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.
Highlights
With the advances in the early diagnosis and effective treatment of many cancer patients, long-time survival has become a reality for many young cancer patients during their reproductive years [1]
The functional role of PI3K signaling was enhanced when Pten, a negative regulator of PI3K, was deleted from oocytes, which resulted in the global activation of oocytes and the exhaustion of the entire primordial follicle pool [15]
Loss of the Pten gene resulted in an enhanced PI3K signaling pathway which was indicated by an increase in phosphorylated Akt (p-Akt)
Summary
With the advances in the early diagnosis and effective treatment of many cancer patients, long-time survival has become a reality for many young cancer patients during their reproductive years [1]. Chemotherapy-induced ovarian failure acts mainly through the prevention of cell division and the inhibition of DNA function, which could induce apoptosis in pre-granulosa cells and damage ovarian stromal components, resulting in the reversible premature exhaustion of the resting primordial follicles [4]. Cyclophosphamide (CTX), one such alkylating agent, is commonly used in the treatment of many types of malignant tumors such as Hodgkin’s disease and breast cancer [7,8]. To examine the effects of CTX on ovaries and investigate which signaling pathway participates in ovarian injury due to CTX treatment. CCyycclloopphhoosspphhaammiiddeeIInndduucceedd PPrriimmoorrddiiaall FFoolllliiccllee LLoossss iinn FFeemmaallee MMiiccee TThheerree wwaassnnooddeaetahthanadndnonaopappapreanrtentotxtiocixtiyciitnyminicemaicfteeraCftTerXCinTjXectiinojne,ctainodn,baonddy-bwoedigyh-wt geaiginhst wgaeirnes nwoerrme anlo(rFmigaul r(eFi1g)u. LAthltohuoguhghfoflolilclilcelsesatadt dififfefreernetntstsatgagesescocouuldldbbeeoobbsseerrvveeddiinnCCTTXX--ttrreeaatteedd mmiiccee,, tthhee oovvaarriieess wweerree mmoossttllyy ccoommppoosseedd ooff ccoollllaappsseedd ooooccyytteess aanndd pprreesseenntteedd mmaarrkkeedd ccoorrttiiccaall ffiibbrroossiiss aanndd aa rreedduucceedd nnuummbbeerr ooff ffoolllliicclleess,, eessppeecciiaallllyy pprriimmoorrddiiaall ffoolllliicclleess ((FFiigguurree 22AA)). AA ssiinnggllee ddoossee ooff CCyycclloopphhoosspphhaammiiddee iinnjjeeccttiioonn ddiidd nnoott cchhaannggee bbooddyy wweeiigghhtt aatt ddiiffffeerreenntt ttiimmee ppooiinnttss.. ((AA)) TThhrreeeeddaayyssaaftfetrerCCTTXXtrteraetamtmenetn;t(;B()BS)eSveevnednadyasyasftaefrteCrTCXTtXreatrtemaetmnte. nTth. eTrheesureltssuslhtsowshtohwe mtheeamnseansSD± .SD
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