Prenatal nicotine exposure induced high sensitivity of hypothalamic-pituitary-adrenal axis in offspring rats under high fat diet / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE To observe prenatal nicotine exposure (PNE) induced high sensitivity of hypo?thalamic-pituitary-adrenal (HPA) axis in offspring rats which were fed with a high-fat diet, and to explore the mechanism. METHODS Nicotine (2 mg·kg-1 per day) was injected subcutaneously to preg?nant Wistar rats from gestational day (GD) 9 to GD20,and then the young rats were naturally delivered. After weaning, half of the offspring was fed with a high-fat diet until postnatal weeks (PW) 20. The others were exposed to unpredictable chronic stress (UCS) from PW17 to PW20. The pathological changes in the hippocampus were analyzed by HE staining. The blood concentration of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) was detected by RIA kits and ELISA kits, respectively. Meanwhile, real-time PCR was used to detect the mRNA expression of ACTH releasing hormone (CRH), arginine vasopressin (AVP), vesicular glutamate transporter 2 (VGluT2), glutamic acid decarboxylase 65 (GAD65), mineralocorticoid receptor (MR),glucocorticoid receptor (GR) and glutamic acid decarboxylase 67 (GAD67). RESULTS In the normal control group,UCS treatment increased the level of serum ACTH and CORT 1.96 and 3.24 times in female rats,but 1.63 and 3.54 times in male rats. In the PNE group, UCS treatment increased the level of serum ACTH and CORT 3.96 and 5.98 times in female rats, but 3.04 and 5.22 times male rats. PNE increased the mRNA expression of AVP in the female and male rats 2.04 and 1.13 times in UCS treatment control group, and the mRNA expression of hypothalamus CRH and the ratio of VGLuT2/ GAD65 were increased 2.49 and 1.14 times in female rats, respectively. Furthermore, the nicotine group exhibited histological changes to different degrees in the hippocampus and dentate gyrus area of the hippocampus. In the female and male nicotine groups, the mRNA ratio of hippocampal MR/GR decreased by 88.0% and 86.0% in comparison with the normal control group without UCS, and the mRNA expression of GAD67 was enhanced 1.38 and 1.97 times in female and male rats without UCS. In the female UCS treatment nicotine groups, the mRNA expression of GAD67 was increased 2.17 times compared with the UCS treatment control group. CONCLUSION PNE can induce a high sensibility of HPA axis in offspring rats fed with a high-fat diet. The imbalance of hippo?campus MR/GR and the enhanced expression of GAD67 mRNA may be involved.