵母细胞中的 TMRM 染色强度（线粒体膜电位的标志物）降低，提示细胞凋亡的发生。当暴露后 5 周进行超排卵时，来自顺铂处理的小鼠的成熟卵母细胞数量明显低于对照组。线粒体定位、质量、膜电位和 ATP 水平在各组之间没有差异。
这些发现表明，线粒体功能障碍可能导致顺铂引起的卵巢储备耗竭，但长期对线粒体的影响可能很小，因为那些幸存顺铂治疗的未成熟卵母细胞发育成具有正常线粒体参数的成熟卵母细胞。
