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Rapamycin preserves the primordial follicle pool during cisplatin treatment in vitro and in vivo
- Source :
- Molecular Reproduction and Development. 87:442-453
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- Rapamycin has been proven to effectively inhibit the activation of primordial follicles while cisplatin-induced the loss of primordial follicles due to the over-activation of the primordial follicle stockpile. Whether rapamycin could inhibit the loss of primordial follicles induced by cisplatin is still unknown. The ovaries of neonatal Sprague Dawley rats were cultured in vitro in different doses of rapamycin (0.08, 0.16, and 0.32 μg/ml) and cisplatin (0.1, 0.4, and 0.8 μg/ml). The immature BALB/c mice were administered cisplatin with or without rapamycin by intraperitoneal injection. Ovaries were collected to analyze the histomorphology, the messenger RNA (mRNA) expression of anti-Mullerian hormone (AMH), growth differentiation factor 9 (GDF9), and bone morphogenetic protein 15 (BMP15) and the expression of key proteins of mammalian target of rapamycin (mTOR) pathway. Growing follicle counts of ovaries cultured in vitro in the R0.16 and R0.32 groups were decreased and the ratio of growing to primordial follicles was also decreased in a dose-dependent manner. In the C0.8 group, growing follicles were decreased compared with the other groups while the ratio was substantially increased in the C0.4 and C0.8 group. Co-treatment attenuated primordial follicle loss and reduced the upregulated ratio induced by cisplatin. Ovarian follicle dynamics in vivo was consistent with the in vitro results. Primordial follicles counts were statistically increased and the ratio was reduced in the rapamycin group compared with the control group. Primordial follicle counts were dramatically reduced in the cisplatin group whereas co-treatment with rapamycin slightly recovered its counts. There was no obvious difference in the number of growing follicles between the cisplatin group and other groups. The ratio was significantly increased in cisplatin-treated mice whereas decreased in the co-treatment group. The apoptosis rate of antral follicles in cisplatin-treated mice was higher than the other groups while the apoptosis rate was decreased in the co-treatment group in vivo. Compared with the control and rapamycin group, the mRNA expression of AMH, GDF9, and BMP15 were downregulated in the cisplatin group. The co-treatment group recovered the mRNA expression of BMP15. In addition, the expression of key protein of mTOR pathway rpS6 and its phosphorylated forms were increased in the cisplatin-treated group while co-treatment decreased their expression. Rapamycin attenuated the loss of primordial follicles induced by cisplatin through the inhibitory effect of rapamycin on the mTOR pathway. These results suggest that rapamycin may be an effective drug for the protection of ovarian function during chemotherapy.
- Subjects :
- Anti-Mullerian Hormone
0301 basic medicine
Growth Differentiation Factor 9
Apoptosis
Biology
Growth differentiation factor-9
Protective Agents
Rats, Sprague-Dawley
Andrology
Mice
03 medical and health sciences
0302 clinical medicine
Ovarian Follicle
Growing Follicle
In vivo
Cell Line, Tumor
Genetics
medicine
Animals
RNA, Messenger
Ovarian follicle
Cells, Cultured
Sirolimus
Cisplatin
Mice, Inbred BALB C
Antibiotics, Antineoplastic
030219 obstetrics & reproductive medicine
Bone morphogenetic protein 15
TOR Serine-Threonine Kinases
Cell Biology
Antral follicle
Rats
030104 developmental biology
medicine.anatomical_structure
Animals, Newborn
Female
Folliculogenesis
Bone Morphogenetic Protein 15
Injections, Intraperitoneal
Signal Transduction
Developmental Biology
medicine.drug
Subjects
Details
- ISSN :
- 10982795 and 1040452X
- Volume :
- 87
- Database :
- OpenAIRE
- Journal :
- Molecular Reproduction and Development
- Accession number :
- edsair.doi.dedup.....cdbc3fe238631fe496b49191ffd9e5dc