PMID- 35595036
OWN - NLM
STAT- MEDLINE
DCOM- 20220616
LR  - 20220616
IS  - 1879-3169 (Electronic)
IS  - 0378-4274 (Linking)
VI  - 364
DP  - 2022 Jul 1
TI  - Altered hippocampal GR/KCC2 signaling mediates susceptibility to convulsion in 
      male offspring following dexamethasone exposure during pregnancy in rats.
PG  - 12-23
LID - S0378-4274(22)00092-3 [pii]
LID - 10.1016/j.toxlet.2022.05.004 [doi]
AB  - Epidemiological research suggests that convulsions may have an intrauterine 
      developmental origin related to the application of dexamethasone, an artificially 
      synthesized glucocorticoid. Here, using a rat animal model of prenatal 
      dexamethasone exposure (PDE) we confirm that PDE can cause susceptibility to 
      convulsions in male offspring and explore the epigenetic programming mechanism 
      underlying this effect related to intrauterine type 2 K(+)-Cl(-) cotransporter 
      (KCC2). Wistar rats were injected with dexamethasone (0.2 mg/kg/d) subcutaneously 
      during the gestational days (GD) 9-20 and part of the offspring was given lithium 
      pilocarpine (LiPC) at postnatal week 10. Our results showed that male offspring 
      of the PDE+LiPC group exhibited convulsions susceptibility, as well as increased 
      hippocampal gamma-aminobutyric acid (GABA) and intracellular chloride ions level 
      and decreased GABA receptor expression. The offspring also showed a decrease of 
      hippocampal KCC2 H3K14ac levels and KCC2 expression. PDE male fetal rats (GD20) 
      showed similar changes to male offspring after birth and exhibited an increased 
      expression of glucocorticoid receptor (GR) and histone deacetylase type 2 
      (HDAC2). We observed effects consistent with those observed in PDE fetal rats 
      following in vitro dexamethasone treatment of the fetal rat hippocampal neuron 
      H19-7 cell line, and the effects could be reversed by treatment with a GR 
      inhibitor (RU486) or HDAC2 inhibitor (romidepsin). Taken together, this study 
      confirmed that PDE causes a reduction of H3K14ac levels in the KCC2 promoter 
      region caused by activation of fetal hippocampal GR-HDAC2-KCC2 signaling. We 
      proposed that this abnormal epigenetic modification is the mechanism underlying 
      offspring convulsions susceptibility. CATEGORIES: Mechanism of toxicity.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Xie, Lulu
AU  - Xie L
AD  - Department of Pediatrics, Renmin Hospital, Wuhan University, Wuhan, China.
FAU - Jiao, Zhexiao
AU  - Jiao Z
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China.
FAU - Zhang, Haiju
AU  - Zhang H
AD  - Department of Pediatrics, Renmin Hospital, Wuhan University, Wuhan, China.
FAU - Wang, Tingting
AU  - Wang T
AD  - Department of pharmacy, Zhongnan Hospital of Wuhan University, School of 
      Pharmaceutical Sciences, Wuhan University, Wuhan, China.
FAU - Qin, Jiaxin
AU  - Qin J
AD  - Department of Pediatrics, Renmin Hospital, Wuhan University, Wuhan, China.
FAU - Zhang, Shuai
AU  - Zhang S
AD  - Department of pharmacy, Zhongnan Hospital of Wuhan University, School of 
      Pharmaceutical Sciences, Wuhan University, Wuhan, China.
FAU - Luo, Mingcui
AU  - Luo M
AD  - Department of pharmacy, Zhongnan Hospital of Wuhan University, School of 
      Pharmaceutical Sciences, Wuhan University, Wuhan, China.
FAU - Lu, Mengxi
AU  - Lu M
AD  - Department of pharmacy, Zhongnan Hospital of Wuhan University, School of 
      Pharmaceutical Sciences, Wuhan University, Wuhan, China.
FAU - Yao, Baozhen
AU  - Yao B
AD  - Department of Pediatrics, Renmin Hospital, Wuhan University, Wuhan, China. 
      Electronic address: professoryao@aliyun.com.
FAU - Wang, Hui
AU  - Wang H
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disease, Wuhan, China. Electronic address: wanghui19@whu.edu.cn.
FAU - Xu, Dan
AU  - Xu D
AD  - Department of pharmacy, Zhongnan Hospital of Wuhan University, School of 
      Pharmaceutical Sciences, Wuhan University, Wuhan, China; Hubei Provincial Key 
      Laboratory of Developmentally Originated Disease, Wuhan, China. Electronic 
      address: xuyidan70188@whu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20220517
PL  - Netherlands
TA  - Toxicol Lett
JT  - Toxicology letters
JID - 7709027
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Symporters)
RN  - 7S5I7G3JQL (Dexamethasone)
SB  - IM
MH  - Animals
MH  - Dexamethasone/toxicity
MH  - Female
MH  - Hippocampus/metabolism
MH  - Humans
MH  - Male
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects/chemically induced
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Glucocorticoid/metabolism
MH  - Seizures/chemically induced
MH  - *Symporters/genetics/metabolism
OTO - NOTNLM
OT  - Convulsions
OT  - Dexamethasone
OT  - Epigenetics
OT  - Intrauterine programming
OT  - KCC2
EDAT- 2022/05/21 06:00
MHDA- 2022/06/18 06:00
CRDT- 2022/05/20 19:25
PHST- 2022/02/11 00:00 [received]
PHST- 2022/05/02 00:00 [revised]
PHST- 2022/05/13 00:00 [accepted]
PHST- 2022/05/21 06:00 [pubmed]
PHST- 2022/06/18 06:00 [medline]
PHST- 2022/05/20 19:25 [entrez]
AID - S0378-4274(22)00092-3 [pii]
AID - 10.1016/j.toxlet.2022.05.004 [doi]
PST - ppublish
SO  - Toxicol Lett. 2022 Jul 1;364:12-23. doi: 10.1016/j.toxlet.2022.05.004. Epub 2022 
      May 17.