title: Follicle Loss and Apoptosis in Cyclophosphamide-Treated Mice: What's the Matter?
abstract: With increasing numbers of young female cancer survivors following chemotherapy, chemotherapy-induced fertility loss must be considered. Menstrual disorder and infertility are of particular concern in female cancer patients. We showed that treatment with the alkylating agent cyclophosphamide (CTX) could cause severe primordial follicle loss and growing follicle apoptosis, resulting in loss of ovarian reserve. SPF C57BL/6 female mice were treated with a single dose of 120 mg/kg of CTX or saline as a control, and both sides of ovaries were collected three or seven days after injection. Following CTX treatment, the ovaries were mostly composed of collapsed oocytes and presented marked cortical fibrosis and a reduced number of follicles, especially primordial follicles. The loss of primordial follicles was confirmed by primordial follicle counting, immunohistochemistry and Western blot detection of DDx4/MVH. Follicle apoptosis was tested by a TUNEL assay and the number of TUNEL-positive follicle cells increased, as expected, in CTX-treated mice. Furthermore, expression of APAF-1 and cleaved caspase-3 was also increased after CTX treatment. Analysis of the PI3K/Akt/mTOR signaling pathway showed that CTX increased phosphorylation of Akt, mTOR and downstream proteins without affecting total levels. These results demonstrated that the CTX treatment led to the hyperactivation of the PI3K/Akt/mTOR signaling pathway in ovaries which may be related to primordial follicle loss and growing follicle apoptosis.
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. chenxiuying36@163.com.|Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, Shanghai 200011, China. chenxiuying36@163.com.|Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China. chenxiuying36@163.com.
authors.forename: Xiu-Ying
authors.initials: XY
authors.lastname: Chen
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. xhx0101@hotmail.com.
authors.forename: He-Xia
authors.initials: HX
authors.lastname: Xia
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. 15211250003@fudan.edu.cn.|Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, Shanghai 200011, China. 15211250003@fudan.edu.cn.|Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China. 15211250003@fudan.edu.cn.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Guan
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. libin782@126.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. zhang.wei.fudan@gmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D003520:Cyclophosphamide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse
keywords: cyclophosphamide; follicle; signaling pathway