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  • Title: Excitotoxicity and compensatory upregulation of GAD67 in fetal rat hippocampus caused by prenatal nicotine exposure are associated with inhibition of the BDNF pathway.
    Author: Pei Y, Jiao Z, Dong W, Pei L, He X, Wang H, Xu D.
    Journal: Food Chem Toxicol; 2019 Jan; 123():314-325. PubMed ID: 30389584.
    Abstract:
    Prenatal nicotine exposure (PNE) can cause hypersensitivity of hypothalamic-pituitary-adrenal (HPA) axis in offspring with intrauterine growth retardation. The purpose of this study was to explore the original mechanism of intrauterine development that mediates hypersensitivity of the HPA axis in offspring due to PNE. Pregnant Wistar rats were injected subcutaneously with 2 mg/kg·d of nicotine on the 9th to the 20th gestational day (GD9-GD20) and the fetuses were extracted at GD20. Compared with the control group, fetal rats by PNE showed increased hippocampal apoptosis, reduced synaptic plasticity and downregulation of the brain-derived neurotrophic factor (BDNF) pathway, whereas glutamic acid decarboxylase 67 (GAD67) expression was upregulated. Rat fetal hippocampal H19-7/IGF1R cell lines were treated with different concentrations of nicotine (1, 10 and 100 μM) for 3 days, the extracellular fluid glutamate (Glu) level increased and similar effects were observed as in vivo. Intervention treatments caused the opposite results. These results indicated that PNE downregulates the BDNF pathway and mediates the hippocampal excitotoxicity; then, the compensatory upregulation of GAD67 causes the imbalance of signal output in the fetal hippocampus. The negative feedback regulation of the paraventricular hypothalamic nucleus by the hippocampus is unbalanced, eventually causing hypersensitivity of the HPA axis of the offspring.
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