title: Prevalence of Prediabetes Risk in Offspring Born to Mothers with Hyperandrogenism.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Pregestational hyperandrogenism may predispose offspring to glucose metabolism disorder via epigenetic oocyte inheritance. Clinical trial registry no.: ChiCTR-OCC-14004537; www.chictr.org.
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China; Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Tian
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Lin
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yi-Meng
authors.initials: YM
authors.lastname: Xiong
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Miao-E
authors.initials: ME
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Yu
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Lv
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Gu-Feng
authors.initials: GF
authors.lastname: Xu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Guo-Lian
authors.initials: GL
authors.lastname: Ding
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Xu
authors.affiliation: Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Reproductive Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Feng
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Wu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Tan
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Lu-Yang
authors.initials: LY
authors.lastname: Jin
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Song-Chang
authors.initials: SC
authors.lastname: Chen
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xin-Mei
authors.initials: XM
authors.lastname: Liu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Jun-Yu
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Chen
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yi-Cong
authors.initials: YC
authors.lastname: Meng
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Zhou
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xin-Zhu
authors.initials: XZ
authors.lastname: Li
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yi-Yu
authors.initials: YY
authors.lastname: Wang
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yu-Qian
authors.initials: YQ
authors.lastname: Xiang
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Liu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Lu-Ting
authors.initials: LT
authors.lastname: Chen
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Hong-Jie
authors.initials: HJ
authors.lastname: Pan
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Fang-Hong
authors.initials: FH
authors.lastname: Zhang
authors.affiliation: Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Xing
authors.affiliation: Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Klausen
authors.affiliation: Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Peter C K
authors.initials: PCK
authors.lastname: Leung
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Ju-Xue
authors.initials: JX
authors.lastname: Li
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Sheng
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, 310006, China; The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: huanghefg@hotmail.com.
authors.forename: He-Feng
authors.initials: HF
authors.lastname: Huang
mesh_terms: D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002681:China / Q000453:epidemiology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D017588:Hyperandrogenism / Q000150:complications / Q000235:genetics*; D007328:Insulin / Q000097:blood; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D009035:Mothers / Q000706:statistics & numerical data*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D011236:Prediabetic State / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D011247:Pregnancy; D015995:Prevalence; D011446:Prospective Studies; D051381:Rats; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; C035170:IGF2 protein, human; D007328:Insulin; D007335:Insulin-Like Growth Factor II
keywords: Epigenetics; Hyperandrogenism; Offspring; Prediabetes