The Effects of Prenatal Stress on Cortical and Hippocampal Gene Expression Profiles of DNA Methyltransferases and Histone Deacetylases in Female Rats

Yıl 2022, , 609 - 621, 31.08.2022

Ezgi Turunç , Yiğit Uyanıkgil , Ayfer Yalçın , Tijen Kaya-temiz

https://doi.org/10.18185/erzifbed.1126806

Öz

The aim of this study was to investigate the effects of prenatal stress (PS) on mRNA levels of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) in cerebral cortex and hippocampus of female rats. PS was induced in rats with dexamethasone (Dex). From gestation day 14 to 21, pregnant rats were injected daily with Dex (100 μg/kg) or saline. After birth, at 3 months of age, female rats were decapitated (n=5). The effects of Dex on epigenetic mechanisms were investigated by real-time PCR through mRNA levels of DNMT1, DNMT3a, DNMT3b, HDAC1 and HDAC2. Statistical significant differences were determined with one-way analysis of variance. Prenatal Dex exposure caused significant increases in DNMT3a, HDAC1 and HDAC2 mRNA levels in cortex and hippocampus. We further found that DNMT3b mRNA levels significantly increased in hippocampus but decreased in cortex of Dex group. No significant differences were found in DNMT1 mRNA levels. It was concluded that PS may trigger dysregulation of epigenetic mechanisms in cortex and hippocampus of female rats through alterations in gene expression profiles of DNMT3a, DNMT3b, HDAC1 and HDAC2.

Anahtar Kelimeler

Prenatal stress, dexamethasone, DNA methyltransferase, histone deacetylase, female rat

Destekleyen Kurum

İzmir Katip Çelebi University

Proje Numarası

2018-ONAP-ECZF-0001

Teşekkür

This study was supported by a grant of İzmir Katip Çelebi University (2018-ONAP-ECZF-0001).

Dişi Sıçanlarda Prenatal Stresin DNA Metiltransferazların ve Histon Deasetilazların Kortikal ve Hipokampal Gen Ekspresyon Profilleri Üzerindeki Etkileri

Öz

Öz
Bu çalışmanın amacı, prenatal stresin (PS) dişi sıçanların serebral korteks ve hipokampüsünde DNA metiltransferazlar (DNMT) ve histon deasetilazların (HDAC) mRNA düzeylerine etkilerini araştırmaktır. PS sıçanlarda deksametazonla (Dex) indüklendi. Gebeliğin 14. gününden 21. gününe, gebe sıçanlara Dex (100 ug/kg/gün) veya salin enjekte edildi. Doğumdan sonra 3 aylıkken dişi sıçanlar (n=5) dekapite edildi. Dex'in epigenetik mekanizmalar üzerindeki etkileri gerçek zamanlı PCR ile DNMT1, DNMT3a, DNMT3b, HDAC1 ve HDAC2 mRNA düzeyleri aracılığıyla araştırıldı. İstatistiksel analizler tek yönlü varyans analiziyle yapıldı. Prenatal Dex maruziyeti, korteks ve hipokampüste DNMT3a, HDAC1 ve HDAC2 mRNA düzeylerinde anlamlı artışlara neden oldu. Ayrıca Dex grubunda DNMT3b mRNA düzeylerinin hipokampüste anlamlı bir şekilde artarken kortekste azaldığı bulundu. DNMT1 mRNA düzeylerinde anlamlı bir farklılık saptanmadı. PS'in dişi sıçanların korteks ve hipokampüsünde; DNMT3a, DNMT3b, HDAC1 ve HDAC2 genlerinin ekspresyon profillerindeki değişiklikler yoluyla epigenetik mekanizmaların düzensizliğini tetikleyebileceği sonucuna varılmıştır.

Anahtar Kelimeler

Prenatal stres, deksametazon, DNA metiltransferaz, histon deasetilaz, dişi sıçan

Proje Numarası

2018-ONAP-ECZF-0001

Kaynakça

• Abbott, P. W., Gumusoglu, S. B., Bittle, J., Beversdorf, D. Q., Stevens, H. E. (2018). Prenatal stress and genetic risk: How prenatal stress interacts with genetics to alter risk for psychiatric illness. Psychoneuroendocrinology, 90, 9-21.
• Baka, M., Uyanikgil, Y., Ateş, U., Kültürsay, N. (2010). Investigation of maternal melatonin effect on the hippocampal formation of newborn rat model of intrauterine cortical dysplasia. Child’s Nervous System, 26(11), 1575-1581.
• Benoit, J. D., Rakic, P., Frick, K. M. (2015). Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. Behavioural Brain Research, 28, 1-8.
• Boersma, G. J., Lee, R. S., Cordner, Z. A., Ewald, E. R, Purcell, R. H., Moghadam, A. A. et al. (2014). Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats. Epigenetics, 9(3), 437-447.
• Bohacek, J., Mansuy, I. M. (2013). Epigenetic inheritance of disease and disease risk. Neuropsychopharmacology, 38(1), 220-236.
• Cacabelos, R., Torrellas, C. (2014). Epigenetic drug discovery for Alzheimer's disease. Epigenetic drug discovery for Alzheimer's disease. Expert Opinion on Drug Discovery, 9(9), 1059-1086.
• Eckschlager, T., Plch, J., Stiborova, M., Hrabeta, J. (2017). Histone Deacetylase Inhibitors as Anticancer Drugs. International Journal of Molecular Sciences, 18(7), 1414.
• Goldstein, J. M., Handa, R. J., Tobet, S. A. (2014). Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease. Frontiers in Neuroendocrinology, 35(1), 140-158.
• Grégoire, S., Jang, S. H., Szyf, M., Stone, L. S. (2020). Prenatal maternal stress is associated with increased sensitivity to neuropathic pain and sex-specific changes in supraspinal mRNA expression of epigenetic- and stress-related genes in adulthood. Behavioural Brain Research, 380, 112396.
• Hiroi, R., Carbone, D. L., Zuloaga, D. G., Bimonte-Nelson, H. A., Handa, R. J. (2016). Sex-dependent programming effects of prenatal glucocorticoid treatment on the developing serotonin system and stress-related behaviors in adulthood. Neuroscience, 320, 43-56.
• Hougaard, K. S., Andersen, M. B., Kjaer, S. L., Hansen, A. M., Werge, T., Lund, S. P. (2005). Prenatal stress may increase vulnerability to life events: comparison with the effects of prenatal dexamethasone. Developmental Brain Research, 159(1), 55-63.
• Huang, S., Dong, W., Jiao, Z., Liu, J., Li, K., Wang, H. et al. (2019). Prenatal Dexamethasone Exposure Induced Alterations in Neurobehavior and Hippocampal Glutamatergic System Balance in Female Rat Offspring. Toxicological Science, 171(2), 369-384.
• Jiang, X., Ma, H., Wang, Y., Liu, Y. (2013). Early life factors and type 2 diabetes mellitus. Journal of Diabetes Research, 2013, 485082.
• Johnson, A. K., Xue, B. (2018). Central nervous system neuroplasticity and the sensitization of hypertension. Nature Reviews Nephrology, 14(12), 750-766.
• Kjaer, S. L., Hougaard, K. S., Tasker, R. A., MacDonald, D. S., Rosenberg, R., Elfving, B. et al. (2011). Influence of diurnal phase on startle response in adult rats exposed to dexamethasone in utero. Physiology and Behavior, 102(5), 444-452.
• Kucharczyk, M., Kurek, A., Pomierny, B., Detka, J., Papp, M., Tota, K. et al. (2018). 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. Psychoneuroendocrinology, 94, 121-133.
• Lardenoije, R., Iatrou, A., Kenis, G., Kompotis, K., Steinbusch, H. W., Mastroeni, D. et al (2015). The epigenetics of aging and neurodegeneration. Progress in Neurobiology, 131, 21-64.
• Lei, L., Wu, X., Gu, H., Ji, M., Yang, J. (2020). Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats. Frontiers in Neuroscience, 14, 573107.
• Livak, K. J., Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25(4), 402-408.
• Lui, C. C., Hsu, M. H., Kuo, H. C., Chen, C. C., Sheen, J. M., Yu, H. R. et al. (2015). Effects of melatonin on prenatal dexamethasone-induced epigenetic alterations in hippocampal morphology and reelin and glutamic acid decarboxylase 67 levels. Developmental Neuroscience, 37(2), 105-114.
• Maccari, S., Darnaudery, M., Morley-Fletcher, S., Zuena, A. R., Cinque, C., Van Reeth, O. (2003). Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neuroscience and Biobehavioral Reviews, 27(1-2), 119-127.
• McEwen, B. S., Gianaros, P. (2011). Stress- and allostasis-induced brain plasticity. Annual Review of Medicine, 62, 431-445.
• Mohd Murshid, N., Aminullah Lubis, F., Makpol, S. (2022). Epigenetic Changes and Its Intervention in Age-Related Neurodegenerative Diseases. Cellular and Molecular Neurobiology, 42(3), 577-595.
• Monteleone, M. C., Pallarés, M. E., Billi, S. C., Antonelli, M. C., Brocco, M. A. (2018). In Vivo and In Vitro Neuronal Plasticity Modulation by Epigenetic Regulators. Journal of Molecular Neuroscience, 65(3), 301-311.
• Rao, R. T., Androulakis, I. P. (2017). Modeling the Sex Differences and Interindividual Variability in the Activity of the Hypothalamic-Pituitary-Adrenal Axis. Endocrinology, 158(11), 4017-4037.
• Saravanaraman, P., Selvam, M., Ashok, C., Srijyothi, L., Baluchamy, S. (2020). De novo methyltransferases: Potential players in diseases and new directions for targeted therapy. Biochimie, 176, 85-102.
• Silberman, D. M., Acosta, G. B., Zorrilla Zubilete, M. A. (2016). Long-term effects of early life stress exposure: Role of epigenetic mechanisms. Pharmacological Research, 109, 64-73.
• Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., Madden, T. L. (2012). Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics, 13, 134.
• Zheng, Y., Fan, W., Zhang, X., Dong, E. (2016). Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus. Epigenetics, 11(2), 150-162.