Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, Hubei 430071, P.R. China.
Mol Med Rep. 2022 Jan;25(1). doi: 10.3892/mmr.2021.12537. Epub 2021 Nov 19.
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.
产前饮食限制（PFR）会导致成年后代下丘脑-垂体-肾上腺（HPA）轴功能障碍。本研究旨在确定这一过程的潜在机制。在妊娠第 11 天至 21 天期间，给怀孕的老鼠喂食限制饮食。后代在高脂肪饮食下喂养，并在出生后第 17 周到 20 周期间接受不可预测的慢性应激（UCS）。PFR 胎儿的血清皮质酮（CORT）水平较高。尽管 PFR 胎儿海马中的精氨酸加压素（AVP）、囊泡谷氨酸转运蛋白 2（vGLUT2）和谷氨酸脱羧酶 65（GAD65）mRNA 表达水平较低，但 vGLUT2 和 GAD65 的 mRNA 表达水平比值较高，这伴随着下丘脑和海马的组织病理学和超微结构异常。然而，海马中的糖皮质激素受体（GR）和盐皮质激素受体（MR）表达水平或 MR/GR 比值没有明显变化。胎儿成熟后，与对照组相比，未接受 UCS 的 PFR 大鼠的血清 CORT 和促肾上腺皮质激素（ACTH）水平较低。与未接受 UCS 的大鼠相比，UCS 后血清 ACTH 的上升率也更高。此外，未接受 UCS 的 PFR 大鼠的下丘脑促肾上腺皮质激素释放激素（CRH）mRNA 表达水平较低，而 UCS 后 CRH、AVP、GAD65 和 vGLUT2 的表达水平升高，同时 vGLUT2/GAD65 表达比值增加。MR mRNA 表达降低，GR mRNA 表达升高。然而，与对照组相比，UCS 后 PFR 大鼠的海马中 MR 和 GR 的 mRNA 表达水平均升高，同时齿状回、角状回（CA1）和 CA3 区出现组织病理学变化。综上所述，产前饮食限制导致 HPA 轴的胎儿改变表现为下丘脑过度兴奋和海马反馈不良，这种改变持续到成年期，并影响大鼠后代的行为。
