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Updated: Jul 18, 2025
Author Spotlight: Understanding DNA Damage Response in Mammalian Oocytes and Preimplantation Embryos
Published on: June 23, 2023
SIRT1 reduction contributes to doxorubicin-induced oxidative stress and meiotic failure in mouse oocytes
Jun Han1, Shuo Wang2, Huarong Wang2
1Jiangsu Academy of Agricultural Sciences, Nanjing 21000, China; State Key Laboratory of Livestock and Poultry Biotechnology Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Abstract:
Impaired fertility is the major side effect of chemotherapy for female cancer patients, accumulated evidence indicates this is associated with damage on oocyte quality, but the underlying mechanisms remain unclear. Previously we reported that doxorubicin (DXR) exposure, one of the most widely used chemotherapy drugs, disrupted mouse oocyte meiotic maturation in vitro. In the current study, we identified that SIRT1 expression was remarkably reduced in DXR exposure oocytes. Next, we found that increasing SIRT1 expression by resveratrol partially alleviated the effects of DXR exposure on oocyte maturation, which was counteracted by SIRT1 inhibition. Furthermore, we revealed that increasing SIRT1 expression mitigated DXR induced oocyte damage through reducing ROS levels, increasing antioxidant enzyme MnSOD expression, and preventing spindle and chromosome disorganization, lowering the incidence of aneuploidy. Importantly, by performing in vitro fertilization and embryo transfer assays, we demonstrated that increasing SIRT1 expression significantly improved the fertilization ability, developmental competence of oocytes and early embryos. In summary, our data uncover that SIRT1 reduction represents one mechanism that mediates the effects of DXR exposure on oocyte quality.
Insights
Chemotherapy drug doxorubicin (DXR) damages female fertility by reducing SIRT1 levels in oocytes. Increasing SIRT1 with resveratrol protects oocyte quality and improves reproductive outcomes in mice.
Area of Science:
- Reproductive Biology
- Molecular Oncology
- Cell Biology
Background:
- Chemotherapy, including doxorubicin (DXR), impairs female fertility by damaging oocyte quality.
- The precise molecular mechanisms underlying chemotherapy-induced oocyte damage remain largely unknown.
Purpose of the Study:
- To investigate the role of SIRT1 in doxorubicin-induced oocyte damage.
- To evaluate the potential of modulating SIRT1 to protect oocyte quality against DXR exposure.
Main Methods:
- Assessing SIRT1 expression in DXR-exposed mouse oocytes.
- Utilizing resveratrol to increase SIRT1 levels and SIRT1 inhibitors to block its activity.
- Evaluating oocyte maturation, reactive oxygen species (ROS) levels, MnSOD expression, spindle/chromosome organization, and aneuploidy incidence.
- Performing in vitro fertilization and embryo transfer assays.
Main Results:
- DXR exposure significantly reduced SIRT1 expression in oocytes.
- Resveratrol partially rescued DXR-induced oocyte maturation defects, an effect reversed by SIRT1 inhibition.
- Increased SIRT1 mitigated DXR-induced oocyte damage by reducing ROS, enhancing MnSOD, and preventing spindle/chromosome abnormalities.
- Enhanced SIRT1 improved fertilization rates and developmental competence of oocytes and early embryos.
Conclusions:
- SIRT1 reduction is a key mechanism mediating doxorubicin's detrimental effects on oocyte quality.
- Targeting SIRT1 may offer a protective strategy against chemotherapy-induced female infertility.
