Doxorubicin exposure affects oocyte meiotic maturation through DNA damage induced meiotic arrest

Toxicological Sciences : an Official Journal of the Society of Toxicology
Zhi-Ming DingLi-Jun Huo

Abstract

Developments in chemotherapeutics have enhanced the survival rate of cancer patients, however adverse effects of chemotherapeutics on ovarian functions causes the fertility loss in young female cancer patients. Doxorubicin (DOX), as an anthracycline antitumor antibiotic, is extensively used to cure various malignancies. Recent studies have suggested that DOX can cause ovarian damage and affect the oocyte maturation, nevertheless the mechanism by which DOX on oocytes meiosis is poorly understood. In this study we explored the mechanism for DOX induced oocytes meiotic failure in vitro at human relevant exposure levels and time periods. Results described that DOX (100 nM) can interrupt the mouse oocytes meiotic maturation directly with reduced first polar body extrusion (PBE). Cell cycle analysis showed most oocytes were arrested at metaphase I (MI) stage. However, DOX treatment had no effect on spindle structure but chromosomal misalignment. We observed kinetochore-microtubule (K-MT) structure was affected and the spindle assemble checkpoint (SAC) was provoked after DOX treatment. Moreover, severe DNA damage was found in DOX treated oocytes indicated by the positive γ-H2A.X foci signal, which then may trigger oocytes early apopto...Continue Reading

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