PMID- 32791177
OWN - NLM
STAT- MEDLINE
DCOM- 20210106
LR  - 20210106
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 404
DP  - 2020 Oct 1
TI  - Epigenetic repression of AT2 receptor is involved in beta cell dysfunction and 
      glucose intolerance of adult female offspring rats exposed to dexamethasone 
      prenatally.
PG  - 115187
LID - S0041-008X(20)30313-6 [pii]
LID - 10.1016/j.taap.2020.115187 [doi]
AB  - Prenatal exposure to dexamethasone (PDE) impairs pancreatic beta cell development 
      and glucose homeostasis in offspring especially females. To explore the 
      underlying intrauterine programming mechanism, pregnant Wistar rats were 
      subcutaneously administered with dexamethasone (0, 0.2 and 0.8 mg/kg.d) from 
      gestational days (GD) 9 to 20. Female offspring were collected on GD20 (fetus) 
      and in postnatal week 28 (adult), respectively. PDE reduced the serum insulin 
      levels, beta cell mass, and pancreatic insulin expressions in fetuses and adults, 
      causing glucose intolerance after maturity. The persistent suppression of 
      pancreatic angiotensin II receptor type 2 (AT2R) expression before and after 
      birth could be observed in the PDE females, which is accompanied with decreased 
      histone 3 lysine 14 acetylation (H3K14ac) and H3K27ac levels in AT2R promoter. 
      PDE increased the gene expressions of glucocorticoid receptor (GR) and histone 
      deacetylase 2 (HDAC2) in fetal pancreas. Furthermore, dexamethasone inhibited 
      insulin biosynthesis while activated GR and HDAC2 expression in the rat INS-1 
      cells. The AT2R expression was repressed by dexamethasone in vitro but only 
      H3K27ac levels in AT2R promoter were lowered. Dexamethasone enhanced the 
      interaction between GR and HDAC2 proteins as well as the binding of GR/HDAC2 
      complex to AT2R promoter. Moreover, overexpression of AT2R could restore the 
      suppressed insulin biosynthesis induced by dexamethasone in vitro, and both GR 
      antagonist and histone deacetylase abolished the decreased H3K27ac level and gene 
      expression of AT2R. In conclusion, continuous epigenetic repression of AT2R 
      before and after birth may be involved in beta cell dysfunction and glucose 
      intolerance of the PDE adult female offspring.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Kou, Hao
AU  - Kou H
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan 430071, China; Department of Pharmacy, Zhongnan Hospital of Wuhan 
      University, Wuhan 40071, China; Hubei Provincial Key Laboratory of 
      Developmentally Originated Diseases, Wuhan 430071, China.
FAU - Gui, Shuxia
AU  - Gui S
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan 430071, China.
FAU - Dai, Yongguo
AU  - Dai Y
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan 430071, China.
FAU - Guo, Yu
AU  - Guo Y
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally 
      Originated Diseases, Wuhan 430071, China. Electronic address: guoy@whu.edu.cn.
FAU - Wang, Hui
AU  - Wang H
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally 
      Originated Diseases, Wuhan 430071, China. Electronic address: 
      wanghui19@whu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200811
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Glucocorticoids)
RN  - 0 (Receptor, Angiotensin, Type 2)
RN  - 7S5I7G3JQL (Dexamethasone)
SB  - IM
MH  - Animals
MH  - Dexamethasone/*toxicity
MH  - Epigenesis, Genetic
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Glucocorticoids/toxicity
MH  - *Glucose Intolerance
MH  - Insulin-Secreting Cells/*metabolism
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - Rats
MH  - Receptor, Angiotensin, Type 2/genetics/*metabolism
OTO - NOTNLM
OT  - Angiotensin Receptor II
OT  - Dexamethasone
OT  - Glucose Intolerance
OT  - Histone Acetylation
OT  - Pancreatic beta Cell
COIS- Declaration of Competing Interest All authors declare they have no conflict of 
      interest.
EDAT- 2020/08/14 06:00
MHDA- 2021/01/07 06:00
CRDT- 2020/08/14 06:00
PHST- 2020/05/17 00:00 [received]
PHST- 2020/07/22 00:00 [revised]
PHST- 2020/08/07 00:00 [accepted]
PHST- 2020/08/14 06:00 [pubmed]
PHST- 2021/01/07 06:00 [medline]
PHST- 2020/08/14 06:00 [entrez]
AID - S0041-008X(20)30313-6 [pii]
AID - 10.1016/j.taap.2020.115187 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2020 Oct 1;404:115187. doi: 10.1016/j.taap.2020.115187. 
      Epub 2020 Aug 11.