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Published on: June 16, 2021
Toxic effects of AZD1208 on mouse oocytes and its possible mechanisms
Feng-Ze Yan1,2, Ying-Chun Ouyang1, Tie-Gang Meng3
1State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Abstract:
AZD1208, a pan-inhibitor that can effectively inhibit PIM kinase, is used for the treatment of advanced solid tumors and malignant lymphomas. Numerous studies have proved its curative effects while its potential cellular toxicity on reproduction was still little known. In this study, we investigated the toxic effects of AZD1208 on mouse oocytes. The results showed that AZD1208 treatment did not affect meiotic resumption, but postponed oocyte maturation as indicated by delayed first polar body extrusion. Further mechanistic study showed that AZD1208 treatment delayed spindle assembly. In addition, we found that oocytes treated with AZD1208 showed mitochondrial dysfunction. Abnormal mitochondrial clusters with decreased mitochondrial membrane potential were observed in oocytes during incubation in vitro. Moreover, increased oxidative stress was observed by testing the level of reactive oxygen species. In summary, our results suggest that AZD1208 treatment influences oocyte meiotic progression by causing mitochondrial dysfunctions and subsequent delayed spindle assembly.
Insights
AZD1208 (PIM kinase inhibitor) delays mouse oocyte maturation by impairing mitochondrial function and spindle assembly. This study reveals potential reproductive toxicity of AZD1208, impacting female fertility.
Area of Science:
- Reproductive biology
- Cellular toxicology
- Pharmacology
Background:
- AZD1208 is a PIM kinase inhibitor used for solid tumors and lymphomas.
- Its reproductive toxicity, particularly on oocytes, is not well understood.
Purpose of the Study:
- To investigate the toxic effects of AZD1208 on mouse oocyte maturation and meiotic progression.
- To elucidate the underlying mechanisms of AZD1208-induced oocyte toxicity.
Main Methods:
- Treatment of mouse oocytes with AZD1208 in vitro.
- Assessment of meiotic resumption and maturation (polar body extrusion).
- Analysis of spindle assembly, mitochondrial membrane potential, and reactive oxygen species levels.
Main Results:
- AZD1208 delayed oocyte maturation and first polar body extrusion.
- Spindle assembly was impaired in AZD1208-treated oocytes.
- Mitochondrial dysfunction, including clustering and decreased membrane potential, and increased oxidative stress were observed.
Conclusions:
- AZD1208 negatively impacts mouse oocyte meiotic progression.
- Mitochondrial dysfunction and subsequent delayed spindle assembly are key mechanisms of AZD1208 toxicity in oocytes.
- Findings highlight potential reproductive risks associated with AZD1208 treatment.
