Wang Hui-Hui, Zhou Cheng-Liang, Lv Min, Yang Qian, Li Ju-Xue, Hou Min, Lin Jing, Liu Xin-Mei, Wu Yan-Ting, Sheng Jian-Zhong, Huang He-Feng
Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China.
Institute of Embryo-Fetal Original Adult Disease, Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Endocrinology. 2018 Jan 1;159(1):465-476. doi: 10.1210/en.2017-03017.
An adverse intrauterine environment may induce adult disease in offspring, but the mechanisms are not well understood. It is reported that fresh embryo transfer (ET) in assisted reproductive technology leads to high maternal estradiol (E2), and prenatal high E2 exposure increases the risk of organ disorders in later life. We found that male newborns and children of fresh ET showed elevated fasting insulin and homeostasis model of assessment for insulin resistance index (HOMA-IR) scores. Male mice with high prenatal estradiol exposure (HE) grew heavier than control mice and developed insulin resistance; they also showed increased food intake, with increased orexigenic hypothalamic neuropeptide Y (NPY) expression. The hypothalamic insulin receptor (INSR) was decreased in male HE mice, associated with elevated promoter methylation. Chronic food restriction (FR) in HE mice reversed insulin resistance and rescued hypothalamic INSR expression by correcting the elevated Insr promoter methylation. Our findings suggest that prenatal exposure to high E2 may induce sex-specific metabolic disorders in later life through epigenetic programming of hypothalamic Insr promoter, and dietary intervention may reverse insulin resistance by remodeling its methylation pattern.
不良的子宫内环境可能会导致后代成年后患病，但其机制尚不清楚。据报道，辅助生殖技术中的新鲜胚胎移植（ET）会导致母体雌二醇（E2）水平升高，产前高E2暴露会增加晚年器官功能紊乱的风险。我们发现，新鲜胚胎移植出生的雄性新生儿和儿童空腹胰岛素水平升高，胰岛素抵抗指数（HOMA-IR）评估的稳态模型得分也升高。产前高雌二醇暴露（HE）的雄性小鼠比对照小鼠体重增加，并出现胰岛素抵抗；它们的食物摄入量也增加，下丘脑促食欲神经肽Y（NPY）表达增加。雄性HE小鼠下丘脑胰岛素受体（INSR）减少，与启动子甲基化升高有关。对HE小鼠进行长期食物限制（FR）可通过纠正Insr启动子甲基化升高来逆转胰岛素抵抗，并挽救下丘脑INSR表达。我们的研究结果表明，产前暴露于高E2可能通过下丘脑Insr启动子的表观遗传编程在晚年诱导特定性别的代谢紊乱，饮食干预可能通过重塑其甲基化模式来逆转胰岛素抵抗。
