Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide

Abstract

Busulfan/cyclophosphamide (Bu/Cy) conditioning regimen has been widely used to treat cancer patients, while their effects on major internal organs in females are not fully understood. We treated female mice with Bu/Cy, and examined the histopathology of major internal organs on Day 30 after the treatment. The results show that Bu/Cy treatment affected the ovaries most extensively, while it had less effect on the spleen, lungs, and kidneys, and no effect on the heart, liver, stomach, and pancreas. To better understand the effect of Bu/Cy on the ovaries, we counted follicles, and determined the levels of ovarian steroids. The Bu/Cy-treated mice showed a reduction of primordial and primary follicles (P<0.01) on Day 30 and a marked loss of follicles at all developmental stages (P<0.01) on Day 60. Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%, respectively. Thus, there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice; this is a profile similar to what is found in women with premature ovarian failure (POF). The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.

iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice and After Gonadotoxic Chemotherapy

“…3D). This accords with previous mouse studies in which the gonadotoxic effects of cyclophosphamide and busulfan have been demonstrated 25 .…”

Estradiol plays a role in regulating the expression of lysyl oxidase family genes in mouse urogenital tissues and human Ishikawa cells

“…The mouse model of accelerated ovarian aging was generated according to the study previously described (Jiang et al, 2013). Twelve female mice at two months of age were injected with busulfan (Bu) in dimethyl sulfoxide (DMSO; 12 mg/kg, subcutaneously) and cyclophosphamide (Cy) in 0.9% (9 g/L) sterile sodium chloride solution (120 mg/kg, intraperitoneally).…”

“…The Bu/Cy-treated mice showed a significant reduction of primordial and primary follicles by 30 d after the treatment. The treated mice showed lower levels of estrogen and decreased expression of LOX family genes and elastin (Jiang et al, 2013). We randomly divided the Bu/Cy-treated mice into two groups: an E2-treated group and a control group (n=6 each group).…”

“…The accelerated ovarian aging mice express lower levels of E2 and LOX family genes. Furthermore, these mice can easily be developed, and this saves time compared with allowing mice to age naturally for use in investigating the role of estrogen (Jiang et al, 2013). We examined the expression of LOX family genes in the urogenital tissues of accelerated ovarian aging mice and Ishikawa cells following treatment with E2.…”

Post-natal oogenesis: a concept for controversy that intensified during the last decade

“…Post-natal follicular renewal does not occur in mammals, and mitotically active DDX4-expressing female germline progenitors do not reside in post-natal mouse ovaries Byskov et al (2011) There is no evidence for the presence of GSCs by staining pluripotent pre-meiotic germ cells markers and oogonia in the post-natal human ovary after final clearing of these cells during the first 1 or 2 years of early life Kerr et al (2012) Neo-folliculogenesis does not occur in mice after eradication of the primary follicle resource by chemicals or ␥ -irradiation Yuan et al (2013) There is no evidence for proliferative GSCs and germ cell renewal in adult monkey and mouse ovaries Lie & Spradling (2013) In adult female mice ovary there is no active GSC and production of new oocytes in vivo eradicate the primordial follicle source (Hemsworth & Jackson, 1963;Burkl & Schiechl, 1978;Pelloux et al, 1988;Meirow et al, 1999;Shirota et al, 2003;Jiang et al, 2013) without stimulating atresia. After treatment with busulphan, cells expressed the meiotic entry marker (SCP3) in juvenile and adult mouse ovaries.…”