Maternal Exposure to High Estrogen Increases Hyperlipidemia Risk of Childhood Offspring

Abstract

Background: Maternal endocrine disorders can cause abnormal metabolism in offspring. The aim of this study was to investigate whether prenatal high E2 exposure influenced the lipid metabolism of childhood offspring. Methods: In a retrospective cohort study of 3,417 women whose E2 levels on the day of Human Chorionic Gonadotropin (hCG) administration were tested, 1326 were pregnant between 2005-2010. Of 803 women who delivered, 298 women declined child testing and 165 were lost to follow up. Finally, 209 children (125 singleton and 84 twins) born to 167 women without high E2 (low E2 group), and 220 children (126 singleton and 94 twins) from 173 women with high E2 (high E2 group) completed our follow-up study. Information about their 429 children at 3-10 years old was available. Serum lipid levels of these children were examined, and, the relationship between serum lipid levels in offspring and maternal estrogen levels was analyzed. Furthermore, animal models of high estrogen exposure were established to study the lipid metabolism in the offspring. Findings: The serum total cholesterol (TC) levels were 4.10±0.67 mmol/L (low E2 group) and 4.24±0.71 mmol/L (high E2 group, p<0.05), respectively, and, serum low density lipoprotein cholesterol (LDL-C) levels were 2.10±0.47 mmol/L (low E2 group) and 2.22±0.50 mmol/L (high E2 group, p<0.05), respectively. Serum triglyceride (TG) levels and high density lipoprotein cholesterol (HDL-C) levels were comparable in the two groups. In addition, children in high E2 group had significantly larger birth length than those in low E2 group, whereas no statistically significant differences were observed in birth weight, age, BMI, singleton and twins’ ratio, gender ratio, feeding pattern, blood pressure and heart rate of children between two groups. On the other hand, there was an independently significant association between serum lipid levels in childhood and prenatally maternal serum E2 levels. It was confirmed in the mouse model that intrauterine high E2 resulted in hypercholesterolemia in offspring until adulthood. Interpretation: This study provides evidence that the offspring exposed to intrauterine high estrogen had significantly higher levels of lipids in childhood, suggesting that prenatal high estrogen exposure may predispose offspring to lipid metabolism disorder in later life. Funding: Research supported by grants from the National Key Research and Development Program of China (2017YFC1001300), National Natural Science Foundation of China (81671519, 81801444, 81490742, 31571556). Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: Our study was approved by the ethical committee of School of Medicine, Zhejiang University, Hangzhou, China. All experiments were conducted in accordance with relevant guidelines and regulations. The project was approved by the Ethics Committee of the School of Medicine, Zhejiang University and registered in the Chinese Clinical Trial Registry (ChiCTR-OCC-14004682). Our animal experiments were approved by the Zhejiang University Animal Care and Use Committee.