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Resveratrol attenuates doxorubicin-induced meiotic failure through inhibiting oxidative stress and apoptosis in mouse oocytes.

ABSTRACT: Doxorubicin (DXR), a widely used chemotherapeutic drug, has adverse effects on female fertility in young cancer patients. However, the underlying mechanisms of doxorubicin exposure on female fertility and how to prevent it have not been well studied yet. Here, mouse oocytes were employed to investigate the issues mentioned above. The results showed that doxorubicin treatment impaired oocyte meiotic maturation by destroying spindle assembly and chromosome arrangement. In addition, doxorubicin caused oxidative stress by increasing reactive oxygen species (ROS) levels. Furthermore, doxorubicin led to severe DNA damage in oocytes, which eventually induced apoptosis through DNA damage-P63-Caspase3 pathway. Conversely, resveratrol (RES) effectively improved oocyte quality by restoring spindle and chromosome configuration, reducing ROS levels and inhibiting apoptosis. In summary, our results indicate that RES can protect oocytes against doxorubicin-induced damage.

SUBMITTER: Han J

PROVIDER: S-EPMC7244048 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Resveratrol attenuates doxorubicin-induced meiotic failure through inhibiting oxidative stress and apoptosis in mouse oocytes.

Han Jun J Wang Huarong H Zhang Tuo T Chen Ziqi Z Zhao Ting T Lin Lin L Xia Guoliang G Wang Chao C

Aging 20200430 9

Doxorubicin (DXR), a widely used chemotherapeutic drug, has adverse effects on female fertility in young cancer patients. However, the underlying mechanisms of doxorubicin exposure on female fertility and how to prevent it have not been well studied yet. Here, mouse oocytes were employed to investigate the issues mentioned above. The results showed that doxorubicin treatment impaired oocyte meiotic maturation by destroying spindle assembly and chromosome arrangement. In addition, doxorubicin cau ...[more]

PMID: 32352929

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Project description:Postovulatory aging of the mammalian oocytes causes deterioration of oocytes through several factors including oxidative stress. Keeping that in mind, we aimed to investigate the potential of a well-known antioxidant, resveratrol (RV), to evaluate the adverse effects of postovulatory aging in porcine oocytes. After in vitro maturation (IVM), a group of (25–30) oocytes (in three replicates) were exposed to 0, 1, 2, and 4 μmol/L of RV, respectively. The results revealed that the first polar body (PB1) extrusion rate of the oocytes significantly increased when the RV concentration reached up to 2 μmol/L (p < 0.05). Considering optimum RV concentration of 2 μmol/L, the potential of RV was evaluated in oocytes aged for 24 and 48 h. We used fluorescence microscopy to detect the relative level of reactive oxygen species (ROS), while GHS contents were measured through the enzymatic method. Our results revealed that aged groups (24 h and 48 h) treated with RV (2 μmol/L) showed higher (p < 0.05) ROS fluorescence intensity than the control group, but lower (p < 0.05) than untreated aged groups. The GSH content in untreated aged groups (24 h and 48 h) was lower (p < 0.05) than RV-treated groups, but both groups showed higher levels than the control. Similarly, the relative expression of the genes involved in antioxidant activity (CAT, GPXGSH-Px, and SOD1) in RV-treated groups was lower (p < 0.05) as compared to the control group but higher than that of untreated aged groups. Moreover, the relative mRNA expression of caspase-3 and Bax in RV-treated groups was higher (p < 0.05) than the control group but lower than untreated groups. Furthermore, the expression of Bcl-2 in the RV-treated group was significantly lower than control but higher than untreated aged groups. Taken together, our findings revealed that the RV can increase the expression of antioxidant genes by decreasing the level of ROS, and its potent antiapoptotic effects resisted against the decline in mitochondrial membrane potential in aged oocytes.

Project description:Overweight or obese women seeking pregnancy is becoming increasingly common. Human maternal obesity gives rise to detrimental effects during reproduction. Emerging evidence has shown that these abnormities are likely attributed to oocyte quality. Oxidative stress induces poor oocyte conditions, but whether mitochondrial calcium homeostasis plays a key role in oocyte status remains unresolved. Here, we established a mitochondrial Ca2+ overload model in mouse oocytes. Knockdown gatekeepers of the mitochondrial Ca2+ uniporters Micu1 and Micu2 as well as the mitochondrial sodium calcium exchanger NCLX in oocytes both increased oocytes mitochondrial Ca2+ concentration. The overload of mitochondria Ca2+ in oocytes impaired mitochondrial function, leaded to oxidative stress, and changed protein kinase A (PKA) signaling associated gene expression as well as delayed meiotic resumption. Using this model, we aimed to determine the mechanism of delayed meiosis caused by mitochondrial Ca2+ overload, and whether oocyte-specific inhibition of mitochondrial Ca2+ influx could improve the reproductive abnormalities seen within obesity. Germinal vesicle breakdown stage (GVBD) and extrusion of first polar body (PB1) are two indicators of meiosis maturation. As expected, the percentage of oocytes that successfully progress to the germinal vesicle breakdown stage and extrude the first polar body during in vitro culture was increased significantly, and the expression of PKA signaling genes and mitochondrial function recovered after appropriate mitochondrial Ca2+ regulation. Additionally, some indicators of mitochondrial performance-such as adenosine triphosphate (ATP) and reactive oxygen species (ROS) levels and mitochondrial membrane potential-recovered to normal. These results suggest that the regulation of mitochondrial Ca2+ uptake in mouse oocytes has a significant role during oocyte maturation as well as PKA signaling and that proper mitochondrial Ca2+ reductions in obese oocytes can recover mitochondrial performance and improve obesity-associated oocyte quality.

Dataset Information

Resveratrol attenuates doxorubicin-induced meiotic failure through inhibiting oxidative stress and apoptosis in mouse oocytes.

Publications

Resveratrol attenuates doxorubicin-induced meiotic failure through inhibiting oxidative stress and apoptosis in mouse oocytes.

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