Journal
LIFE SCIENCES
Volume 239, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2019.116999
Keywords
CTX; POF; RNA-seq; Mice; Transcriptome
Funding
- National Key R&D Program of China [2017YFA0104400]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT_16R32]
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Aims: The present study aimed to investigate the effects of cyclophosphamide (Cytoxan, CTX) on premature ovarian failure (POF) in mice and its regulatory mechanisms by transcriptome analysis. Main methods: Female C57BL/6 mice were treated with a single intraperitoneal injection of 70 mg/kg CTX. Serum levels of estradiol (E-2) and follicle stimulating hormone (FSH) were measured by enzyme-linked im-munosorbent assay (ELISA), and follicular structure differences were observed by hematoxylin and eosin (H&E) staining. The main mechanism of POF was investigated by RNA-seq data, protein-protein interaction (PPI) networks and qPCR analysis. Key findings: The serum levels of E-2 were significantly decreased and those of FSH were significantly increased compared to the control group. The ovarian weights of the mice in the CTX group were reduced, and abnormal follicular structures were also observed in the CTX group. The RNA-seq data show that the downregulated genes were related to the cholesterol biosynthesis pathway. The PPI network and qPCR analyses further confirm that the PPAR signaling pathway and the ovarian infertility genes were also involved in blocking the cholesterol biosynthesis pathway. The differences were statistically significant. Significance: Our results indicate that CTX may exert its anti-tumor effects by inactivating the cholesterol biosynthesis pathway, and simultaneously reducing the supply of estrogen precursor materials, ultimately leading to the occurrence of POF. Our data provided a preliminary theoretical basis for resolving the clinical toxicity and side effects of CTX.
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