IVF过程对子代MSH2和MSH6错配修复基因表达的影响及表观遗传调控研究

ART已经成为临床上治疗不孕症最有效的方法。然而流行病学资料显示ART出生子代发生健康状况受损的风险增高，其发生可能与IVF过程中涉及的非自然妊娠环节如药物控制性促排卵和胚胎体外培养等密切相关。我们的前期研究发现IVF人早孕期胎儿和小鼠出生子代脑组织中MSH2和MSH6错配修复基因的表达和DNA甲基化修饰水平存在持续性的改变。因此，我们拟通过建立小鼠模型获取经过药物控制性促排卵和胚胎体外培养两个环节处理的卵母细胞和受精后胚胎，然后通过高雌激素和高氧气浓度模拟IVF上述两个环节培养小鼠胚胎干细胞和拟胚体，最后辅以人IVF卵母细胞和受精后胚胎检测，阐明IVF过程中的药物控制性促排卵和胚胎体外培养环节对卵母细胞和受精后胚胎、早孕期胎儿和出生子代脑组织中MSH2和MSH6基因的表达和表观遗传调控水平的影响，以期寻找到合适的干预手段改进IVF技术，为降低IVF出生子代健康受损风险提供科学依据。

Assisted reproductive technology (ART), represented by in vitro fertilization and embryo transfer (IVF-ET), has become the most effective treatment for infertility at present. However, decreased birth weight and increased incidence of birth defects are two of the main potential risks for the newborns conceived by ART. Controlled ovarian stimulation, in vitro embryo culture and other processes involved in IVF may all have potential impacts on the health condition of ART offspring. Our preliminary study observed altered expression levels and DNA methylation modification levels of MSH2 and MSH6 genes in human early fetus samples and mice brain tissue samples conceived by IVF. To understand the detailed effect and mechanism of two main IVF aspects on the expression and epigenetic modification of MSH2 and MSH6 genes, mouse models will be established to obtain oocytes, two-cell embryos and blastocysts treated by controlled ovarian stimulation and in vitro embryo culture and to explore the initial process and time point that how IVF procedure could lead to these alterations. Then in vitro experiments of mouse embryo stem cells and embryoid bodies treated with different concentration of estrogen and oxygen will be carried out. This study will illuminate the effect of two different aspects of IVF procedure on MSH2 and MSH6 genes in gamete/embryo, early fetus and post-natal stage and provide possible methods to improve IVF technology and reduce the safety risks of IVF offspring.