Skip to main content
SpringerLink
Log in

Sevoflurane Exposure Results in Sex-Specific Transgenerational Upregulation of Target IEGs in the Subiculum

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Large body of animal work and emerging clinical findings have suggested that early exposure to anesthetics may result in increased risk of learning disabilities and behavioral impairments. Recent studies have begun to investigate anesthesia-induced epigenetic modifications to elucidate their role in behavioral and neurodevelopmental abnormalities. Here we examine sevoflurane-induced transgenerational modifications of subicular neuronal DNA methylation and expression of immediate early genes (IEGs), arc and junB, crucial to synaptic plasticity and normal neuronal development. We show that 6 h sevoflurane exposure in postnatal day 7 rat pups resulted in decreased neuronal 5-methycytosine, indicating reduced DNA methylation. This effect is transgenerationally expressed in offspring born to exposed mothers which is of importance considering that decreased DNA methylation in the brain has been linked with functional decline in learning and memory. We further show that sevoflurane exposure induces upregulation of Arc and JunB mRNA expression, 42.7% and 35.2%, respectively. Transgenerational changes in Arc and JunB mRNA were sexually dimorphic only occurring in males born to exposed females, expressed as upregulation of Arc and JunB mRNA, 71.6% and 74.0%, respectively. We further investigated correlation between altered arc promoter methylation and observed upregulation of Arc mRNA and observed that sevoflurane reduced methylation in the 5-upstream promoter region of females exposed to sevoflurane. Transgenerational hypomethylation and modifications to IEGs crucial to synaptic plasticity, observed following neonatal sevoflurane exposure could contribute to morphological and cognitive deficits known to occur with neonatal sevoflurane exposure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

Gen0:

Generation 0

Gen1:

Generation 1

GA:

General anesthesia

5-mC:

5-Methylcytosine

5-hmC:

5-Hydroxymethylcytosine

CpG:

Cytosine-phosphate-guanine

IEGs:

Immediate early genes

References

  1. U.S. Food & Drug Administration. (2016) FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fdareview-results-new-warnings-about-using-general-anesthetics-and. Accessed 01 Dec 2018

  2. Fan CH, Peng B, Zhang FC (2018) The postoperative effect of sevoflurane inhalational anesthesia on cognitive function and inflammatory response of pediatric patients. Eur Rev Med Pharmacol Sci 22:3971–3975

    PubMed  Google Scholar 

  3. Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR et al (2009) Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 110:796–804. https://doi.org/10.1097/01.anes.0000344728.34332.5d

    Article  PubMed  Google Scholar 

  4. Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL et al (2011) Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 128:273–292. https://doi.org/10.1542/peds.2011-0351

    Article  Google Scholar 

  5. Shen X, Xiao Y, Li W, Chen K, Yu H (2018) Sevoflurane anesthesia during pregnancy in mice induces hearing impairment in the offspring. Drug Des Devel Ther 12:1827–1836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ozer A, Ceribasi S, Ceribasi A et al (2017) Effects of sevoflurane on apoptosis, BDNF and cognitive functions in neonatal rats. Bratisl Med J 118:80–84. https://doi.org/10.4149/BLL

    Article  CAS  Google Scholar 

  7. Shih J, May L d V, Gonzalez HE et al (2012) Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats. Anesthesiology 116:586–602. https://doi.org/10.1038/jid.2014.371

    Article  CAS  PubMed  Google Scholar 

  8. Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M, Imaki J (2009) Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology 110:628–637. https://doi.org/10.1097/ALN.0b013e3181974fa2

    Article  CAS  PubMed  Google Scholar 

  9. Zhang DX, Jiang S, Yu LN et al (2015) The effect of sevoflurane on the cognitive function of rats and its association with the inhibition of synaptic transmission. Int J Clin Exp Med 8:20853–20860 https://doi.org/10.1016/j.anai.2009.10.002

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano SG, Sun D, Baxter MG et al (2013) Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology 118:502–515. https://doi.org/10.1097/ALN.0b013e3182834d77

    Article  CAS  PubMed  Google Scholar 

  11. Tao G, Luo Y, Xue Q, Li G, Tan Y, Xiao J, Yu B (2016) Docosahexaenoic acid rescues synaptogenesis impairment and long-term memory deficits caused by postnatal multiple sevoflurane exposures. Biomed Res Int 2016:1–7. https://doi.org/10.1155/2016/4062579

    Article  CAS  Google Scholar 

  12. Chalon J, Tang CK, Ramanathan S et al (1981) Exposure to halothane and enflurane affects learning function of murine progeny. Anesth Analg 60:794–797. https://doi.org/10.1097/IAE.0b013e3181dde5f5

    Article  CAS  PubMed  Google Scholar 

  13. Massara LD, Osuru HP, Ph D et al (2016) General anesthesia causes epigenetic histone modulation of c-Fos and brain-derived neurotrophic factor, target genes important for neuronal development in the immature rat hippocampus. Am Sciety Anesthesiol 124:1311–1327

    Article  Google Scholar 

  14. Jia M, Ji M, Yang J (2017) Epigenetic regulation of general anesthesia-induced neonatal neurodegeneration. Oncotarget 8:5652–5653

    PubMed  PubMed Central  Google Scholar 

  15. L sha J, Jia M, Sun J et al (2016) Hypermethylation of hippocampal synaptic plasticity-related genes is involved in neonatal sevoflurane exposure-induced cognitive impairments in rats. Neurotox Res 29:243–255. https://doi.org/10.1007/s12640-015-9585-1

    Article  CAS  Google Scholar 

  16. Joksimovic SM, Osuru HP, Oklopcic A, Beenhakker MP, Jevtovic-Todorovic V, Todorovic SM (2018) Histone deacetylase inhibitor entinostat (MS-275) restores anesthesia-induced alteration of inhibitory synaptic transmission in the developing rat hippocampus. Mol Neurobiol 55:222–228. https://doi.org/10.1007/s12035-017-0735-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Oliveira AMM (2016) DNA methylation: a permissive mark in memory formation and maintenance. Learn Mem 23:587–593. https://doi.org/10.1101/lm.042739.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu L, van Groen T, Kadish I, Tollefsbol TO (2009) DNA methylation impacts on learning and memory in aging. Neurobiol Aging 30:549–560. https://doi.org/10.1016/j.neurobiolaging.2007.07.020

    Article  CAS  PubMed  Google Scholar 

  19. Smeester L, Rager JE, Bailey KA et al (2017) An overview of epigenetic assays. J Neurosci 8:e0163690. https://doi.org/10.1371/journal.pone.0163690

    Article  CAS  Google Scholar 

  20. Ju LS, Yang JJ, Morey TE, Gravenstein N, Seubert CN, Resnick JL, Zhang J (2018) Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane to the next generation of male, but not female, rats. Br J Anaesth 121:406–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A, Todorovic SM, Jevtovic-Todorovic V (2011) General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology 115:992–1002. https://doi.org/10.1097/OPX.0b013e3182540562.The

    Article  PubMed  Google Scholar 

  22. O’Mara S (2005) The subiculum: what it does, what it might do, and what neuroanatomy has yet to tell us. J Anat 207:271–282. https://doi.org/10.1111/j.1469-7580.2005.00446.x

    Article  PubMed  PubMed Central  Google Scholar 

  23. Behr J, Wozny C, Fidzinski P, Schmitz D (2009) Synaptic plasticity in the subiculum. Prog Neurobiol 89:334–342. https://doi.org/10.1016/J.PNEUROBIO.2009.09.002

    Article  PubMed  Google Scholar 

  24. McNaughton N (2006) The role of the subiculum within the behavioural inhibition system. Behav Brain Res 174:232–250. https://doi.org/10.1016/j.bbr.2006.05.037

    Article  CAS  PubMed  Google Scholar 

  25. Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136. https://doi.org/10.1098/rstb.2002.1230

    Article  CAS  PubMed  Google Scholar 

  26. Tischmeyer W, Grimm R (1999) Activation of immediate early genes and memory formation. Cell Mol Life Sci 55:564–574

    Article  CAS  PubMed  Google Scholar 

  27. Sommerlandt FMJ, Brockmann A, Rössler W, Spaethe J (2018) Immediate early genes in social insects: a tool to identify brain regions involved in complex behaviors and molecular processes underlying neuroplasticity. Cell Mol Life Sci 76:1–15. https://doi.org/10.1007/s00018-018-2948-z

    Article  CAS  Google Scholar 

  28. Srivas S, Thakur MK (2017) Epigenetic regulation of neuronal immediate early genes is associated with decline in their expression and memory consolidation in scopolamine-induced amnesic mice. 5107–5119. https://doi.org/10.1007/s12035-016-0047-4

    Article  PubMed  Google Scholar 

  29. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 3:1101–1108. https://doi.org/10.1038/nprot.2008.73

    Article  CAS  PubMed  Google Scholar 

  30. Penner MR, Roth TL, Chawla MK et al (2011) Age-related changes in Arc transcription and DNA methylation within the hippocampus. Neurobiol Aging 32:2198–2210. https://doi.org/10.1038/jid.2014.371

    Article  CAS  PubMed  Google Scholar 

  31. Dyrvig M, Hansen HH, Christiansen SH, Woldbye DPD, Mikkelsen JD, Lichota J (2012) Epigenetic regulation of Arc and c-Fos in the hippocampus after acute electroconvulsive stimulation in the rat. Brain Res Bull 88:507–513. https://doi.org/10.1016/j.brainresbull.2012.05.004

    Article  CAS  PubMed  Google Scholar 

  32. Zhang L y, Li P l, Wang T z, Zhang X c (2015) Prognostic values of 5-hmC, 5-mC and TET2 in epithelial ovarian cancer. Arch Gynecol Obstet 292:891–897. https://doi.org/10.1007/s00404-015-3704-3

    Article  CAS  PubMed  Google Scholar 

  33. Hicks MJ, Hu QP, Macrae E, DeWille J (2015) Mitogen-activated protein kinase signaling controls basal and oncostatin M-mediated JUNB gene expression. Mol Cell Biochem 403:115–124. https://doi.org/10.1007/s11010-015-2342-1

    Article  CAS  PubMed  Google Scholar 

  34. Wilkerson JR, Albanesi JP, Huber KM (2018) Roles for Arc in metabotropic glutamate receptor-dependent LTD and synapse elimination: Implications in health and disease. Semin Cell Dev Biol 77:51–62. https://doi.org/10.1016/j.semcdb.2017.09.035

    Article  CAS  PubMed  Google Scholar 

  35. Alberini CM (2014) Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89:1–46. https://doi.org/10.1152/physrev.00017.2008.Transcription

    Article  Google Scholar 

  36. Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y et al (2013) Global epigenomic reconfiguration during mammalian brain development. Science (80- ) 341:1237905. https://doi.org/10.1126/science.1237905

    Article  CAS  Google Scholar 

  37. Bogdanović O, Veenstra GJC (2009) DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma 118:549–565. https://doi.org/10.1007/s00412-009-0221-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ambrosi C, Manzo M, Baubec T (2017) Dynamics and context-dependent roles of DNA methylation. J Mol Biol 429:1459–1475. https://doi.org/10.1016/j.jmb.2017.02.008

    Article  CAS  PubMed  Google Scholar 

  39. Korb E, Finkbeiner S (2011) Arc in synaptic plasticity: from gene to behavior. Trends Neurosci 34:591–598. https://doi.org/10.1016/j.tins.2011.08.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Eagle AL, Gajewski PA, Robison AJ (2016) Role of hippocampal activity-induced transcription in memory consolidation. Rev Neurosci 27:559–573. https://doi.org/10.1515/revneuro-2016-0010.Role

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Clayton DF (2000) The genomic action potential. Neurobiol Learn Mem 74:185–216. https://doi.org/10.1006/nlme.2000.3967

    Article  CAS  PubMed  Google Scholar 

  42. Itoh, Masayuki & Okuno, Hiroyuki & Yamada, Daisuke & Yamashita, Mariko & Abe, Manabu & Natsume, Rie & Kaizuka, Toshie & Sakimura, Kenji & Hoshino, Mikio & Mishina, Masayoshi & Wada, Keiji & Sekiguchi, Masayuki & Hayashi, Takashi. (2018). Perturbed expression pattern of the immediate early gene Arc in the dentate gyrus of GluA1 C‐terminal palmitoylation‐deficient mice. Neuropsychopharmacology Reports. 39.https://doi.org/10.1002/npr2.12044

  43. Xiao H, Liu B, Chen Y, Zhang J (2016) Learning, memory and synaptic plasticity in hippocampus in rats exposed to sevoflurane. Int J Dev Neurosci 48:38–49. https://doi.org/10.1016/j.ijdevneu.2015.11.001

    Article  CAS  PubMed  Google Scholar 

  44. Zimering JH, Dong Y, Fang F, Huang L, Zhang Y, Xie Z (2016) Anesthetic sevoflurane causes rho-dependent filopodial shortening in mouse neurons. PLoS One 11:1–15. https://doi.org/10.1371/journal.pone.0159637

    Article  CAS  Google Scholar 

  45. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882. https://doi.org/10.1523/JNEUROSCI.23-03-00876.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Loepke AW, Istaphanous GK, McAuliffe JJ et al (2009) The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 108:90–104. https://doi.org/10.1017/S0031182016001955

    Article  CAS  PubMed  Google Scholar 

  47. Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA et al (2011) Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 33:220–230. https://doi.org/10.1016/j.ntt.2011.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Supported in part by funds from the Department of Anesthesiology at the University of Colorado Anschutz Medical campus and R0144517, R0144517-S, R01 GM118197, R01 GM118197, and R21 HD080281, March of Dimes National Award, CU Medicine Endowment.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, University of Colorado School of Medicine, 13001 E. 17th Pl., Aurora, CO, 80045, USA

    Shelby E. Chastain-Potts, Vesna Tesic, Quy L. Tat, Omar H. Cabrera, Nidia Quillinan & Vesna Jevtovic-Todorovic

Authors
  1. Shelby E. Chastain-Potts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vesna Tesic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Quy L. Tat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Omar H. Cabrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nidia Quillinan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vesna Jevtovic-Todorovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vesna Jevtovic-Todorovic.

Ethics declarations

These experiments were approved by the Animal Use and Care Committee of the University of Colorado Anschutz Medical Campus, the Office of Laboratory Animal Resources (OLAR), Aurora, CO. All experiments were conducted in accordance with Public Health Service’s Policy on Humane Care and Use of Laboratory Animals.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chastain-Potts, S.E., Tesic, V., Tat, Q.L. et al. Sevoflurane Exposure Results in Sex-Specific Transgenerational Upregulation of Target IEGs in the Subiculum. Mol Neurobiol 57, 11–22 (2020). https://doi.org/10.1007/s12035-019-01752-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-01752-0

Keywords

Search

Navigation