Alpha-lipoic acid supplementation reverses the declining quality of oocytes exposed to cyclophosphamide

Abstract

Cyclophosphamide (CY) is a chemotherapeutic drug that is commonly used to treat malignancies of the ovary, breast, and hematology, as well as autoimmune disorders. As a cofactor of mitochondrial multienzyme complexes, alpha lipoic acid (ALA) is well known for its antioxidant characteristics, which operate directly on the scavenging of reactive oxygen species (ROS) and indirectly on the intracellular recycling of other antioxidants. However, the underlying mechanisms through which CY exerts its toxic effects on meiosis and oocyte quality, as well as a viable approach for protecting oocyte quality and preserving fertility, remain unknown. In present study, immunostaining and fluorescence intensity quantification were applied to assess the effects of CY and ALA supplementation on the key processes during the oocyte meiotic maturation. Our results show that supplementing oocytes with ALA, a well-known antioxidant and free radical scavenger, can reverse CY-induced oocyte meiotic maturation failure. Specifically, we found that CY exposure caused oocyte meiotic failure by disrupting meiotic organelle dynamics and arrangement, as well as a prominently impaired cytoskeleton assembly. In addition, CY caused an abnormal distribution of mitochondrion and cortical granules, two indicators of oocyte cytoplasmic maturation. More importantly, we show that ALA supplementation effectively reverses CY-induced meiotic failure and oocyte quality decline by suppressing oxidative stress-induced DNA damage and apoptosis in oocytes. Collectively, our data reveal that ALA supplementation is a feasible approach to protect oocytes from CY-exposed deterioration, providing a better understanding of the mechanisms involved in chemotherapy-induced meiotic failure.

Keywords: Alpha lipoic acid; Cyclophosphamide; Cytoskeleton; Meiotic maturation; Oocyte quality; Oxidative stress.