Prenatal Dexamethasone Exposure in Male Rats Alters Gene Expression Patterns of Epigenetic Enzymes in Hippocampus and Cortex

Ezgi Turunç; Yiğit Uyanıkgil; Tijen Kaya Temiz; Ayfer  Yalçın

doi:10.5152/EurJTher.2022.22056

Authors

Ezgi Turunç Department of Biochemistry, İzmir Katip Çelebi University, Faculty of Pharmacy, İzmir, Turkey https://orcid.org/0000-0002-7587-7443
Yiğit Uyanıkgil Department of Histology and Embryology, Ege University, Faculty of Medicine, İzmir, Turkey https://orcid.org/0000-0002-4016-0522
Tijen Kaya Temiz Department of Pharmacology, İzmir Katip Çelebi University, Faculty of Medicine, İzmir, Turkey https://orcid.org/0000-0002-0069-6576
Ayfer Yalçın Department of Biochemistry, Ege University, Faculty of Pharmacy, İzmir, Turkey https://orcid.org/0000-0003-0407-3218

DOI:

https://doi.org/10.5152/EurJTher.2022.22056

Keywords:

Dexamethasone, epigenetic enzymes, prenatal stress, rat

Abstract

Objective: This study aimed to examine the effects of prenatal stress (PS) induced by dexamethasone exposure on gene expression levels of epigenetic enzymes in hippocampus and cerebral cortex of male rats through relative mRNA levels of histone acetyltransferases (activating transcription factor 2, P300), histone deacetylases (HDAC1, HDAC2), and DNA methyltransferases (DNMT1, DNMT3a, DNMT3b).Pregnant rats were daily injected subcutaneously with dexamethasone (0.2 mg/kg) or saline during the third week of gestation. After birth, male rats were killed at 90 days of age (n = 5 for control and dexamethasone groups). Hippocampal and cortical tissues were used for gene expression analyses. The effects of dexamethasone on epigenetic mechanisms were investigated by real-time polymerase chain reaction through relative mRNA levels of DNMT1, DNMT3a, DNMT3b, activating transcription factor 2, P300, HDAC1, and HDAC2. Statistical comparisons were performed with Student’s t-test.

Results: Prenatal dexamethasone exposure (PDE) caused increased DNMT1, DNMT3a, DNMT3b, activating transcription factor 2 and decreased P300 mRNA levels in hippocampus while increased DNMT3a, DNMT3b, activating transcription factor 2, P300, HDAC1, and HDAC2 mRNA levels were achieved in cortex. Furthermore, no significant differences were obtained in cortical DNMT1 and hippocampal HDAC1 and HDAC2 gene expression levels between control and prenatally stressed rats.

Conclusion: Our results emphasize the effect of prenatal dexamethasone exposure on gene expression levels of epigenetic enzymes involved in histone acety latio n/dea cetyl ation and DNA methylation in male rats and suggest that prenatal stress may lead to epigenetic dysregulation through alterations in hippocampal and cortical gene expression patterns of DNMT1, DNMT3a, DNMT3b, activating transcription factor 2, P300, HDAC1, and HDAC2.

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References

Benoit JD, Rakic P, Frick KM. Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. Behav Brain Res. 2015;281:1-8.

Boersma GJ, Lee RS, Cordner ZA, et al. Prenatal stress decreases bdnf expression and increases methylation of bdnf exon IV in rats. Epigenetics. 2014;9(3):437-447.

Abbott PW, Gumusoglu SB, Bittle J, Beversdorf DQ, Stevens HE. Prenatal stress and genetic risk: how prenatal stress interacts with genetics to alter risk for psychiatric illness. Psych oneur oendo crino logy. 2018;90:9-21.

Johnson AK, Xue B. Central nervous system neuroplasticity and the sensitization of hypertension. Nat Rev Nephrol. 2018;14(12):750-766.

Jiang X, Ma H, Wang Y, Liu Y. Early life factors and type 2 diabetes mellitus. J Diabetes Res. 2013;2013:485082.

Mohd Murshid N, Aminullah Lubis F, Makpol S. Epigenetic changes and its intervention in age-related neurodegenerative diseases. Cell Mol Neurobiol. 2022;42(3):577-595.

Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017;18(7):1414.

Huebner K, Procházka J, Monteiro AC, Mahadevan V, Schneider-Stock R. The activating transcription factor 2: an influencer of cancer progression. Mutagenesis. 2019;34(5-6):375-389.

Kumar V, Kundu S, Singh A, Singh S. Understanding the role of histone deacetylase and their inhibitors in neurodegenerative disorders: current targets and future perspective. Curr Neuropharmacol. 2022;20(1):158-178.

Saravanaraman P, Selvam M, Ashok C, Srijyothi L, Baluchamy S. De novo methyltransferases: potential players in diseases and new directions for targeted therapy. Biochimie. 2020;176:85-102.

Kucharczyk M, Kurek A, Pomierny B, et al. The reduced level of growth factors in an animal model of depression is accompanied by regulated necrosis in the frontal cortex but not in the hippocampus. Psych oneur oendo crino logy. 2018;94:121-133.

Kjaer SL, Hougaard KS, Tasker RA, et al. Influence of diurnal phase on startle response in adult rats exposed to dexamethasone in utero. Physiol Behav. 2011;102(5):444-452.

Bartlett AA, Lapp HE, Hunter RG. Epigenetic mechanisms of the glucocorticoid receptor. Trends Endocrinol Metab. 2019;30(11):807-818.

Baka M, Uyanikgil Y, Ateş U, Kültürsay N. Investigation of maternal melatonin effect on the hippocampal formation of newborn rat model of intrauterine cortical dysplasia. Childs Nerv Syst. 2010;26(11):1575-1581.

Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics. 2012;13:134.

Bikandi J, San Millán R, Rementeria A, Garaizar J. In silico analysis of complete bacterial genomes: PCR, AFLP-PCR and endonuclease restriction. Bioinformatics. 2004;20(5):798-799.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T) Method. Methods. 2001;25(4):402-408.

Shoener JA, Baig R, Page KC. Prenatal exposure to dexamethasone alters hippocampal drive on hypot halam ic-pi tuita ry-ad renal axis activity in adult male rats. Am J Physiol Regul Integr Comp Physiol. 2006;290(5):R1366-R1373.

Lei L, Wu X, Gu H, Ji M, Yang J. Differences in DNA methylation reprogramming underlie the sexual dimorphism of behavioral disorder caused by prenatal stress in rats. Front Neurosci. 2020;14:573107.

Monteleone MC, Pallarés ME, Billi SC, Antonelli MC, Brocco MA. In vivo and in vitro neuronal plasticity modulation by epigenetic regulators. J Mol Neurosci. 2018;65(3):301-311.

Cacabelos R, Torrellas C. Epigenetic drug discovery for Alzheimer's disease. Expert Opin Drug Discov. 2014;9(9):1059-1086.

Song Q, Fan C, Wang P, Li Y, Yang M, Yu SY. Hippocampal CA1 βCaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression. J Neuroinflammation. 2018;15(1):338.

Lipinski M, Del Blanco B, Barco A. CBP/p300 in brain development and plasticity: disentangling the KAT's cradle. Curr Opin Neurobiol. 2019;59:1-8.

Hu S, Yi Y, Jiang T, et al. Intrauterine RAS programming alterationmediated susceptibility and heritability of temporal lobe epilepsy in male offspring rats induced by prenatal dexamethasone exposure. Arch Toxicol. 2020;94(9):3201-3215.

Lui CC, Hsu MH, Kuo HC, et al. Effects of melatonin on prenatal dexam ethas one-i nduce d epigenetic alterations in hippocampal morphology and reelin and glutamic acid decarboxylase 67 levels. Dev Neurosci. 2015;37(2):105-114.

Grégoire S, Jang SH, Szyf M, Stone LS. Prenatal maternal stress is associated with increased sensitivity to neuropathic pain and sexspecific changes in supraspinal mRNA expression of epigeneticand stress-related genes in adulthood. Behav Brain Res. 2020;380:112396.

Gupta R, Ambasta RK, Kumar P. Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders. Life Sci. 2020;243:117278.

Zheng Y, Fan W, Zhang X, Dong E. Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus. Epigenetics. 2016;11(2):150-162.

Wei J, Xiong Z, Lee JB, et al. Histone modification of Nedd4 ubiquitin ligase controls the loss of AMPA receptors and cognitive impairment induced by repeated stress. J Neurosci. 2016;36(7):2119-2130.