OTSSP167 leads to follicular dysplasia and negatively affects oocyte quality in mice
Xin-Ran Zhang1, Ying-Chun Ouyang2, Tie-Gang Meng2
1State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China; College of Life Science, University of Chinese Academy of Science, 100101 Beijing, China.
Abstract:
OTSSP167 is an anti-tumor drug significantly inhibiting tumor growth in xenotransplantation studies using mouse breast, lung, prostate, and pancreatic cancer cell lines. Its phase I clinical trial has been completed, indicating its great potential for future treatment of solid tumors. However, its drug-related adverse effects on reproductive systems have not yet been reported. In this study, we evaluated the effects of OTSSP167 on reproduction of female mice by determining oocyte quality and follicular development. We selected four-week-old female ICR mice for a 21-day intraperitoneal injection of OTSSP167 at a dose of 5 mg/kg/d. We found that OTSSP167 could block the meiotic process of oocytes, leading to a decrease in oocyte maturation and ovulated oocyte numbers, as well as a decrease in the quality of oocytes. The results showed that OTSSP167 treatment caused disordered spindle assembly, decreased mitochondria membrane potential, and increased accumulation of reactive oxygen species in oocytes. Further investigation showed that OTSSP167 induced DNA double-strand breaks, as indicated by increased levels of γH2AX in oocytes of primordial follicles and granulosa cells of growing follicles, which induced follicular atresia and decreased the numbers of follicles at various growing stages. Our study suggests that OTSSP167 treatment may have serious effects on the ovary and consequences for female cancer patients, providing strong evidence for the necessity of protecting female fertility in clinical OTSSP167 trials.
Insights
The anti-tumor drug OTSSP167 impairs female mouse fertility by disrupting oocyte maturation and causing ovarian damage. This highlights the need for fertility preservation strategies in women undergoing treatment with this promising cancer therapy.
Area of Science:
- Reproductive biology
- Oncology
- Pharmacology
Background:
- OTSSP167 is a novel anti-tumor agent demonstrating significant efficacy in preclinical cancer models.
- Phase I clinical trials indicate OTSSP167's potential for treating solid tumors.
- Adverse effects of OTSSP167 on female reproductive systems remain largely uncharacterized.
Purpose of the Study:
- To investigate the impact of OTSSP167 on female mouse reproductive parameters.
- To assess OTSSP167's effects on oocyte quality and follicular development.
- To evaluate the potential risks of OTSSP167 treatment on female fertility.
Main Methods:
- Four-week-old female ICR mice received daily intraperitoneal injections of OTSSP167 (5 mg/kg/d) for 21 days.
- Oocyte quality was assessed by evaluating meiotic progression, spindle assembly, mitochondrial membrane potential, and reactive oxygen species levels.
- Follicular development was examined by quantifying follicle numbers and assessing DNA damage (γH2AX) in oocytes and granulosa cells.
Main Results:
- OTSSP167 treatment blocked oocyte meiosis, reducing maturation rates and the number of ovulated oocytes.
- Oocyte quality declined, evidenced by disordered spindle assembly, decreased mitochondrial membrane potential, and increased reactive oxygen species.
- OTSSP167 induced DNA double-strand breaks in oocytes and granulosa cells, leading to follicular atresia and reduced follicle counts.
Conclusions:
- OTSSP167 treatment adversely affects female mouse reproductive function, impacting oocyte quality and ovarian follicle reserve.
- These findings underscore the potential for OTSSP167 to cause significant ovarian toxicity in female patients.
- Fertility preservation measures should be considered for women undergoing clinical trials or treatment with OTSSP167.
