Examination of the ovotoxicity of 5-fluorouracil in mice
Undesirable side effects of cancer treatments are common and include damage to the ovary, and depletion of the follicle reserve, which if severe enough, can lead to infertility and early menopause. Antimetabolite drugs, such as 5-fluorouracil (5-FU), are not considered to be detrimental to the ovary, but the ovotoxicity of 5-FU has not been evaluated in any detail. The purpose of this study was to evaluate the effects of 5-FU on follicle number.
In this study, adult female C57Bl6 mice (n = 4–6 animals/group) received a single dose of saline or 5-FU (150 mg/kg) and markers of ovarian damage and follicle depletion were assessed 12 h and 7 days later.
Exposure to 5-FU did not alter primordial and primary follicle numbers. Atresia of secondary and antral follicles was increased significantly 12 h after 5-FU treatment, but atresia rates returned to levels similar to that of saline treated controls at 7 days. The number of corpora lutea were reduced 7 days after exposure to 5-FU, possibly as a consequence of earlier follicular atresia.
These findings suggest that a single dose of 5-FU is mildly ovotoxic, but any effects on ovarian function are likely transient because the primordial follicle population is not depleted. Collectively, these data support the notion that 5-FU is unlikely to impact on the long-term fertility of women.
Keywords5-FU Apoptosis Fertility Ovary Follicles Chemotherapy
We thank the Monash Micro Imaging and the Monash Histology Platform.
KJH and HA designed the experiments; ML, SHL, KH and JMS performed the experiments; ML and KJH interpreted the data; ML and KJH wrote the manuscript; HA, SHL, KH and JMS critically revised the manuscript. All authors approved the final manuscript.
This work was supported by the National Health and Medical Research Council (KJH #1050130). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. The funding bodies played no role in the design of the study and collection, analysis and interpretation of data and in writing the manuscript.
Compliance with ethical standards
Conflicts of interests
The authors declare that they have no conflicts of interest.
All applicable international, national and/or institutional guidelines for the care and use of animals were followed.
- 5.Yuksel A, Bildik G, Senbabaoglu F, Akin N, Arvas M, Unal F, et al. The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells. Hum Reprod. 2015;30(12):2926–35.Google Scholar
- 14.Dynes, J., The effects of chemotherapy schedules on ovarian function. 2014.Google Scholar
- 15.Koyama H, Wada T, Nishizawa Y, Iwanaga T, Aoki Y, Terasawa T, et al. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer. 1977;39(4):1403–9.Google Scholar
- 18.Tal, R., et al., A murine 5-fluorouracil-based submyeloablation model for the study of bone marrow-derived cell trafficking in reproduction. Endocrinology, 2016: p. en20161418.Google Scholar
- 24.Liew SH, Vaithiyanathan K, Cook M, Bouillet P, Scott CL, Kerr JB, et al. Loss of the proapoptotic BH3-only protein BCL-2 modifying factor prolongs the fertile life span in female mice. Biol Reprod. 2014;90(4):77.Google Scholar
- 29.Howard, V. and M. Reed, Unbiased stereology: three-dimensional measurement in microscopy. 2004: Garland Science.Google Scholar