Chronic unpredictable mild stress-induced mouse ovarian insufficiency by interrupting lipid homeostasis in the ovary

Ovarian insufficiency results from a number of disorders, and a certain causal relationship between psychological stress and ovarian insufficiency has been reported, but the underlying mechanism remains unclear. In our study, C57BL/6J female mice were subjected to chronic unpredictable mild stress (CUMS), and depression-like mice were selected and identified according to the behavioral tests. The defective ovarian follicle development, low 17 β-estradiol (E₂), and anti-Mullerian hormone (AMH) levels, which were consistent with the clinical characteristics of ovarian insufficiency, indicated that depression-like mice may be used to assess the effects of psychological stress on female reproductive function. To investigate a possible mechanism, lipid homeostasis of the ovary was detected by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis, and the decreased abundance of cholesteryl ester (CE 24:4) was supported to be associated with the downregulated E₂. Moreover, granulosa cells did undergo more apoptosis in response to psychological stress, which was caused by downregulated Bcl2 and Bcl2/Bax in granulosa cells. Additionally, the disorder of cell death and growth-related pathways in depression-like mouse ovaries was confirmed by RNA-seq analysis. Taken together, this study will provide a better understanding of the female reproductive problem under psychological stress.