The intrauterine programming of hypothalamic-pituitary-adrenal (HPA) axis hypersensitivity is associated with chronic adult diseases. Our previous studies demonstrated the HPA-axis hypersensitivity in offspring rats induced by prenatal nicotine exposure. The goal of the present study is to further investigate the intrauterine programming mechanism. Pregnant Wistar rats were subcutaneously administered with 2.0 mg/kg day of nicotine from gestational day (GD) 9-20. A group of the pregnant rats was euthanized at GD20, and the fetal rats were extracted. The remaining rats were left to come to term, and the adult offspring were exposed to chronic stress. For adult offspring rats, prenatal nicotine exposure induced HPA-axis hypersensitivity after chronic stress, accompanied by imbalanced glutamatergic/GABAergic afferent inputs. Moreover, prenatal nicotine exposure enhanced the expression of hippocampal glutamic acid decarboxylase 67 (GAD67), accompanied by a decreased methylation ratio within nt -1019 to -689 of the GAD67 promoter, decreased expression of Dnmt1, and an increased GABA content and density of GABAergic neurons. The fetal rats exhibited changes consistent with the adult rats. Similar effects were also observed by treating the fetal hippocampal cell line H19-7 with 1-100 μM nicotine, while dihydro-β-erythroidine hydrobromide (DHβE), the specific inhibitor of α4β2nAChR, can reverse the effects caused by nicotine. These results indicate that prenatal nicotine exposure can enhance the potential excitability of the hypothalamus via the intrauterine programming of up-regulation of hippocampal GAD67. All of these results contribute to the HPA-axis hypersensitivity in adult offspring.
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Article Synopsis
- Substance use disorders among pregnant and postpartum individuals are increasing, highlighting the need for better education and intervention for healthcare providers.
- The review covers the impact of various substances like nicotine, cannabis, and opioids on maternal and fetal health, along with treatment options.
- It also discusses ethical and legal issues related to substance use during pregnancy, advocating for equitable, non-stigmatizing care practices.
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