Human epidemiological studies have indicated the inheritance

Human epidemiological studies have indicated the inheritance of environment-induced phenotype (Huang and Sheng, 2014). Offspring of in utero malnutrition are associated with increased prevalence of type 2 diabetes risk (Petry and Hales, 2000). Famine experiences in grandfathers increased the risk of obesity and cardiovascular diseases in grandchildren (Painter et al., 2008). Although the exact mechanism is unclear, these studies indicate that the environmental factors are associated with the inheritance of disease risk in next generations. Recently, a series of animal studies have revealed that adverse paternal factors increase the susceptibility to adult metabolic diseases in offspring through gametic epigenetic alterations (Carone et al., 2010; Radford et al., 2014; Wei et al., 2015). Paternal high-fat-diet exposure may program β-cell dysfunction in first-generation (F1) female offspring in rat (Ng et al., 2010). Intrauterine undernutrition impairs lipid metabolism in second-generation (F2) offspring by transmission of DNA methylation alteration via paternal linage (Martinez et al., 2014). Likewise, paternal prediabetes can be transgenerationally inherited through the male germ line depending on methylation changes in mice (Wei et al., 2014). A recent study in rodent, using IVF and prostaglandin receptor transfer (IVF-ET) and foster mother, demonstrated that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes in a sex- and parent of origin-specific mode (Huypens et al., 2016). Two studies showed that maternal diabetes and obesity resulted in altered oocyte methylation patterns of specific genes (Ge et al., 2013, 2014). Hence, it is very important to investigate whether oocytes, especially human oocytes, from mother with endocrine disorders are associated with increased risks of metabolic disorders in their children, and what mechanisms are involved. The aim of this study was to investigate whether mothers with pregestational hyperandrogenism could predispose offspring to glucose metabolism disorder through epigenetic oocyte inheritance. Our results demonstrated that children born to mothers with pregestational hyperandrogenism manifested increased serum fasting glucose and insulin levels, and were more prone to prediabetes. High androgen levels significantly upregulated IGF2, an imprinting gene, expression in human oocytes. In parallel, study in rats clearly showed that pregestational hyperandrogenism induced diabetic phenotypes and impaired insulin secretion in offspring. Exposure of rat oocytes with high androgen concentration increased the expression level of Igf2 not only in mothers\' oocytes but also in β-cells of F1 pancreatic islets.
Materials & Methods
Results
Discussion In this clinical cohort study, we found that hyperandrogenism in mothers might increase the risks of abnormal glucose metabolism in their children. According to the Barker\'s Theory “fetal origins of adult diseases”, adverse intrauterine environment during pregnancy can predispose offspring to diabetes, cardiovascular diseases and obesity in later life. Recently, animal studies demonstrated that high-fat-diet exposure in fathers (Ng et al., 2010) or mothers (Huypens et al., 2016) before conception might also induce metabolic disorders in their offspring via gametic epigenetic alterations. The present study is an investigation in humans to examine whether hyperandrogenism in mothers may induce the alteration of glucose metabolism in their offspring via epigenetic inheritance from mother\'s oocyte to offspring\'s somatic cells. Hyperandrogenemia is a common disorder in women of reproductive age, especially in subfertile women (Qiao and Feng, 2011). In this investigation, 147 women manifesting hyperandrogenism among the 1116 women were recruited (13.17%). Some clinic study indicated that in vivo fertilization rates women with hyperandrogenism were normal (Franks et al., 2003) meanwhile some showed that they might have poor oocyte quality leading to decreased fertilization and implantation rates (Qiao and Feng, 2011; Murray et al., 2008; Teissier et al., 2000). The long term health of their children is well worth studying. Our previous work reported that maternal excessive estrogen exposure before pregnancy might predispose offspring to cardiovascular dysfunction (Xu et al., 2014). Here, we provide evidence that pregestational hyperandrogenism may induce alteration of glucose metabolism in offspring. We found that children born to mothers with pregestational hyperandrogenism had the increased fasting glucose, insulin and HOMA-IR levels. Importantly, they were more susceptible to prediabetes at as early as 5years old. The risk for prediabetes was still significant after adjusting for gestational complications, suggesting a relationship between pregestational hyperandrogenism in mothers and prediabetes in their children.