Abstract
Frozen and thawed embryo transfer (FET) is currently widely applied in routine assisted reproductive technology (ART) procedure. It is of great necessity to assess the safety of FET and investigate the long-term effect including glucose metabolism on FET-conceived offspring. The mouse model is a highly efficient method to figure out the relationship between the process of FET and offspring health. In this study, we obtained mouse offspring of natural conception (NC), in vitro fertilization (IVF), and FET. Glucose and insulin tolerance test (GTT/ITT) were performed on both chow fed or high fat diet (HFD) fed offspring to examine the glucose metabolism status. We detected hepatic PI3K/AKT pathway by western blotting and transcriptome status by RNA-sequencing. Impaired glucose tolerance (IGT) and decreased insulin tolerance were occurred in FET conceived male offspring. After challenged with the HFD-fed, male offspring in FET group performed earlier and severer IGT than IVF group. Furthermore, higher HOMA-IR index and higher serum insulin level post glucose injected in FET-chow group suggested the insulin resistance status. The PI3K/AKT signaling pathway, the major pathway of insulin in the liver, were also disrupted in FET group. Transcriptomics of the liver reveals significantly downregulated in glucose metabolic process and insulin resistance in the FET-chow group. In our study, FET-conceived male mouse offspring presented glucose metabolism dysfunction mainly manifesting insulin resistance. The hepatic insulin signaling pathway were in concordance with reduced glycogen synthesis, increased glycolysis and enhanced gluconeogenesis status in FET-conceived male offspring.
Highlights
Since the first baby born from in vitro fertilization and embryo transfer (IVF-ET) in 1978, assisted reproductive technologies (ART) have rapidly developed over the past decades
There was no significant difference in the pregnancy rates and embryo implantation rates between the IVF-ET and IVF-frozen-thawed embryo transfer (FET) groups (Supplementary Table 3)
In contrast to the glucose metabolism status in female offspring conceived by IVF-ET and IVF-FET, we found that the glucose tolerance test (GTT) area under the curves (AUCs) of female offspring conceived by IVF-ET and IVF-FET under metabolic stress were higher than those in the offspring of the natural conception (NC)-high fat diet (HFD) group at both 8 and 20-weeks-old (Supplementary Figure 1), the insulin sensitivities were similar
Summary
Since the first baby born from in vitro fertilization and embryo transfer (IVF-ET) in 1978, assisted reproductive technologies (ART) have rapidly developed over the past decades. Children conceived by ART are at risk of adverse short-term and long-term effects, Glucose Metabolism in Offspring Conceived by FET such as neurodevelopmental disorders, poor school performance in childhood and cardiometabolic dysfunction, which has raised concerns by many researchers (Savage et al, 2011; Sandin et al, 2013; Sharpe, 2018; Gu et al, 2019; Hargreave et al, 2019; Pinborg, 2019; Cui et al, 2020). The use of FET cycles in ART programs has maintained an increasing trend worldwide (European IVF monitoring Consortium et al, 2017). Several follow-up studies have suggested that newborns conceived by FET often show abnormal lipid metabolism and an increased risk of childhood cancer compared with children born after natural conception and fresh embryo transfer (Green et al, 2013; Hargreave et al, 2019). The limited clinical applications duration of FET prevented researchers from investigating the long-term effects of FET on human offspring
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