Abstract
ABSTRACTThe prevalence of diabetes is increasing worldwide with the trend of patients being young and creating a significant burden on health systems, including reproductive problems, but the effects of diabetes on embryo implantation are still poorly understood. Our study was to examine effects of diabetes on mouse embryo implantation, providing experimental basis for treating diabetes and its complications. Streptozotocin (STZ) was applied to induce type 1 diabetes from day 2 of pregnancy or pseudopregnancy in mice. Embryo transfer was used to analyze effects of uterine environment on embryo implantation. Our results revealed that the implantation rate is significantly reduced in diabetic mice compared to controls, and the change of uterine environment is the main reason leading to the decreased implantation rate. Compared to control, the levels of LIF and p-STAT3 are significantly decreased in diabetic mice on day 4 of pregnancy, and serum estrogen level is significantly higher. Estrogen stimulates LIF expression under physiological level, but the excessive estrogen inhibits LIF expression. LIF, progesterone or insulin supplement can rescue embryo implantation in diabetic mice. Our data indicated that the dysregulated LIF-STAT3 pathway caused by the high level of estrogen results in the impaired implantation in diabetic mice, which can be rescued by LIF, progesterone or insulin supplement.
Highlights
Embryo implantation involves an intricate discourse between the embryo and uterus, including synchronized development of the embryo to the blastocyst stage, differentiation of the uterus to the receptive state, and cross-talk between the blastocyst and uterine luminal epithelium (Lim and Dey, 2009)
We showed that the high level of estrogen in diabetic mice may disturb Leukemia inhibitory factor (LIF)-Signal transducer and activator of transcription 3 (STAT3) pathway and lead to impaired embryo implantation
Because diabetes can affect the expressions of many cytokines related to immunity and inflammation (Shankar et al, 2011), we examined uterine expressions of tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β)
Summary
Embryo implantation involves an intricate discourse between the embryo and uterus, including synchronized development of the embryo to the blastocyst stage, differentiation of the uterus to the receptive state, and cross-talk between the blastocyst and uterine luminal epithelium (Lim and Dey, 2009). Estrogen is essential for preparation of uterine receptivity and embryo implantation. Leukemia inhibitory factor (LIF) is highly expressed in mouse uterus during receptivity phase and essential for embryo implantation (Stewart et al, 1992). Signal transducer and activator of transcription 3 (STAT3), a downstream target of LIF, is phosphorylated in the luminal epithelium before embryo implantation (Cheng et al, 2001). The inhibition or uterine conditional deletion of STAT3 leads to the failure of mouse embryo implantation (Nakamura et al, 2006; Sun et al, 2013)
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