Pemetrexed negatively impacts embryonic development by inducing oxidative stress in mouse oocytes

Chemotherapy patients have a desire to have children under certain circumstances, but the effect of pemetrexed on female germ cells is unknown. Pemetrexed is an antitumor drug that acts as a folic acid analogue to inhibit the synthesis of purines and pyrimidines through a variety of pathways. Commonly reported side effects of pemetrexed were caused by its apoptotic toxicity. Here we found that the developmental ratio of pemetrexed-exposed oocytes declined steeply. Further tests showed that cytoplasmic maturation and nuclear maturation detected of mouse oocytes were all impaired. An analysis of untargeted metabolomics indicated that pemetrexed exposure caused significant disruptions in oocyte metabolic homeostasis. We identified the choline-methyl metabolism pathway as a key pathway targeted by pemetrexed in oocytes. This phenomenon is generated high reactive oxygen species (ROS) and low mitochondrial activity. And the signal of Annexin-V suggested that pemetrexed led oocytes to apoptotic. Overall, our findings revealed that pemetrexed exposure could have detrimental effects on female fertility and result in inferior oocyte quality in female mice.