Abstract
Background Premature ovarian insufficiency (POI) is characterized by a loss of ovarian function before 40 years-of-age and represents a major cause of female infertility. POI is one of the dominant causes of cis-diaminedichloroplatinum (cisplatin, CDDP)-induced reproductive impairment. However, the detailed mechanisms underlying POI induced by CDDP remain unclear. Methods The POI C57B6/J mouse model was created by administering CDDP. The effects of FKBP4 were investigated using isobaric tags for relative and absolute quantification analysis (iTRAQ), real-time quantitative PCR (qRT-PCR) and western blotting. Target prediction was predicted using TargetScan software. Levels of sex hormones were tested using Enzyme-linked immunosorbent assays (ELISA). Results We found that the FKBP4 protein was down-regulated in the ovaries of CDDP model. Target prediction identified FKBP4 as a potential target for miR-483-5p , which was expressed at high levels in both the ovaries and serum of CDDP-POI mice, and in the serum from POI patients. In vitro experiments further confirmed that FKBP4 was the target for miR-483-5p in human cervical cancer cells (HeLa). The overexpression of FKBP4 in human granulosa cells (KGN) alleviated the apoptosis caused by CDDP and the overexpression of miR-483-5p . Furthermore, the overexpression of miR-483-5p in oocytes caused injury to the ovaries, and disrupted the levels of sex hormones in CDDP-POI mice (AMH: P <0.01; E 2 : P <0.01; FSH: P <0.01). Conclusions Analyses showed that miR-483-5p targets the FKBP4 protein in a mouse model of POI induced by CDDP. Elevated levels of miR-483-5p in oocytes aggravated POI induced by CDDP by targeting FKBP4. Overall, our data demonstrate that miR-483-5p was responsible for the underlying pathophysiology of POI induced by chemotherapeutic treatments, such as CDDP.
Comparison of different methods for the absolute quantification of harbour seal transferrin glycoforms using HPLC-ICP-MS
