title: High Maternal Serum Estradiol Levels Induce Dyslipidemia in Human Newborns via a Hepatic HMGCR Estrogen Response Element.
abstract: While the intrauterine environment is essential for the health of offspring, the impact of high maternal serum estradiol (E2) on lipid metabolism in offspring and the mechanisms are unknown. We found that ovarian stimulation (OS) could result in high E2 levels in women throughout pregnancy. Strikingly, their newborns showed elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels that were positively related with E2 in newborns. In vitro, E2 dose-dependently stimulated TC and LDL-C secretion, and increased expression of the cholesterol synthesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) in HepG2 cells and mouse fetal hepatocytes. In vivo, high maternal E2 was detected and fetal livers also showed significantly higher HMGCR expression in an OS mouse model. Notably, an estrogen response element (ERE) was identified in the HMGCR promoter, indicating that high maternal serum E2 could up-regulate HMGCR expression in fetal hepatocytes via an ERE that in turn induces elevated levels of TC and LDL-C in offspring.
  
  
  CONCLUSIONS
  OS can induce a high maternal E2 environment, which up-regulates HMGCR expression in fetal hepatocytes via an ERE in the promoter, and induces elevated levels of TC and LDL-C in newborns that may be related to increased risk of metabolic disease in adulthood.
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Lv
authors.affiliation: 1] International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China [2] Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: Guo-Lian
authors.initials: GL
authors.lastname: Ding
authors.affiliation: 1] International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China [2] Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Yu
authors.affiliation: 1] International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China [2] Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Hu
authors.affiliation: 1] International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China [2] Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China [3] Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Lin
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Tian
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Lv
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Meng-Xi
authors.initials: MX
authors.lastname: Guo
authors.affiliation: Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China.
authors.forename: Zhang-Hong
authors.initials: ZH
authors.lastname: Ke
authors.affiliation: 1] International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China [2] Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: 1] Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China [2] Department of Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Sheng
authors.affiliation: 1] International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China [2] Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: Feng-Tao
authors.initials: FT
authors.lastname: Shi
authors.affiliation: 1] International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China [2] Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang 310006, China [3] Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
authors.forename: He-Feng
authors.initials: HF
authors.lastname: Huang
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood* / Q000209:etiology; D004958:Estradiol / Q000097:blood*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000097:blood* / Q000209:etiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood*
chemical_list: D008078:Cholesterol, LDL; D004958:Estradiol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases