PMID- 35917217
OWN - NLM
STAT- MEDLINE
DCOM- 20221011
LR  - 20221017
IS  - 1522-7278 (Electronic)
IS  - 1520-4081 (Linking)
VI  - 37
IP  - 11
DP  - 2022 Nov
TI  - The upregulation of glutamate decarboxylase 67 against hippocampal excitability 
      damage in male fetal rats by prenatal caffeine exposure.
PG  - 2703-2717
LID - 10.1002/tox.23630 [doi]
AB  - As a kind of xanthine alkaloid, caffeine is widely present in beverages, food, 
      and analgesic drugs. Our previous studies have shown that prenatal caffeine 
      exposure (PCE) can induce programmed hypersensitivity of the 
      hypothalamic-pituitary-adrenal (HPA) axis in offspring rats, which is involved in 
      developing many chronic adult diseases. The present study further examined the 
      potential molecular mechanism and toxicity targets of hippocampal dysfunction, 
      which might mediate the programmed hypersensitivity of the HPA axis in offspring. 
      Pregnant rats were intragastrically administered with 0, 30, and 120 mg/kg/day 
      caffeine from gestational days (GD) 9-20, and the fetal rats were extracted at 
      GD20. Rat fetal hippocampal H19-7/IGF1R cell line was treated with caffeine, 
      adenosine A2A receptor (A2AR) agonist (CGS-21680) or adenylate cyclase agonist 
      (forskolin) plus caffeine. Compared with the control group, hippocampal neurons 
      of male fetal rats by PCE displayed increased apoptosis and reduced synaptic 
      plasticity, whereas glutamate decarboxylase 67 (GAD67) expression was increased. 
      Moreover, the expression of A2AR was down-regulated, PCE inhibited the 
      cAMP/PKA/CREB/BDNF/TrkB pathway. Furthermore, the results in vitro were 
      consistent with the in vivo study. Both CGS21680 and forskolin could reverse the 
      above alteration caused by caffeine. These results indicated that PCE inhibits 
      the BDNF pathway and mediates the hippocampus's glutamate (Glu) excitotoxicity. 
      The compensatory up-regulation of GAD67 unbalanced the Glu/gamma-aminobutyric 
      acid (GABA)ergic output, leading to the impaired negative feedback to the 
      hypothalamus and hypersensitivity of the HPA axis.
CI  - (c) 2022 Wiley Periodicals LLC.
FAU - Lu, Mengxi
AU  - Lu M
AD  - Department of Pharmacology, School of Pharmaceutical Sciences, Wuhan University, 
      Wuhan, China.
FAU - He, Xia
AU  - He X
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China.
FAU - Jiao, Zhexiao
AU  - Jiao Z
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China.
FAU - Hu, Zewen
AU  - Hu Z
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China.
FAU - Guo, Zijing
AU  - Guo Z
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China.
FAU - Dai, Shiyun
AU  - Dai S
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China.
FAU - Wang, Hui
AU  - Wang H
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      Wuhan, China.
AD  - Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 
      China.
FAU - Xu, Dan
AU  - Xu D
AUID- ORCID: 0000-0003-4408-2469
AD  - Department of Pharmacology, School of Pharmaceutical Sciences, Wuhan University, 
      Wuhan, China.
AD  - Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 
      China.
LA  - eng
GR  - 2019ACA140/Major Technological Innovation Projects of Hubei Province/
GR  - TFJC2018001/Medical Science Advancement Program (Basic Medical Sciences) of Wuhan 
      University/
GR  - 2020YFA0803900/National Key R&D Program of China/
GR  - 81973405/National Natural Science Foundation of China/
GR  - 82122071/National Natural Science Foundation of China/
GR  - 82030111/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20220802
PL  - United States
TA  - Environ Toxicol
JT  - Environmental toxicology
JID - 100885357
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Receptor, Adenosine A2A)
RN  - 1F7A44V6OU (Colforsin)
RN  - 3G6A5W338E (Caffeine)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - EC 4.1.1.15 (Glutamate Decarboxylase)
RN  - EC 4.1.1.15 (glutamate decarboxylase 1)
RN  - EC 4.6.1.1 (Adenylyl Cyclases)
SB  - IM
MH  - Adenylyl Cyclases/metabolism
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - *Caffeine/toxicity
MH  - Colforsin/metabolism
MH  - Female
MH  - *Glutamate Decarboxylase/genetics/metabolism
MH  - Glutamic Acid/metabolism
MH  - Hippocampus/metabolism
MH  - Hypothalamo-Hypophyseal System/metabolism
MH  - Male
MH  - *Pituitary-Adrenal System
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Receptor, Adenosine A2A/metabolism
MH  - Up-Regulation
MH  - gamma-Aminobutyric Acid
OTO - NOTNLM
OT  - caffeine
OT  - glutamate decarboxylase 67
OT  - hippocampus
OT  - hypothalamic-pituitary-adrenal axis
EDAT- 2022/08/03 06:00
MHDA- 2022/10/12 06:00
CRDT- 2022/08/02 12:42
PHST- 2022/06/25 00:00 [revised]
PHST- 2022/03/25 00:00 [received]
PHST- 2022/07/13 00:00 [accepted]
PHST- 2022/08/03 06:00 [pubmed]
PHST- 2022/10/12 06:00 [medline]
PHST- 2022/08/02 12:42 [entrez]
AID - 10.1002/tox.23630 [doi]
PST - ppublish
SO  - Environ Toxicol. 2022 Nov;37(11):2703-2717. doi: 10.1002/tox.23630. Epub 2022 Aug 
      2.