Advertisement

Journal of Neuroimmune Pharmacology

, Volume 11, Issue 4, pp 680–692 | Cite as

Effects of Moderate Prenatal Alcohol Exposure during Early Gestation in Rats on Inflammation across the Maternal-Fetal-Immune Interface and Later-Life Immune Function in the Offspring

  • Laurne S. Terasaki
  • Jaclyn M. SchwarzEmail author
ORIGINAL ARTICLE

Abstract

During early brain development, microglial activation can negatively impact long-term neuroimmune and cognitive outcomes. It is well-known that significant alcohol exposure during early gestation results in a number of cognitive deficits associated with fetal alcohol spectrum disorders (FASD). Additionally, microglia are activated following high levels of alcohol exposure in rodent models of FASD. We sought to examine whether moderate prenatal alcohol exposure (70 mg/dL blood alcohol concentration) activates microglia in the fetal rat brain, and whether moderate fetal alcohol exposure has long-term negative consequences for immune function and cognitive function in the rat. We also measured inflammation within the placenta and maternal serum following moderate alcohol exposure to determine whether either could be a source of cytokine production in the fetus. One week of moderate prenatal alcohol exposure produced a sex-specific increase in cytokines and chemokines within the fetal brain. Cytokines were also increased within the placenta, regardless of the sex of the fetus, and independent of the low levels of circulating cytokines within the maternal serum. Adult offspring exposed to alcohol prenatally had exaggerated cytokine production in the brain and periphery in response to lipopolysaccharide (25 μg/kg), as well as significant memory deficits precipitated by this low-level of inflammation. Thus the immune system, including microglia, may be a key link to understanding the etiology of fetal alcohol spectrum disorders and other unexplored cognitive or health risks associated with even low levels of fetal alcohol exposure.

Keywords

Microglia Development Cytokines Chemokines Placenta Cognition 

Notes

Acknowledgments

The authors would like to acknowledge the Klintsova Lab, including Karen Boschen and Kerry Cris, for assistance with the Analox machine; Kenneth Kirschner for assistance with the multiplex analysis; as well as Andrew Blades, Julie Gomez, Caitlin Posillico, and Jasmine Caulfield for their additional technical assistance.

Compliance with Ethical Standards

Funding

This study was funded by P5P20GM103653-02.

Conflict of Interest

Laurne S. Terasaki declares that she has no conflicts of interest. Jaclyn M. Schwarz declares that she has no conflicts of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

11481_2016_9691_MOESM1_ESM.docx (20 kb)
ESM 1 (DOCX 19 kb)

References

  1. Akkerman S, Prickaerts J, Steinbusch HW, Blokland A (2012) Object recognition testing: statistical considerations. Behav Brain Res 232(2):317–322. doi: 10.1016/j.bbr.2012.03.024
  2. Antony JM, Paquin A, Nutt SL, Kaplan DR, Miller FD (2011) Endogenous microglia regulate development of embryonic cortical precursor cells. J Neurosci Res 89(3):286–298. doi: 10.1002/jnr.22533 CrossRefPubMedGoogle Scholar
  3. Baker P, Sibley C (2006) In: Baker P, Sibley C (eds) The placenta and neurodisability. Cambridge University Press, CambridgeGoogle Scholar
  4. Bielawski DM, Abel EL (2002) The effect of administering ethanol as single vs. divided doses on blood alcohol levels in the rat. Neurotoxicol Teratol 24(4):559–562CrossRefPubMedGoogle Scholar
  5. Bilbo SD, Schwarz JM (2009) Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci 3:14. doi: 10.3389/neuro.08.014.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bilbo SD, Schwarz JM (2012) The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33(3):267–286. doi: 10.1016/j.yfrne.2012.08.006 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Blaser R, Heyser C (2015) Spontaneous object recognition: a promising approach to the comparative study of memory. Front Behav Neurosci 9:183. doi: 10.3389/fnbeh.2015.00183
  8. Centers for Disease Control and Prevention (CDC) (2015) Center for disease control and prevention: Alcohol and public health FAQs. Retrieved from http://www.cdc.gov/alcohol/faqs.htm
  9. Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia: New concepts. Brain Res Rev 53(2):344–354CrossRefPubMedGoogle Scholar
  10. Chen H, Simar D, Lambert K, Mercier J, Morris MJ (2008) Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism. Endocrinology 149(11):5348–5356. doi: 10.1210/en.2008-0582 CrossRefPubMedGoogle Scholar
  11. Corbier P, Edwards DA, Roffi J (1992) The neonatal testosterone surge: a comparative study. Arch Int Physiol Biochim Biophys 100(2):127–131PubMedGoogle Scholar
  12. Crews FT, Nixon K (2009) Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol (Oxford, Oxfordshire) 44(2):115–127. doi: 10.1093/alcalc/agn079 CrossRefGoogle Scholar
  13. Cuadros MA, Navascues J (1998) The origin and differentiation of microglial cells during development. Prog Neurobiol 56(2):173–189CrossRefPubMedGoogle Scholar
  14. Cunningham CL, Martinez-Cerdeno V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci 33(10):4216–4233. doi: 10.1523/JNEUROSCI.3441-12.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Drew PD, Kane CJ (2014) Fetal alcohol spectrum disorders and neuroimmune changes. Int Rev Neurobiol 118:41–80. doi: 10.1016/B978-0-12-801284-0.00003-8 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Drew PD, Johnson JW, Douglas JC, Phelan KD, Kane CJ (2015) Pioglitazone blocks ethanol induction of microglial activation and immune responses in the hippocampus, cerebellum, and cerebral cortex in a mouse model of fetal alcohol spectrum disorders. Alcohol Clin Exp Res 39(3):445–454. doi: 10.1111/acer.12639 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ennaceur A (2010) One-trial object recognition in rats and mice: methodological and theoretical issues. Behav Brain Res 215(2):244–254. doi: 10.1016/j.bbr.2009.12.036
  18. Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. Behav Brain Res 31(1):47–59Google Scholar
  19. Estes ML, McAllister AK (2015) Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nature Reviews. Neuroscience 16(8):469–486. doi: 10.1038/nrn3978 PubMedGoogle Scholar
  20. Falgreen Eriksen HL, Mortensen EL, Kilburn T, Underbjerg M, Bertrand J, Stovring H, et al. (2012) The effects of low to moderate prenatal alcohol exposure in early pregnancy on IQ in 5-year-old children. BJOG 119(10):1191–1200. doi: 10.1111/j.1471-0528.2012.03394.x CrossRefPubMedGoogle Scholar
  21. Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, et al. (2004) The LPS receptor (CD14) links innate immunity with alzheimer’s disease. FASEB J : Official Publication of the Federation of American Societies for Experimental Biology 18(1):203–205. doi: 10.1096/fj.03-0364fje Google Scholar
  22. Feigenson KA, Kusnecov AW, Silverstein SM (2014) Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev 38:72–93. doi: 10.1016/j.neubiorev.2013.11.006 CrossRefPubMedGoogle Scholar
  23. Goodfellow MJ, Lindquist DH (2014) Significant long-term, but not short-term, hippocampal-dependent memory impairment in adult rats exposed to alcohol in early postnatal life. Dev Psychobiol 56(6):1316–1326. doi: 10.1002/dev.21210 PubMedGoogle Scholar
  24. Guan Z, Fang J (2006) Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain Behav Immun 20(1):64–71CrossRefPubMedGoogle Scholar
  25. Jablonski SA, Stanton ME (2014) Neonatal alcohol impairs the context preexposure facilitation effect in juvenile rats: Dose-response and post-training consolidation effects. Alcohol (Fayetteville, N.Y.) 48(1):35–42. doi: 10.1016/j.alcohol.2013.11.002 CrossRefGoogle Scholar
  26. Kane CJ, Phelan KD, Han L, Smith RR, Xie J, Douglas JC, Drew PD (2011) Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-gamma agonists. Brain Behav Immun 25(Suppl 1):S137–S145. doi: 10.1016/j.bbi.2011.02.016 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kane CJ, Phelan KD, Douglas JC, Wagoner G, Johnson JW, Xu J, Drew PD (2013) Effects of ethanol on immune response in the brain: Region-specific changes in aged mice. J Neuroinflammation 10:66. doi: 10.1186/1742-2094-10-66 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kelly YJ, Sacker A, Gray R, Kelly J, Wolke D, Head J, Quigley MA (2012) Light drinking during pregnancy: still no increased risk for socioemotional difficulties or cognitive deficits at 5 years of age? J Epidemiol Community Health 66(1):41–48. doi: 10.1136/jech.2009.103002 CrossRefPubMedGoogle Scholar
  29. Kent S, Bluthe RM, Dantzer R, Hardwick AJ, Kelley KW, Rothwell NJ, Vannice JL (1992) Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1. Proc Natl Acad Sci U S A 89(19):9117–9120CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lewis CE, Thomas KG, Dodge NC, Molteno CD, Meintjes EM, Jacobson JL, Jacobson SW (2015) Verbal learning and memory impairment in children with fetal alcohol spectrum disorders. Alcohol Clin Exp Res 39(4):724–732. doi: 10.1111/acer.12671 CrossRefPubMedGoogle Scholar
  31. Livy DJ, Parnell SE, West JR (2003) Blood ethanol concentration profiles: A comparison between rats and mice. Alcohol (Fayetteville, N.Y.) 29(3):165–171CrossRefGoogle Scholar
  32. Losco P (1992) Normal development, growth, and aging of the spleen. In: Mohr U, Dungwörth DL, Capen CC (eds) Pathobiology of the aging rat, vol 1. ILSI Press, Washington, D.C., pp. 75–94Google Scholar
  33. Lupton C, Burd L, Harwood R (2004) Cost of fetal alcohol spectrum disorders. Am J Med Genet 127C(1):42–50. doi: 10.1002/ajmg.c.30015 CrossRefPubMedGoogle Scholar
  34. Mattson SN, Calarco KE, Lang AR (2006) Focused and shifting attention in children with heavy prenatal alcohol exposure. Neuropsychology 20(3):361–369CrossRefPubMedPubMedCentralGoogle Scholar
  35. Monji A, Kato TA, Mizoguchi Y, Horikawa H, Seki Y, Kasai M, et al. (2013) Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuro-Psychopharmacol Biol Psychiatry 42:115–121. doi: 10.1016/j.pnpbp.2011.12.002 CrossRefGoogle Scholar
  36. Murawski NJ, Klintsova AY, Stanton ME (2012) Neonatal alcohol exposure and the hippocampus in developing male rats: effects on behaviorally induced CA1 c-fos expression, CA1 pyramidal cell number, and contextual fear conditioning. Neuroscience 206:89–99. doi: 10.1016/j.neuroscience.2012.01.006 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Qin L, He J, Hanes RN, Pluzarev O, Hong JS, Crews FT (2008) Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflammation 5:10. doi: 10.1186/1742-2094-5-10 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Rezaie P, Patel K, Male DK (1999) Microglia in the human fetal spinal cord--patterns of distribution, morphology and phenotype. Brain Res Dev Brain Res 115(1):71–81CrossRefPubMedGoogle Scholar
  39. Rezaie P, Dean A, Male D, Ulfig N (2005) Microglia in the cerebral wall of the human telencephalon at second trimester. Cereb Cortex (New York, N.Y.: 1991) 15(7):938–949Google Scholar
  40. Schwarz JM, Sholar PW, Bilbo SD (2012) Sex differences in microglial colonization of the developing rat brain. J Neurochem 120(6):948–963. doi: 10.1111/j.1471-4159.2011.07630.x PubMedPubMedCentralGoogle Scholar
  41. Skaper SD, Facci L, Giusti P (2014) Neuroinflammation, microglia and mast cells in the pathophysiology of neurocognitive disorders: A review. CNS Neurol Disord Drug Targets 13(10):1654–1666CrossRefPubMedGoogle Scholar
  42. Skogerbo A, Kesmodel US, Wimberley T, Stovring H, Bertrand J, Landro NI, Mortensen EL (2012) The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on executive function in 5-year-old children. BJOG 119(10):1201–1210. doi: 10.1111/j.1471-0528.2012.03397.x CrossRefPubMedPubMedCentralGoogle Scholar
  43. Squarzoni P, Oller G, Hoeffel G, Pont-Lezica L, Rostaing P, Low D, et al. (2014) Microglia modulate wiring of the embryonic forebrain. Cell Rep 8(5):1271–1279. doi: 10.1016/j.celrep.2014.07.042 CrossRefPubMedGoogle Scholar
  44. Streit WJ, Xue QS, Tischer J, Bechmann I (2014) Microglial pathology. Acta Neuropathol Commun 2:142. doi: 10.1186/s40478-014-0142-6 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Weisz J, Ward IL (1980) Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology 106(1):306–316. doi: 10.1210/endo-106-1-306 CrossRefPubMedGoogle Scholar
  46. Westbrook SR, Brennan LE, Stanton ME (2014) Ontogeny of object versus location recognition in the rat: acquisition and retention effects. Dev Psychobiol 56(7):1492–1506. doi: 10.1002/dev.21232
  47. Wyper KR, Rasmussen CR (2011) Language impairments in children with fetal alcohol spectrum disorders. J Popul Ther Clin Pharmacol = Journal De La Therapeutique Des Populations Et De La Pharamcologie Clinique 18(2):e364–e376PubMedGoogle Scholar
  48. Yang JY, Xue X, Tian H, Wang XX, Dong YX, Wang F, et al. (2014) Role of microglia in ethanol-induced neurodegenerative disease: pathological and behavioral dysfunction at different developmental stages. Pharmacol Ther 144(3):321–337. doi: 10.1016/j.pharmthera.2014.07.002 CrossRefPubMedGoogle Scholar
  49. Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: An update. Biochim Biophys Acta 1772(4):494–502CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Psychological and Brain SciencesUniversity of DelawareNewarkUSA

Personalised recommendations