Prenatal High Estradiol Exposure Induces Sex-Specific and Dietarily Reversible Insulin Resistance Through Decreased Hypothalamic INSR.

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.

Prevalence of Prediabetes Risk in Offspring Born to Mothers with Hyperandrogenism.

BACKGROUND: Excessive androgen exposure during pregnancy has been suggested to induce diabetic phenotypes in offspring in animal models. The aim of this study was to investigate whether pregestational maternal hyperandrogenism in human influenced the glucose metabolism in offspring via epigenetic memory from mother's oocyte to child's somatic cells. METHODS: Of 1782 reproductive-aged women detected pregestational serum androgen, 1406 were pregnant between 2005 and 2010. Of 1198 women who delivered, 1116 eligible mothers (147 with hyperandrogenism and 969 normal) were recruited. 1216 children (156 children born to mothers with hyperandrogenism and 1060 born to normal mother) were followed up their glycometabolism in mean age of 5years. Imprinting genes of oocyte from mothers and lymphocytes from children were examined. A pregestational hyperandrogenism rat model was also established. FINDINGS: Children born to women with hyperandrogenism showed increased serum fasting glucose and insulin levels, and were more prone to prediabetes (adjusted RR: 3.98 (95%CI 1.16-13.58)). Oocytes from women with hyperandrogenism showed increased insulin-like growth factor 2 (IGF2) expression. Lymphocytes from their children also showed increased IGF2 expression and decreased IGF2 methylation. Treatment of human oocytes with dihydrotestosterone upregulated IGF2 and downregulated DNMT3a levels. In rat, pregestational hyperandrogenism induced diabetic phenotypes and impaired insulin secretion in offspring. In consistent with the findings in human, hyperandrogenism also increased Igf2 expression and decreased DNMT3a in rat oocytes. Importantly, the same altered methylation signatures of Igf2 were identified in the offspring pancreatic islets. INTERPRETATION: Pregestational hyperandrogenism may predispose offspring to glucose metabolism disorder via epigenetic oocyte inheritance. Clinical trial registry no.: ChiCTR-OCC-14004537; www.chictr.org.

Altered DNA methylation in neonates born large-for-gestational-age is associated with cardiometabolic risk in children.

BACKGROUND: Infants being born Large-for-gestational-age (LGA) are prone to developing cardiometabolic disease. However, the underlying mechanisms remain unclear. RESULTS: Clinical investigation showed that children born LGA had significantly higher serum level of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and insulin, ratio of TC/high-density lipoprotein-cholesterol (HDL-c) compared to children born appropriate for gestational age (AGA). Birth weight (BW) was positively correlated to TC, LDL-c, and the ratio of TC/HDL in serum. Genome-wide DNA methylation analyzed in umbilical cord blood of controls and macrosomia cases. We identified 3459 methylation variable positions (MVPs) achieving genome-wide significance (adjusted P-value < 0.05) with methylation differences of ≥ 5%. A total of 327 MVPs were filtered by methylation differences of ≥ 7% located within an island, which mapped to 213 genes. Function analysis using Ingenuity Pathway Analysis showed 16 genes enriched in "cardiovascular disease". Four genes included contributed to hyperlipidemia. MATERIALS AND METHODS: Fifty-eight children aged 3-6 years born LGA and 123 subjects born AGA were enrolled. Anthropometric parameters and blood pressure (BP) were measured, and metabolic assessment was performed in all subjects. Genome-wide DNA methylation in umbilical blood was assayed by the 450K BeadChip in six AGA and six macrosomia newborns. CONCLUSIONS: Our data indicate that excess birth weight may increase the risk of lipid dysfunction in children aged 3-6 years. It might through reprogramming a group of genes correlated to cardiovascular disease. The genes identified in this study might be potential biomarker for cardiometabolic disease.

[Establishment of a new method for early embryo culture in vitro].

A new method, nest culture method, was developed in this study. The culture effects of different methods for embryo culture in vitro were compared. The results showed that whether the suspension in phi35mm dish in nest culture method was covered with mineral oil or not, the developmental rates of embryos had no significant difference. Compared to the nest culture method, the developmental rates of embryos in Brinster's method were significant lower. However, all embryos cultured in the single dish in which the suspensions were not covered with mineral oil were blocked at 2-cell stage. The nest culture method is an effective method for early embryo culture in vitro.