The Yin and Yang of Low-Dose Radiobiology

  • Tom K. Hei
  • Hongning Zhou
  • Vladimir N. Ivanov


Two conflicting phenomena, bystander effect and adaptive response, are important in determining the biological responses at low doses of radiation and have the potential to impact the shape of the dose-response relationship. Using the Columbia University charged-particle microbeam and the highly sensitive human-hamster hybrid (AL) cells mutagenic assay, we show here that nonirradiated cells acquire mutagenesis through direct contact with cells whose nuclei have been traversed with a lethal dose of 20 alpha (α-)particles each. Pretreatment of cells with a low dose of X-rays 4 h before α-particle irradiation significantly decreased this bystander mutagenic response. Although adaptive response is largely protective in nature and the bystander response, in general, signifi es detrimental effects, the two processes share many common characteristics. There is evidence that extracellular signal-related kinase (ERK), nuclear factor-ΚB, cytokines, and mitochondrial functions play an important role in the bystander effects. However, all these signaling events are applicable to the adaptive response as well. These data suggest a common lineage between these two stress-related phenomena. A better understanding of how these two effects interact at the cellular, tissue, and organ levels will address some of the pressing issues on target size, radiation dose response, and, ultimately, low dose risk assessment.

Key words

Bystander effects Adaptive response Mitochondrial function Nuclear factor-ΚB Signaling events 


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  1. 1.
    International Commission on Radiological Protection (1990) Recommendations of the ICRP. ICRP Publication 60. Pergamon Press, Oxford, EnglandGoogle Scholar
  2. 2.
    Nagasawa H, Little J (1992) Induction of sister chromatid exchanges by extremely low doses of α-particles. Cancer Res 52:6394–6396PubMedGoogle Scholar
  3. 3.
    Zhou H, Randers-Pehrson G, Waldren CA, et al (2000) Induction of a bystander mutagenic effect of alpha particles in mammalian cells. Proc Natl Acad Sci U S A 97:2099–2104PubMedCrossRefGoogle Scholar
  4. 4.
    Belyakov OV, Malcolmson AM, Folkard M, et al (2001) Direct evidence for a bystander effect of ionizing radiation in primary human fibroblasts. Br J Cancer 84:674–679PubMedCrossRefGoogle Scholar
  5. 5.
    Olivieri G, Bodycote J, Wolff S (1984) Adaptive response of human lymphocytes to low concentrations of radioactive thymidine. Science 223:594–597PubMedCrossRefGoogle Scholar
  6. 6.
    Rigaud O, Moustacchi E (1996) Radioadaptation for gene mutation and the possible molecular mechanisms of the adaptive response (review). Mutat Res 358:127–134PubMedGoogle Scholar
  7. 7.
    Sawant SG, Randers-Pehrson G, Metting NF, et al (2001) Adaptive response and the bystander effect induced by radiation in C3H10T1/2 cells in culture. Radiat Res 156:177–180PubMedCrossRefGoogle Scholar
  8. 8.
    Iyer R, Lehnert BE (2002) Low dose, low-LET ionizing radiation-induced radioadaptation and associated early responses in unirradiated cells. Mutat Res 503:1–9PubMedGoogle Scholar
  9. 9.
    Iyer R, Lehnert BE (2002) Alpha-particle-induced increases in the radioresistance of normal human bystander cells. Radiat Res 157:3–7PubMedCrossRefGoogle Scholar
  10. 10.
    Waldren CA, Jones C, Puck TT (1979) Measurement of mutagenesis in mammalian cells. Proc Natl Acad Sci U S A 76:1358–1362PubMedCrossRefGoogle Scholar
  11. 11.
    Hei TK, Waldren CA, Hall EJ (1988) Mutation induction and relative biological effectiveness of neutrons in mammalian cells. Radiat Res 115:281–291PubMedCrossRefGoogle Scholar
  12. 12.
    Zhou H, Randers-Pehrson G, Geard CR, et al (2003) Interaction between radiation induced adaptive response and bystander mutagenesis in mammalian cells. Radiat Res 160:512–516PubMedCrossRefGoogle Scholar
  13. 13.
    Wang X, Ohnishi T (1997) p53 dependent signal transduction induced by stress. J Radiat Res 38:179–194PubMedCrossRefGoogle Scholar
  14. 14.
    Boothman DA, Meyers M, Odegaard E, et al (1996) Altered G1 checkpoint control determines adaptive responses to ionizing radiation. Mutat Res 358:143–154PubMedGoogle Scholar
  15. 15.
    Kadhim MA, Moore SR, Goodwin EH (2004) Interrelationships amongst radiation induced genomic instability, bystander effects and the adaptive response. Mutat Res 568:21–32PubMedGoogle Scholar
  16. 16.
    Matsumoto H, Hamada N, Takahashi A, et al (2007) Vanguards of paradigm shift in radiation biology: radiation induced adaptive and bystander responses. J Radiat Res 48:97–106PubMedCrossRefGoogle Scholar
  17. 17.
    Yang H, Asaad N, Held KD (2005) Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts. Oncogene 24:2096–2103PubMedCrossRefGoogle Scholar
  18. 18.
    Lyng FM, Maquire P, McClean B, et al (2006) The involvement of calcium and MAP kinase signaling pathways in the production of radiation induced bystander effects. Radiat Res 165:400–409PubMedCrossRefGoogle Scholar
  19. 19.
    Zhou H, Ivanov HN, Lien YC, et al (2008) Mitochondrial function and NF-ΚB mediated signaling in radiation induced bystander effects. Cancer Res 68:2233–2240PubMedCrossRefGoogle Scholar
  20. 20.
    Matsumoto H, Hayashi S, Hatashita M, et al (2001) Induction of radio-resistance by a nitric oxide mediated bystander effect. Radiat Res 155:387–396PubMedCrossRefGoogle Scholar
  21. 21.
    Zhou H, Ivanov VN, Gillespie J, et al (2005) Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway. Proc Natl Acad Sci U S A 41:14641–14646CrossRefGoogle Scholar
  22. 22.
    Shimizu T, Kato T Jr, Tachibana A, et al (1999) Coordinated regulation of radioadaptive response by protein kinase C and p38 mitogen activated protein kinase. Exp Cell Res 251:424–432PubMedCrossRefGoogle Scholar
  23. 23.
    Azzam EI, DeToledo SM, Spitz DR, et al (2002) Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha particle irradiated normal human fi broblast cultures. Cancer Res 62:5426–5442Google Scholar
  24. 24.
    Ahmed KM, Li JJ (2008) NF-?B mediated adaptive resistance to ionizing radiation. Free Radic Biol Med 44:1–13PubMedCrossRefGoogle Scholar
  25. 25.
    Fan M, Ahmed KM, Coleman MC, et al (2007) NF?B and MnSOD mediate adaptive radioresistance in low dose irradiated mouse skin epithelial cells. Cancer Res 67:3220–3228PubMedCrossRefGoogle Scholar
  26. 26.
    Cong XL, Wang XL, Su Q, et al (1998) Protective effects of extracted human liver RNA, a known interferon inducer, against radiation induced cytogenetic damage in male mice. Toxicol Lett 95:189–198CrossRefGoogle Scholar
  27. 27.
    Coates PJ, Lorimore SA, Wright EG (2004) Damaging and protective cell signaling in the untargeted effects of ionizing radiation. Mutat Res 568:5–20PubMedGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Tom K. Hei
    • 1
    • 2
  • Hongning Zhou
    • 1
    • 2
  • Vladimir N. Ivanov
    • 2
  1. 1.Center for Radiological Research, College of Physicians and SurgeonsColumbia
  2. 2.Department of Environmental Health Sciences, Mailman School of Public HealthColumbia

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