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Dysfunction of the hypothalamic‑pituitary‑adrenal axis in male rat offspring with prenatal food restriction: Fetal programming of hypothalamic hyperexcitability and poor hippocampal feedback.

ABSTRACT: Prenatal food restriction (PFR) induces dysfunction of the hypothalamic‑pituitary‑adrenal (HPA) axis in the adult offspring. The aim of the present study was to identify the underlying mechanism of this process. Pregnant rats were placed on a restricted diet between gestational day 11 and 21. The offspring were fed with a high‑fat diet and were subjected to unpredictable chronic stress (UCS) from postnatal week 17 to 20. A higher serum corticosterone (CORT) level was observed in the PFR fetuses. Although lower arginine vasopressin (AVP), hippocampal vesicular glutamate transporter 2 (vGLUT2) and glutamic acid decarboxylase 65 (GAD65) mRNA expression levels were detected in the hippocampi of PFR fetuses, the ratio of the mRNA expression levels of vGLUT2 and GAD65 was higher compared with that of the controls, which was accompanied by histopathological and ultrastructural abnormalities of both the hypothalamus and hippocampus. However, there were no marked changes in the hippocampal expression levels of glucocorticoids receptor (GR) and mineralocorticoids receptor (MR) or the ratio of MR/GR ratio. After the fetuses had matured, lower serum CORT and adrenocorticotropic hormone (ACTH) levels were observed in PFR rats without UCS when compared with the control. A higher rise rate of serum ACTH was also observed after UCS when compared with that in rats without UCS. Furthermore, the hypothalamic mRNA expression level of corticotrophin‑releasing hormone (CRH) was lower in PFR rats without UCS, while expression levels of CRH, AVP, GAD65 and vGLUT2 were enhanced after UCS when compared with the control, accompanied by an increased vGLUT2/GAD65 expression ratio. MR mRNA expression was lower, and GR mRNA expression was higher in the hippocampus of the PFR rats without UCS when compared with the control. However, the mRNA expression levels of both MR and GR in the PFR rats were higher compared with those of the control after UCS, which was accompanied histopathological changes in the dentate gyrus, cornu ammonis (CA1) and CA3 areas. In summary, it was suggested that PFR induced fetal alterations of the HPA axis manifesting as hypothalamic hyperexcitability and poor hippocampal feedback, which persisted to adulthood and affected the behavior of the rat offspring.

SUBMITTER: Wen Y

PROVIDER: S-EPMC8619836 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An imbalance of excitatory and inhibitory signals in the brain has been proposed to be one of the main pathological features of various diseases related to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction. Excessive glutamate release induces neuronal excitotoxicity, while glutamic acid decarboxylase (GAD) 67 promotes the transformation of excessive glutamate to ?-aminobutyric acid (GABA). Our previous studies demonstrated that prenatal ethanol exposure (PEE) causes foetal over-exposure to maternal corticosterone and hypersensitivity of the HPAA after birth, but its intrauterine programming mechanism is unknown. In this study, PEE was shown to lead to an enhanced potential excitatory ability of the hypothalamus and hypersensitivity of the HPAA, as well as mild abnormal hippocampal morphology, demethylation of the -1019 to -691-bp region in the hippocampal GAD67 promoter and upregulation of GAD67 expression accompanied by a reduction in glutamatergic neurons and increase in GABAergic neurons in PEE male offspring. Similar changes were also found in PEE male foetal rats. Furthermore, corticosterone increased the expression of the glucocorticoid receptor (GR) and GAD67 in foetal hippocampal H19-7 cells in a concentration-dependent manner, accompanied by demethylation of the GAD67 promoter, a decrease in glutamatergic neurons and increase in GABAergic neurons. The GR inhibitor, mifepristone, reversed the effects of corticosterone on H19-7 cells. These results suggested that PEE-induced excessive corticosterone can lead to upregulation of GAD67 through epigenetic modification mediated by the GR in the male foetal hippocampus, thereby weakening the negative regulation of the HPAA by the hippocampus and increasing the potential excitatory ability of the hypothalamus. These changes persisted until after birth, resulting in hypersensitivity of the HPAA. However, gender differences were observed in the hippocampal development, morphology and GAD67 expression associated with PEE. Programming for the increased expression of hippocampal GAD67 is a potential mechanism responsible for the hypersensitivity of the HPAA in PEE male rats.

Project description:Our previous studies have demonstrated that mice with reduced or absent serotonin transporter (SERT+/- and SERT-/- mice, respectively) are more sensitive to stress relative to their SERT normal littermates (SERT+/+ mice). The aim of the present study was to test the hypothesis that the hypothalamic-pituitary-adrenal (HPA) axis and its feedback regulation are impaired in these mice. The function and gene expression of several components in the HPA axis and its feedback regulation in SERT+/+, +/( and -/- mice were studied under basal (non-stressed) and stressed conditions. The results showed that (1) under basal conditions, corticotrophin-releasing factor (CRF) mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus was lower in both SERT+/( and (/( mice relative to SERT+/+ mice; (2) an increased response to CRF challenge was found in SERT(/( mice, suggesting that the function of CRF type 1 receptors (CRF R1) in the pituitary is increased. Consistent with these findings, (125)I-sauvagine (a CRF receptor antagonist) binding revealed an increased density of CRF R1 in the pituitary of SERT(/( under basal conditions. These data suggest that CRF R1 in the pituitary of SERT(/( mice is up-regulated. However, in the pituitary of SERT+/( mice, the function of CRF R1 was not changed and the density of CRF R1 was reduced relative to SERT+/+ mice; and (3) the expression of the glucocorticoid receptor (GR) in the hypothalamus, pituitary and adrenal cortex was significantly reduced in SERT+/( and (/( mice in comparison with SERT+/+ mice under basal conditions. Consistent with these findings, the corticosterone response to dexamethasone was blunted in SERT(/( mice relative to SERT+/+ and +/( mice. Furthermore, stress induces a rapid increase of the GR expression in the hypothalamus of SERT+/( and (/( mice relative to their basal levels. Together, the present results demonstrated that the HPA axis and its feedback regulation are altered in SERT knockout mice, which could account for the increased sensitivity to stress in these mice.

Project description:Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11?-hydroxysteroid dehydrogenase-2 (11?-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11?-HSD-2, promote the expression of 11?-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11?-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of caffeine and in exploring the fetal origin of adult HPA axis dysfunction and metabolic syndrome susceptibility for offspring with IUGR induced by caffeine.

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Dysfunction of the hypothalamic‑pituitary‑adrenal axis in male rat offspring with prenatal food restriction: Fetal programming of hypothalamic hyperexcitability and poor hippocampal feedback.

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