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Current Issues in Developmental Immunotoxicity

  • Jamie C. DeWittEmail author
  • Deborah E. Keil
Chapter
Part of the Molecular and Integrative Toxicology book series (MOLECUL)

Abstract

Developmental immunotoxicity (DIT) occurs when early-life events reshape immune development to the point of altering immune system responses, often with negative consequences for an organism. Within the vein of toxicology, such events include exposure to exogenous risk factors, including chemical, biological, or physical agents that change the course of immune system development. Early-life exposure to such events may result in suppression, hyperactivation , and/or misregulation of a host of immune responses to result in inflammatory diseases, allergy and asthma, autoimmune diseases, and/or decreased resistance to infectious agents. This chapter will review current issues associated with DIT, including an overview of current guidelines for assessing DIT in experimental animal models, lifetime health risks thought to be associated with DIT, the need for DIT testing in safety assessments of chemical substances, and the impacts of “twenty-first century toxicology” on DIT approaches and methods.

Keywords

DIT Immunosuppression Hyperactivation Misregulation Early-life exposures Critical windows 

References

  1. Ahmed S, Ahsan KB, Kippler M, Mily A, Wagatsuma Y, Hoque AW, Vahter M (2012) In utero arsenic exposure is associated with impaired thymic function in newborns possibly via oxidative stress and apoptosis. Toxicol Sci 129:305–314CrossRefPubMedGoogle Scholar
  2. Arbibe L, Sansonetti PJ (2007) Epigenetic regulation of host response to LPS: causing tolerance while avoiding toll errancy. Cell Host Microbe 1:244–246CrossRefPubMedGoogle Scholar
  3. Arita A, Costa M (2009) Epigenetics in metal carcinogenesis: nickel, arsenic, chromium and cadmium. Metallomics 1:222–228CrossRefPubMedPubMedCentralGoogle Scholar
  4. Barker D (1997) The fetal origins of coronary heart disease. Acta Paediatr 422:78–82CrossRefGoogle Scholar
  5. Barker DJ (2001) A new model for the origins of chronic disease. Med Health Care Philos 4:31–35CrossRefPubMedGoogle Scholar
  6. Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley RA et al (2004) Developmental plasticity and human health. Nature 430:419–421CrossRefPubMedGoogle Scholar
  7. Ben-Shlomo Y (2007) Rising to the challenges and opportunities of life course epidemiology. Int J Epidemiol 36:481–483CrossRefPubMedGoogle Scholar
  8. Brown RC, Barone S Jr, Kimmel CA (2008) Children’s health risk assessment: incorporating a lifestage approach into the risk assessment process. Birth Defects Res B Dev Reprod Toxicol 83:511–521CrossRefPubMedGoogle Scholar
  9. Bunn TL, Parsons PJ, Kao E, Dietert RR (2001) Exposure to lead during critical windows of embryonic development: differential immunotoxic outcome based on stage of exposure and gender. Toxicol Sci 64:57–66CrossRefPubMedGoogle Scholar
  10. Burns-Naas LA, Hastings KL, Ladics GS, Makris SL, Parker GA, Holsapple MP (2008) What’s so special about the developing immune system? Int J Toxicol 27:223–254CrossRefPubMedGoogle Scholar
  11. Collinge M, Burns-Naas LA, Chellman GJ, Kawabata TT, Komocsar WJ, Piccotti JR, Shenton J, Wierda D (2012) Developmental immunotoxicity (DIT) testing of pharmacueticals: current practices, state of the science, knowledge gaps, and recommendations. J Immunotoxicol 9:210–230CrossRefPubMedGoogle Scholar
  12. Collins FA, Gray GM, Bucher JR (2008) Toxicology. Transforming environmental health protection. Science 319:906–907CrossRefPubMedPubMedCentralGoogle Scholar
  13. Daston G, Faustman E, Ginsberg G, Fenner-Crisp P, Olin S, Sonawane B, McLaughlin TJ (2004) A framework for assessing risks to children from exposure to environmental agents. Environ Health Perspect 112:238–256CrossRefPubMedPubMedCentralGoogle Scholar
  14. DeWitt JC, Peden-Adams MM, Keil DE, Dietert RR (2012a) Current status of developmental immunotoxicity early-life patterns and testing. Toxicol Pathol 40:230–236CrossRefPubMedGoogle Scholar
  15. DeWitt JC, Peden-Adams MM, Keil DE, Dietert RR (2012b) Developmental immunotoxicity (DIT): assays for evaluating effects of exogenous agents on development of the immune system. Curr Protoc Toxicol chapter 18:unit18.15Google Scholar
  16. Dietert R (2009) Developmental immunotoxicology: focus on health risks. Chem Res Toxicol 22:17–23CrossRefPubMedGoogle Scholar
  17. Dietert RR (2011a) Fractal immunology and immune patterning: potential tools for immune protection and optimization. J Immunotoxicol 8:101–110CrossRefPubMedGoogle Scholar
  18. Dietert RR (2011b) Role of developmental immunotoxicity and immune dysfunction in chronic disease and cancer. Reprod Toxicol 31:319–326CrossRefPubMedGoogle Scholar
  19. Dietert RR (2008) Developmental immunotoxicology (DIT): windows of vulnerability, immune dysfunction and safety assessment. J Immunotoxicol 5:401–412CrossRefPubMedGoogle Scholar
  20. Dietert RR (2014) Developmental immunotoxicity, perinatal programming, and noncommunicable diseases: focus on human studies. Adv Med 2014:867805CrossRefPubMedPubMedCentralGoogle Scholar
  21. Dietert RR, DeWitt J (2010) Developmental Immunotoxicity (DIT): the why, when, and how of DIT testing. In: Dietert RR (ed) Immunotoxicity testing methods and protocols. Humana Press, New York, pp. 17–25CrossRefGoogle Scholar
  22. Dietert RR, Etzel RA, Chen D, Halonen M, Holladay SD, Jarabek AM, Landreth K, Peden DB, Pinkerton K, Smialowicz RJ, Zoetis T (2000) Workshop to identify critical windows of exposure for children’s health: immune and respiratory systems work group summary. Environ Health Perspect 108(Suppl 3):483–490.Google Scholar
  23. Dietert RR, DeWitt JC, Germolec DR, Zelikoff JT (2010) Breaking patterns of environmentally influenced disease for health risk reduction: immune perspectives. Eviron Health Perspect 118:1091–1099CrossRefGoogle Scholar
  24. Dietert RR, Holsapple MP (2007) Methodologies for developmental immunotoxicity (DIT) testing. Methods 41:123–131CrossRefPubMedGoogle Scholar
  25. Dietert RR, Lee JE, Hussain I, Piepenbrink M (2004) Developmental immunotoxicology of lead. Toxicol Appl Pharmacol 198:86–94CrossRefPubMedGoogle Scholar
  26. Dietert RR, Luebke RW (eds) (2012) Immunotoxicity, immune dysfunction, and chronic disease. Humana Press, New YorkGoogle Scholar
  27. Dietert RR, Zelikoff JT (2010) Identifying patterns of immune-related disease: use in disease prevention and management. World J Pediatr 6:111–118CrossRefPubMedGoogle Scholar
  28. Dietert RR, Zelikoff JT (2009) Pediatric immune dysfunction and health risks following early-life immune insult. Curr Pediatr Rev 5:36–51CrossRefGoogle Scholar
  29. Dietert RR, Zelikoff JT (2008) Early-life environment, developmental immunotoxicology, and the risk of pediatric allergic disease including asthma. Birth Defects Res B Dev Reprod Toxicol 83:547–560CrossRefPubMedGoogle Scholar
  30. Fedeli D, Montani M, Carloni M, Nasuti C, Amici A, Gabbianelli R (2012) Leukocyte Nurr1 as peripheral biomarker of early-life environmental exposure to permethrin insecticide. Biomarkers 17:604–609CrossRefPubMedGoogle Scholar
  31. Filiberto A, Maccani M, Koestler D, Wilhelm-Benartzi C, Gagne L, Marsit C (2011) Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in the human placenta. Epigenetics 6:566–572CrossRefPubMedPubMedCentralGoogle Scholar
  32. FRB (Federal Reserve Board) (2015) G.17—Industrial production and capacity utilization, industrial production for chemicals (NAICS=325). http://www.federalreserve.gov/. Accessed 3 Aug 2015
  33. Grandjean P, Andersen EW, Budtz-Jørgensen E, Nielsen F, Mølbak K, Weihe P, Heilmann C (2012) Serum vaccine antibody concentrations in children exposed to perfluorinated compounds. JAMA 307:391–397CrossRefPubMedPubMedCentralGoogle Scholar
  34. Grandjean P, Poulsen LK, Heilmann C, Steuerwald U, Weihe P (2010) Allergy and sensitization during childhood associated with prenatal and lactational exposure to marine pollutants. Environ Health Perspect 118:1429–1433CrossRefPubMedPubMedCentralGoogle Scholar
  35. Gundacker C, Hengstschläger M (2012) The role of the placenta in fetal exposure to heavy metals. Wien Med Wochenschr 162:201CrossRefPubMedGoogle Scholar
  36. Halfon N, Hochstein M (2002) Life course health development: an integrated framework for developing health, policy, and research. Milbank Q 80:433–479CrossRefPubMedPubMedCentralGoogle Scholar
  37. Hartung T, Corsini E (2013) Immunotoxicology: challenges in the 21st century and in vitro opportunities. ALTEX 30:4111–4426Google Scholar
  38. Heilmann C, Budtz-Jørgensen E, Nielsen F, Heinzow B, Weihe P, Grandjean P (2010) Serum concentrations of antibodies against vaccine toxoids in children exposed perinatally to immunotoxicants. Environ Health Perspect 118:1434–1438CrossRefPubMedPubMedCentralGoogle Scholar
  39. Heilmann C, Grandjean P, Weihe P, Nielsen F, Budtz-Jorgensen E (2006) Reduced antibody responses to vaccinations in children exposed to polychlorinated biphenyls. PLoS Med 3:e311CrossRefPubMedPubMedCentralGoogle Scholar
  40. Hessel EV, Tonk EC, Bos PM, van Loveren H, Piersma AH (2015) Developmental immunotoxicity of chemicals in rodents and its possible regulatory impact. Crit Rev Toxicol 45:68–82CrossRefPubMedGoogle Scholar
  41. Holsapple MP, Paustenbach DJ, Charnley G, West LJ, Luster MI, Dietert RR, Burns-Naas LA (2004) Symposium summary: children’s health risk—what’s so special about the developing immune system? Toxicol Appl Pharmacol 199:61–70CrossRefPubMedGoogle Scholar
  42. Kang SH, Jung YH, Kim HY, Seo JH, Lee JY, Kwon JW, Hong SJ (2013) Effect of paracetamol use on the modification of the development of asthma by reactive oxygen species genes. Ann Allergy Asthma Immunol 110:364–369CrossRefPubMedGoogle Scholar
  43. Kanno Y, Vahedi G, Hirahara K, Singleton K, O’Shea JJ (2012) Transcriptional and epigenetic control of T helper cell specificiation: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol 30:707–731CrossRefPubMedPubMedCentralGoogle Scholar
  44. Keil D, Dudley A, EuDaly J, Dempsey J, Butterworth L, Gilkeson G, Peden-Adams M (2004) Immunological and hematological effects observed in B6C3F1 mice exposed to JP-8 jet fuel for 14 days. J Toxicol Environ Health A 67:1109–1129CrossRefPubMedGoogle Scholar
  45. Keil DE, McGuinn WD, Dudley AC, EuDaly JG, Gilkeson GS, Peden-Adams MM (2009) N,N,-diethyl-m-toluamide (DEET) suppresses humoral immunological function in B6C3F1 mice. Toxicol Sci 108:110–123CrossRefPubMedGoogle Scholar
  46. Krewski D, Andersen ME, Mantus E, Zeise L (2009) Toxicity in the 21st century: implications for human health risk assessment. Risk Anal 29:474–479CrossRefPubMedGoogle Scholar
  47. Landreth KS (2002) Critical windows in development of the rodent immune system. Hum Exp Toxicol 21:493–498CrossRefPubMedGoogle Scholar
  48. Lawn JE, Wilczynska-Ketende K, Cousens SN (2006) Estimating the causes of 4 million neonatal deaths in the year 2000. Int J Epidemiol 35:706–718CrossRefPubMedGoogle Scholar
  49. Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, Black RE (2015) Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 385:430–440CrossRefPubMedGoogle Scholar
  50. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Fouhani SJ, Peske JD, Derecki NC, Castle D et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341CrossRefPubMedPubMedCentralGoogle Scholar
  51. Luebke RW, Chen DH, Dietert R, Yang Y, King M, Luster MI (2006) The comparative immunotoxicity of five selected compounds following developmental or adult exposure. J Toxicol Environ Health B 9:1–26CrossRefGoogle Scholar
  52. Luster MI, Dean JH, Germolec DR (2003) Consensus workshop on methods to evaluate developmental immunotoxicity. Environ Health Perspect 111:579–583CrossRefPubMedPubMedCentralGoogle Scholar
  53. Maccani JZ, Koestler DC, Houseman EA, Marsit CJ, Kelsey KT (2013) Placental DNA methylation alterations associated with maternal tobacco smoking at the RUNX3 gene are also associated with gestational age. Epigenomics 5:619–630CrossRefPubMedPubMedCentralGoogle Scholar
  54. MacGillivray DM, Kollmann TR (2014) The role of environmental factors in modulating immune responses in early life. Front Immunol 5:434CrossRefPubMedPubMedCentralGoogle Scholar
  55. National Research Council (NRC) (2007). Toxicity testing in the 21st century: a vision and a strategy. Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council. http://www.nap.edu/catalog/11970.html
  56. Ornoy A, Ergaz Z (2010) Alcohol abuse in pregnant women: effects on the fetus and newborn, mode of action and maternal treatment. Int J Environ Res Public Health 7:364–379CrossRefPubMedPubMedCentralGoogle Scholar
  57. Peden-Adams MM, Keller JM, Eudaly JG, Berger J, Gilkeson GS, Keil DE (2008) Suppression of humoral immunity in mice following exposure to perfluorooctane sulfonate. Toxicol Sci 104:144–154CrossRefPubMedGoogle Scholar
  58. Peden-Adams MM, Liu J, Knutson S, Dancik J, Bryant K, Bodine AB, Dickerson RL (2007) Alterations in immune function and CYP450 activity in adult male deer mice (Peromyscus maniculatus) following exposure to benzo[a]pyrene, pyrene, or chrysene. J Toxicol Environ Health A 70:1783–1791CrossRefPubMedGoogle Scholar
  59. Pennings JL, Jennen DG, Nygaard UC, Namork E, Haug LS, van Loveren H, Granum B (2015) Cord blood gene expression supports that prenatal exposure to perfluoroalkyl substances causes depressed immune functionality in early childhood. J Immunotoxicol (Epub ahead of print) 13(2):173–180Google Scholar
  60. Prescott S, Saffery R (2011) The role of epigenetic dysregulation in the epidemic of allergic disease. Clin Epigenetics 2:223–232CrossRefPubMedPubMedCentralGoogle Scholar
  61. Renz H, Conrad M, Brand S, Teich R, Garn H, Pfefferle PI (2011) Allergic diseases, gene-environment interactions. Allergy 66:10–12CrossRefPubMedGoogle Scholar
  62. Robins JC, Marsit CJ, Padbury JF, Sharma SS (2011) Endocrine disruptors, environmental oxygen, epigenetics and pregnancy. Front Biosci 3:690–700Google Scholar
  63. Rocha-Amador DO, Calderón J, Carrizales L, Costilla-Salazar R, Pérez-Maldonado IN (2011) Apoptosis of peripheral blood mononuclear cells in children exposed to arsenic and fluoride. Environ Toxicol Pharmacol 32:399–405CrossRefPubMedGoogle Scholar
  64. Sathyan P, Golden HB, Miranda RC (2007) Competing interactions between micro-RNAs determine neural progenitor survival and proliferation after ethanol exposure: evidence from an ex vivo model of the fetal cerebral cortical neuroepithelium. J Neurosci 27:8546–8557CrossRefPubMedPubMedCentralGoogle Scholar
  65. Schaible TD, Harris RA, Dowd SE, Smith CW, Kellermayer R (2011) Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Hum Mol Genet 20:1687–1696CrossRefPubMedPubMedCentralGoogle Scholar
  66. Selgrade MK (2007) Immunotoxicity: the risk is real. Toxicol Sci 100:328–332CrossRefPubMedGoogle Scholar
  67. Seiler A, Oelgeschläger M, Liebsch M, Pirow R, Riebeling C, Tralau T, Luch A (2011) Developmental toxicity testing in the 21st century: the sword of Damocles shattered by embryonic stem cell assays? Arch Toxicol 85:1361–1372CrossRefPubMedGoogle Scholar
  68. Smirnova L, Hogber HT, Leist M, Hartung T (2014) Developmental neurotoxicity – challenges in the 21st century and in vitro opportunities. ALTEX 31:129–156PubMedPubMedCentralGoogle Scholar
  69. Soto-Peña GA, Luna AL, Acosta-Saavedra L, Conde P, López-Carrillo L, Cebrián ME, Vega L (2006) Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic. FASEB J 20:779–781PubMedGoogle Scholar
  70. Stølevik SB, Nygaard UC, Namork E, Haugen M, Meltzer HM, Alexander J, Granum B (2013) Prenatal exposure to polychlorinated biphenyls and dioxins from the maternal diet may be associated with immunosuppressive effects that persist into early childhood. Food Chem Toxicol 51:165–172CrossRefPubMedGoogle Scholar
  71. Tonk EC, de Groot DM, Wolterbeek AP, Penninks AH, Waalkens-Berendsen ID, Piersma AH, van Loveren H (2013) Developmental immunotoxicity of ethanol in an extended one-generation reproductive toxicity study. Arch Toxicol 87:323–335CrossRefPubMedGoogle Scholar
  72. Turner S (2012) Perinatal programming of childhood asthma: early fetal size, growth trajectory during infancy, and childhood asthma outcomes. Clin Dev Immunol 2012:962923CrossRefPubMedPubMedCentralGoogle Scholar
  73. Vahter M (2009) Effects of arsenic on maternal and fetal health. Annu Rev Nutr 29:381–399CrossRefPubMedGoogle Scholar
  74. Weng NP, Araki Y, Subedi K (2012) The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat Rev Immunol 12:306–315CrossRefPubMedPubMedCentralGoogle Scholar
  75. Wilson CB, Kollmann TR (2008) Induction of antigen-specific immunity in human neonates and infants. Nestle Nutr Workshop Ser Pediatr Program 61:183–195CrossRefPubMedGoogle Scholar
  76. Wilson CB, Rowell E, Sekimata M (2009) Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 9:91–105CrossRefPubMedGoogle Scholar
  77. Wolstenholme JT, Edwards M, Shetty SR, Gatewood JD, Taylor JA, Rissman EF, Connelly JJ (2012) Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. Endocrinology 153:3828–3838CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, Brody School of MedicineEast Carolina UniversityGreenvilleUSA
  2. 2.Department of Microbiology and ImmunologyMontana State UniversityBozemanUSA

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