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Updated: Mar 5, 2026
Culture and Co-Culture of Mouse Ovaries and Ovarian Follicles
Published on: March 17, 2015
Doxorubicin Has Dose-Dependent Toxicity on Mouse Ovarian Follicle Development, Hormone Secretion, and Oocyte
Shuo Xiao1,2, Jiyang Zhang1,3, Mingjun Liu1,3
1Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Abstract:
Doxorubicin (DOX), one of the most commonly used anticancer medications, has been reported to affect fertility by damaging ovarian follicles; however, the dose-dependent toxicity of DOX on the dynamic follicle development and oocyte maturation has not been well-defined. Our objective is to determine the effects of human-relevant exposure levels of DOX on follicular functions across developmental time. In vitro cultured multilayered secondary mouse follicles were treated with DOX at 0, 2, 20, 100, and 200 nM for 24 h, and follicle development, hormone secretion, and oocyte maturation were analyzed. DOX caused dose-dependent toxicity on follicle growth, survival, and secretion of 17β-estradiol (E2). At 200 nM, DOX induced DNA damage and apoptosis in follicle somatic cells first and then in oocytes, which was correlated with the uptake of DOX first to the somatic cells followed by germ cells. Follicles treated with DOX at 0, 2, and 20 nM showed similar oocyte metaphase II (MII) percentages after in vitro oocyte maturation; however, 20 nM DOX significantly increased the number of MII oocytes with abnormal spindle morphology and chromosome misalignment. In an effort to harmonize the in vitro study to in vivo treatment, dose-dependent toxicity on oocyte meiotic maturation was found in 16-day-old CD-1 mice treated with DOX at 0, 0.4, 2, and 10 mg/kg, consistent with the in vitro oocyte maturation outcomes. Our study demonstrates that DOX has dose-dependent toxicity on ovarian follicle development, hormone secretion, and oocyte maturation, which are three key factors to support the female reproductive and endocrine functions.
Insights
Doxorubicin (DOX) chemotherapy damages ovarian follicles and impairs oocyte maturation in a dose-dependent manner. This study defines DOX
Area of Science:
- Reproductive Biology
- Toxicology
- Endocrinology
Background:
- Doxorubicin (DOX) is a widely used chemotherapy agent with known fertility-damaging effects.
- The precise dose-dependent impact of DOX on ovarian follicle dynamics and oocyte maturation remains incompletely understood.
Purpose of the Study:
- To investigate the effects of human-relevant Doxorubicin (DOX) exposure levels on ovarian follicle development and oocyte maturation.
- To establish dose-dependent toxicity thresholds for DOX in female reproductive functions.
Main Methods:
- In vitro culture of mouse secondary follicles treated with varying DOX concentrations (0–200 nM).
- Analysis of follicle growth, 17β-estradiol (E2) secretion, DNA damage, apoptosis, and oocyte maturation (MII stage, spindle, chromosome alignment).
- In vivo validation using CD-1 mice treated with DOX (0–10 mg/kg) to assess oocyte meiotic maturation.
Main Results:
- DOX exhibited dose-dependent toxicity, inhibiting follicle growth, survival, and E2 secretion.
- DOX induced DNA damage and apoptosis in somatic and germ cells, correlating with cellular uptake.
- While MII percentages were similar at lower doses, 20 nM DOX increased abnormal spindle and chromosome configurations in oocytes.
- In vivo studies corroborated in vitro findings, showing dose-dependent toxicity on oocyte meiotic maturation.
Conclusions:
- Doxorubicin exerts significant dose-dependent toxicity on ovarian follicle development, hormone secretion, and oocyte maturation.
- These effects impact key factors supporting female reproductive and endocrine health.
- Findings highlight the need for careful consideration of DOX dosage in women of reproductive age undergoing chemotherapy.
