PMID- 32112509 OWN - NLM STAT- MEDLINE DCOM- 20210520 LR - 20211204 IS - 1098-2795 (Electronic) IS - 1040-452X (Linking) VI - 87 IP - 4 DP - 2020 Apr TI - Rapamycin preserves the primordial follicle pool during cisplatin treatment in vitro and in vivo. PG - 442-453 LID - 10.1002/mrd.23330 [doi] AB - 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 mug/ml) and cisplatin (0.1, 0.4, and 0.8 mug/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. CI - (c) 2020 Wiley Periodicals, Inc. FAU - Xie, Yanqiu AU - Xie Y AUID- ORCID: 0000-0002-1080-7479 AD - Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China. AD - Department of Obstetrics and Gynecology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Gongdong, China. FAU - Li, Song AU - Li S AD - Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China. FAU - Zhou, Linyan AU - Zhou L AD - Department of Reproductive Medicine Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Gongdong, China. FAU - Lin, Haiyan AU - Lin H AD - Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China. FAU - Jiao, Xuedan AU - Jiao X AD - Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China. FAU - Qiu, Qi AU - Qiu Q AD - Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China. FAU - Liang, Yihua AU - Liang Y AD - Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China. FAU - Zhang, Qingxue AU - Zhang Q AUID- ORCID: 0000-0002-8166-7813 AD - Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Gongdong, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200228 PL - United States TA - Mol Reprod Dev JT - Molecular reproduction and development JID - 8903333 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Bmp15 protein, mouse) RN - 0 (Bmp15 protein, rat) RN - 0 (Bone Morphogenetic Protein 15) RN - 0 (Gdf9 protein, mouse) RN - 0 (Gdf9 protein, rat) RN - 0 (Growth Differentiation Factor 9) RN - 0 (Protective Agents) RN - 0 (RNA, Messenger) RN - 80497-65-0 (Anti-Mullerian Hormone) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - Q20Q21Q62J (Cisplatin) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Animals, Newborn MH - Anti-Mullerian Hormone/metabolism MH - Antibiotics, Antineoplastic/*administration & dosage MH - Apoptosis/drug effects MH - Bone Morphogenetic Protein 15/metabolism MH - Cell Line, Tumor MH - Cells, Cultured MH - Cisplatin/*administration & dosage MH - Female MH - Growth Differentiation Factor 9/metabolism MH - Injections, Intraperitoneal MH - Mice MH - Mice, Inbred BALB C MH - Ovarian Follicle/drug effects/*metabolism MH - Protective Agents/*administration & dosage MH - RNA, Messenger/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects MH - Sirolimus/*administration & dosage MH - TOR Serine-Threonine Kinases/metabolism OTO - NOTNLM OT - chemotherapy OT - cisplatin OT - mTOR signaling pathway OT - primordial follicle OT - rapamycin EDAT- 2020/03/01 06:00 MHDA- 2021/05/21 06:00 CRDT- 2020/03/01 06:00 PHST- 2019/03/25 00:00 [received] PHST- 2020/01/16 00:00 [accepted] PHST- 2020/03/01 06:00 [pubmed] PHST- 2021/05/21 06:00 [medline] PHST- 2020/03/01 06:00 [entrez] AID - 10.1002/mrd.23330 [doi] PST - ppublish SO - Mol Reprod Dev. 2020 Apr;87(4):442-453. doi: 10.1002/mrd.23330. Epub 2020 Feb 28.