Transcriptome analysis reveals that cyclophosphamide induces premature ovarian failure by blocking cholesterol biosynthesis pathway

• Published in: Life sciences (1973) 2019-12, Vol.239, p.116999-116999, Article 116999
• Main Authors: Li, Qi, An, Xinglan, Man, Xiaxia, Chu, Meiran, Zhao, Tianchuang, Yu, Hao, Li, Ziyi
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Animals; Antineoplastic Agents, Alkylating - toxicity; Biosynthesis; Cholesterol; Cholesterol - biosynthesis; CTX; Cyclophosphamide; Cyclophosphamide - toxicity; Down-Regulation - drug effects; Enzyme-linked immunosorbent assay; Estradiol - blood; Failure analysis; Female; Follicle Stimulating Hormone - biosynthesis; Follicle-stimulating hormone; Gene expression; Gene Expression Profiling; Genes; Infertility; Metabolic Networks and Pathways - drug effects; Mice; Mice, Inbred C57BL; Organ Size - drug effects; Ovarian Follicle - drug effects; Ovarian Follicle - pathology; Peroxisome proliferator-activated receptors; Peroxisome Proliferator-Activated Receptors - genetics; POF; Primary Ovarian Insufficiency - chemically induced; Primary Ovarian Insufficiency - genetics; Primary Ovarian Insufficiency - metabolism; Protein interaction; Protein Interaction Maps; Proteins; Regulatory mechanisms (biology); Reproductive status; Ribonucleic acid; RNA; RNA-seq; Serum levels; Sex hormones; Signal transduction; Statistical analysis; Transcriptome
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.116999

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. Female C57BL/6 mice were treated with a single intraperitoneal injection of 70 mg/kg CTX. Serum levels of estradiol (E2) and follicle stimulating hormone (FSH) were measured by enzyme-linked immunosorbent 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. The serum levels of E2 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. 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.