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

Wen,Yinxian; Cheng,Siyuan; Lu,Juan; He,Xia; Jiao,Zhexiao; Xu,Dan; Wang,Hui

doi:10.3892/mmr.2021.12537

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

Authors:
- Yinxian Wen
- Siyuan Cheng
- Juan Lu
- Xia He
- Zhexiao Jiao
- Dan Xu
- Hui Wang
View Affiliations

Affiliations: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: November 18, 2021 https://doi.org/10.3892/mmr.2021.12537
Article Number: 21
Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Zhang C, Xu D, Luo H, Lu J, Liu L, Ping J and Wang H: Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration. Toxicology. 325:74–84. 2014. View Article : Google Scholar : PubMed/NCBI
2	Barker DJ: The developmental origins of chronic adult disease. Acta Paediatr Suppl. 93:26–33. 2004. View Article : Google Scholar : PubMed/NCBI
3	Clark PM: Programming of the hypothalamo-pituitary-adrenal axis and the fetal origins of adult disease hypothesis. Eur J Pediatr. 157 (Suppl 1):S7–S10. 1998. View Article : Google Scholar : PubMed/NCBI
4	Lesage J, Sebaai N, Leonhardt M, Dutriez-Casteloot I, Breton C, Deloof S and Vieau D: Perinatal maternal undernutrition programs the offspring hypothalamo-pituitary-adrenal (HPA) axis. Stress. 9:183–198. 2006. View Article : Google Scholar : PubMed/NCBI
5	Poore KR and Fowden AL: The effect of birth weight on hypothalamo-pituitary-adrenal axis function in juvenile and adult pigs. J Physiol. 547((Pt 1)): 107–116. 2003. View Article : Google Scholar : PubMed/NCBI
6	Zhang L, Xu D, Zhang B, Liu Y, Chu F, Guo Y, Gong J, Zheng X, Chen L and Wang H: Prenatal food restriction induces a hypothalamic-pituitary-adrenocortical axis-associated neuroendocrine metabolic programmed alteration in adult offspring rats. Arch Med Res. 44:335–345. 2013. View Article : Google Scholar : PubMed/NCBI
7	Holsboer F and Ising M: Stress hormone regulation: Biological role and translation into therapy. Annu Rev Psychol. 61:81–109. 2010. View Article : Google Scholar : PubMed/NCBI
8	Tasker JG and Herman JP: Mechanisms of rapid glucocorticoid feedback inhibition of the hypothalamic-pituitary-adrenal axis. Stress. 14:398–406. 2011. View Article : Google Scholar : PubMed/NCBI
9	National Research Council (US), . Committee for the Update of the Guide for the Care Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals. (8th edition). National Academies Press. (Washington, DC). 2011.
10	Brenes Sáenz JC, Villagra OR and Fornaguera Trías J: Factor analysis of forced swimming test, sucrose preference test and open field test on enriched, social and isolated reared rats. Behav Brain Res. 169:57–65. 2006. View Article : Google Scholar : PubMed/NCBI
11	Deacon RM and Rawlins JN: T-maze alternation in the rodent. Nat Protoc. 1:7–12. 2006. View Article : Google Scholar : PubMed/NCBI
12	Ye J, McGinnis S and Madden TL: BLAST: Improvements for better sequence analysis. Nucleic Acids Res 34 (Web Server Issue). W6–W9. 2006. View Article : Google Scholar : PubMed/NCBI
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
14	Flak JN, Ostrander MM, Tasker JG and Herman JP: Chronic stress-induced neurotransmitter plasticity in the PVN. J Comp Neurol. 517:156–165. 2009. View Article : Google Scholar : PubMed/NCBI
15	Smith SM and Vale WW: The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 8:383–395. 2006. View Article : Google Scholar : PubMed/NCBI
16	Sebaai N, Lesage J, Breton C, Vieau D and Deloof S: Perinatal food deprivation induces marked alterations of the hypothalamo-pituitary-adrenal axis in 8-month-old male rats both under basal conditions and after a dehydration period. Neuroendocrinology. 79:163–173. 2004. View Article : Google Scholar : PubMed/NCBI
17	Hawkins P, Hanson MA and Matthews SG: Maternal undernutrition in early gestation alters molecular regulation of the hypothalamic-pituitary-adrenal axis in the ovine fetus. J Neuroendocrinology. 13:855–861. 2001. View Article : Google Scholar : PubMed/NCBI
18	Vieau D, Sebaai N, Leonhardt M, Dutriez-Casteloot I, Molendi-Coste O, Laborie C, Breton C, Deloof S and Lesage J: HPA axis programming by maternal undernutrition in the male rat offspring. Psychoneuroendocrinology. 32 (Suppl 1):S16–S20. 2007. View Article : Google Scholar : PubMed/NCBI
19	Leonhardt M, Lesage J, Croix D, Dutriez-Casteloot I, Beauvillain JC and Dupouy JP: Effects of perinatal maternal food restriction on pituitary-gonadal axis and plasma leptin level in rat pup at birth and weaning and on timing of puberty. Boil Reprod. 68:390–400. 2003. View Article : Google Scholar : PubMed/NCBI
20	Hawkins P, Steyn C, McGarrigle HH, Saito T, Ozaki T, Stratford LL, Noakes DE and Hanson MA: Effect of maternal nutrient restriction in early gestation on responses of the hypothalamic-pituitary-adrenal axis to acute isocapnic hypoxaemia in late gestation fetal sheep. Exp Physiol. 85:85–96. 2000. View Article : Google Scholar : PubMed/NCBI
21	Tegethoff M, Pryce C and Meinlschmidt G: Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans: A systematic review. Endocr Rev. 30:753–789. 2009. View Article : Google Scholar : PubMed/NCBI
22	Gohlke JM, Griffith WC and Faustman EM: A systems-based computational model for dose-response comparisons of two mode of action hypotheses for ethanol-induced neurodevelopmental toxicity. Toxicol Sci. 86:470–484. 2005. View Article : Google Scholar : PubMed/NCBI
23	Herman JP, Mueller NK and Figueiredo H: Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration. Ann N Y Acad Sci. 1018:35–45. 2004. View Article : Google Scholar : PubMed/NCBI
24	de Kloet ER, Meijer OC, de Nicola AF, de Rijk RH and Joëls M: Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation. Front Neuroendocrinol. 49:124–145. 2018. View Article : Google Scholar : PubMed/NCBI
25	Kozlovsky N, Matar MA, Kaplan Z, Zohar J and Cohen H: A distinct pattern of intracellular glucocorticoid-related responses is associated with extreme behavioral response to stress in an animal model of post-traumatic stress disorder. Eur Neuropsychopharmacol. 19:759–771. 2009. View Article : Google Scholar : PubMed/NCBI
26	Treccani G, Musazzi L, Perego C, Milanese M, Nava N, Bonifacino T, Lamanna J, Malgaroli A, Drago F, Racagni G, et al: Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex. Mol Psychiatry. 19:433–443. 2014. View Article : Google Scholar : PubMed/NCBI
27	Matthews SG: Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab. 13:373–380. 2002. View Article : Google Scholar : PubMed/NCBI
28	Sapolsky RM and Meaney MJ: Maturation of the adrenocortical stress response: Neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res. 396:64–76. 1986. View Article : Google Scholar : PubMed/NCBI
29	Krishnamurthy S, Garabadu D and Joy KP: Risperidone ameliorates post-traumatic stress disorder-like symptoms in modified stress re-stress model. Neuroendocrinology. 75:62–77. 2013.
30	Liao XM, Yang XD, Jia J, Li JT, Xie XM, Su YA, Schmidt MV, Si TM and Wang XD: Blockade of corticotropin-releasing hormone receptor 1 attenuates early-life stress-induced synaptic abnormalities in the neonatal hippocampus. Hippocampus. 24:528–540. 2014. View Article : Google Scholar : PubMed/NCBI
31	de Quervain DJ, Aerni A, Schelling G and Roozendaal B: Glucocorticoids and the regulation of memory in health and disease. Front Neuroendocrinol. 30:358–370. 2009. View Article : Google Scholar : PubMed/NCBI
32	Arbel I, Kadar T, Silbermann M and Levy A: The effects of long-term corticosterone administration on hippocampal morphology and cognitive performance of middle-aged rats. Brain Res. 657:227–235. 1994. View Article : Google Scholar : PubMed/NCBI
33	De Kloet ER, Vreugdenhil E, Oitzl MS and Joëls M: Brain corticosteroid receptor balance in health and disease. Endocr Rev. 19:269–301. 1998. View Article : Google Scholar : PubMed/NCBI
34	Arends N, Johnston L, Hokken-Koelega A, van Duijn C, de Ridder M, Savage M and Clark A: Polymorphism in the IGF-I gene: Clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab. 87:27202002. View Article : Google Scholar : PubMed/NCBI
35	Qiu XS, Huang TT, Deng HY, Shen ZY, Ke ZY, Mei KY and Lai F: Effects of early nutrition intervention on IGF1, IGFBP3, intestinal development, and catch-up growth of intrauterine growth retardation rats. Chin Med Sci J. 19:189–192. 2004.PubMed/NCBI
36	Thamotharan M, Shin BC, Suddirikku DT, Thamotharan S, Garg M and Devaskar SU: GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring. Am J Physiol Endocrinol Metab. 288:E935–E947. 2005. View Article : Google Scholar : PubMed/NCBI
37	Sloboda DM, Moss TJ, Li S, Matthews SG, Challis JR and Newnham JP: Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: Ontogeny and effects of prenatal glucocorticoid exposure. J Endocrinol. 197:213–220. 2008. View Article : Google Scholar : PubMed/NCBI
38	Tan Y, Liu J, Deng Y, Cao H, Xu D, Cu F, Lei Y, Magdalou J, Wu M, Chen L and Wang H: Caffeine-induced fetal rat over-exposure to maternal glucocorticoid and histone methylation of liver IGF-1 might cause skeletal growth retardation. Toxicol Lett. 214:279–287. 2012. View Article : Google Scholar : PubMed/NCBI
39	Xu D, Chen M, Pan XL, Xia LP and Wang H: Dexamethasone induces fetal developmental toxicity through affecting the placental glucocorticoid barrier and depressing fetal adrenal function. Environ Toxicol Pharmacol. 32:356–363. 2011. View Article : Google Scholar : PubMed/NCBI
40	Chen M, Wang T, Liao ZX, Pan XL, Feng YH and Wang H: Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat. Exp Toxicol Pathol. 59:245–251. 2007. View Article : Google Scholar : PubMed/NCBI
41	Xu D, Zhang B, Liang G, Ping J, Kou H, Li X, Xiong J, Hu D, Chen L, Magdalou J and Wang H: Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats. PLoS One. 7:e444972012. View Article : Google Scholar : PubMed/NCBI