PMID- 31306741
OWN - NLM
STAT- MEDLINE
DCOM- 20190916
LR  - 20211204
IS  - 1879-3169 (Electronic)
IS  - 0378-4274 (Linking)
VI  - 314
DP  - 2019 Oct 10
TI  - Decreased H3K9ac level of KLF4 mediates podocyte developmental toxicity induced 
      by prenatal caffeine exposure in male offspring rats.
PG  - 63-74
LID - S0378-4274(19)30193-6 [pii]
LID - 10.1016/j.toxlet.2019.07.011 [doi]
AB  - This study aimed to verify the toxic effects of prenatal caffeine exposure (PCE) 
      on the podocyte development in male offspring, and to explore the underlying 
      intrauterine programming mechanisms. The pregnant rats were administered with 
      caffeine (30 to 120 mg/kg⋅d) during gestational day (GD) 9 to 20. The male fetus 
      on GD20 and the offspring at postnatal week (PW) 6 and PW28 were sacrificed. The 
      results indicated that PCE caused ultrastructural abnormalities on podocyte, and 
      inhibited the expression of podocyte marker genes such as Nephrin, Wilms tumor 1 
      (WT1), the histone 3 lysine 9 acetylation (H3K9ac) level in the Kruppel-like 
      factor 4 (KLF4) promoter and its expression in the male offspring from GD20 to 
      PW28. Meanwhile, the expression of glucocorticoid receptor (GR) and histone 
      deacetylase 7 (HDAC7) in the fetus were increased by PCE. In vitro, 
      corticosterone increased GR and HDAC7 whereas reduced the H3K9ac level of KLF4 
      and KLF4/Nephrin expression. KLF4 over-expression reversed the reduction of 
      Nephrin expression, knockdown of HDAC7 and GR antagonist RU486 partially reversed 
      the inhibitory effects of corticosterone on H3K9ac level and KLF4 expression. In 
      conclusion, PCE caused podocyte developmental toxicity in male offspring, which 
      was associated with corticosterone-induced low-functional programming of KLF4 
      through GR/HDAC7/H3K9ac pathway.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Zhu, Yanan
AU  - Zhu Y
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China.
FAU - Chen, Haiyun
AU  - Chen H
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China.
FAU - Zhao, Xiaoqi
AU  - Zhao X
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China.
FAU - Li, Bin
AU  - Li B
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China; Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan 
      University, Wuhan, 430071, China.
FAU - He, Hangyuan
AU  - He H
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China; Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan 
      University, Wuhan, 430071, China.
FAU - Cheng, Hui
AU  - Cheng H
AD  - Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, 
      China.
FAU - Wang, Hui
AU  - Wang H
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disorder, Wuhan 430071, China.
FAU - Ao, Ying
AU  - Ao Y
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disorder, Wuhan 430071, China. Electronic address: yingao@whu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20190712
PL  - Netherlands
TA  - Toxicol Lett
JT  - Toxicology letters
JID - 7709027
RN  - 0 (Central Nervous System Stimulants)
RN  - 0 (Glucocorticoids)
RN  - 0 (Histones)
RN  - 0 (Klf4 protein, rat)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (nephrin)
RN  - 3G6A5W338E (Caffeine)
RN  - EC 3.5.1.98 (HDAC7 protein, rat)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Acetylation
MH  - Animals
MH  - Caffeine/*toxicity
MH  - Cells, Cultured
MH  - Central Nervous System Stimulants/*toxicity
MH  - Female
MH  - Gene Expression Regulation, Developmental/drug effects
MH  - Gestational Age
MH  - Glucocorticoids/metabolism
MH  - Histone Deacetylases/genetics/metabolism
MH  - Histones/*metabolism
MH  - Kidney Diseases/*chemically induced/embryology/genetics/metabolism
MH  - Kruppel-Like Factor 4
MH  - Kruppel-Like Transcription Factors/genetics/*metabolism
MH  - Lysine
MH  - Male
MH  - Maternal Exposure
MH  - Membrane Proteins/genetics/metabolism
MH  - Phenotype
MH  - Podocytes/*drug effects/metabolism/ultrastructure
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - Promoter Regions, Genetic
MH  - Rats, Wistar
MH  - Receptors, Glucocorticoid/genetics/metabolism
MH  - Signal Transduction/drug effects
OTO - NOTNLM
OT  - Glucocorticoid
OT  - Intrauterine programming
OT  - Kruppel-like factor 4
OT  - Podocyte developmental toxicity
OT  - Prenatal caffeine exposure
EDAT- 2019/07/16 06:00
MHDA- 2019/09/17 06:00
CRDT- 2019/07/16 06:00
PHST- 2019/05/26 00:00 [received]
PHST- 2019/06/30 00:00 [revised]
PHST- 2019/07/04 00:00 [accepted]
PHST- 2019/07/16 06:00 [pubmed]
PHST- 2019/09/17 06:00 [medline]
PHST- 2019/07/16 06:00 [entrez]
AID - S0378-4274(19)30193-6 [pii]
AID - 10.1016/j.toxlet.2019.07.011 [doi]
PST - ppublish
SO  - Toxicol Lett. 2019 Oct 10;314:63-74. doi: 10.1016/j.toxlet.2019.07.011. Epub 2019 
      Jul 12.