Skip to main content
Log in

Radiation-induced bystander effects in the Atlantic salmon (salmo salar L.) following mixed exposure to copper and aluminum combined with low-dose gamma radiation

  • Original Paper
  • Published:
Radiation and Environmental Biophysics Aims and scope Submit manuscript

An Erratum to this article was published on 13 February 2014

Abstract

Very little is known about the combined effects of low doses of heavy metals and radiation. However, such “multiple stressor” exposure is the reality in the environment. In the work reported in this paper, fish were exposed to cobalt 60 gamma irradiation with or without copper or aluminum in the water. Doses of radiation ranged from 4 to 75 mGy delivered over 48 or 6 h. Copper doses ranged from 10 to 80 μg/L for the same time period. The aluminum dose was 250 μg/L. Gills and skin were removed from the fish after exposure and explanted in tissue culture flasks for investigation of bystander effects of the exposures using a stress signal reporter assay, which has been demonstrated to be a sensitive indicator of homeostatic perturbations in cells. The results show complex synergistic interactions of radiation and copper. Gills on the whole produce more toxic bystander signals than skin, but the additivity scores show highly variable results which depend on dose and time of exposure. The impacts of low doses of copper and low doses of radiation are greater than additive, medium levels of copper alone have a similar level of effect of bystander signal toxicity to the low dose. The addition of radiation stress, however, produces clear protective effects in the reporters treated with skin-derived medium. Gill-derived medium from the same fish did not show protective effects. Radiation exposure in the presence of 80 μg/L led to highly variable results, which due to animal variation were not significantly different from the effect of copper alone. The results are stressor type, stressor concentration and time dependent. Clearly co-exposure to radiation and heavy metals does not always lead to simple additive effects.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Abramowitz J, Birnbaumer L (2009) Physiology of pathophysiology of canonical transient receptor potential channels. FASEB J 23:297–328

    Article  Google Scholar 

  • Abumrad N, Harmon C, Ibrahimi A (1998) Membrane transport of long-chain fatty acids: evidence for a facilitated process. J Lipid Res 39:2309–2318

    Google Scholar 

  • Anbar M (1963) Possible role of copper ions in radio-biological damage. Nature 200:376

    Article  ADS  Google Scholar 

  • Asur R, Balasubramaniam M, Marples B, Thomas RA, Tucker JD (2010a) Involvement of MAPK proteins in bystander effects induced by chemicals and ionizing radiation. Mutat Res 686:15–29

    Article  Google Scholar 

  • Asur R, Balasubrmaniam M, Marples B, Thomas RA, Tucker JD (2010b) Bystander effects induced by chemicals and ionizing radiation: evaluation of changes in gene expression of downstream MAPK targets. Mutagenesis 25:271–279

    Article  Google Scholar 

  • Asur RS, Sharma S, Chang CW, Penagaricano J, Kommuru IM, Morosm EG, Corry PM, Griffin RJ (2012) Spatially fractionated radiation induces cytotoxicity and changes in gene expression in bystander and radiation adjacent murine carcinoma cells. Radiat Res 177:751–765

    Article  Google Scholar 

  • Babu TS, Akhtar TA, Lampi MA, Tripuranthakam S, Dixon DG, Greenberg BM (2003) Similar stress responses are elicited by copper and ultraviolet radiation in the aquatic plant Lemna gibba: implication of reactive oxygen species as common signals. Plant Cell Physiol 44:1320–1329

    Article  Google Scholar 

  • Bacq ZM, Herve A (1953) Radioprotective action of copper antagonists (chelating agents). Arch Int Physiol 61:433–434

    Article  Google Scholar 

  • Barjhoux I, Baudrimont M, Morin B, Landi L, Gonzalez P, Cachot J (2012) Effects of copper and cadmium spiked-sediments on embryonic development of Japanese medaka (Oryzias latipes). Ecotoxicol Environ Saf 79:272–282

    Article  Google Scholar 

  • Bassi DE, Fu J, Lopez de Cicco R, Klein-Szanto AJ (2005) Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol Carcinog 44:151–161

    Article  Google Scholar 

  • Bergendi L, Krätsmár-Smogrovic J, Duracková Z, Zitnanova I (1991) The superoxide dismutase-like activity of some copper (II) complexes derived from tridentate Schiff bases. Free Radic Res Commun 12–13:195–204

    Article  Google Scholar 

  • Bréchignac F, Bradshaw C, Carroll S, Fuma S, Håkanson L, Jaworska A, Kapustka L, Kawaguchi I, Monte L, Oughton D, Sazykina T, Strand P (2012) Towards an ecosystem approach for environment protection with emphasis on radiological hazards. IUR, Report 7

    Google Scholar 

  • Cai L, Cherian MG (1996) Adaptive response to ionizing radiation-induced chromosome aberrations in rabbit lymphocytes: effect of pre-exposure to zinc, and copper salts. Mutat Res 369:233–241

    Article  Google Scholar 

  • Cai I, Koropatnick J, Cherian MG (2001) Roles of vitamin C in radiation-induced DNA damage in presence and absence of copper. Chem Biol Interact 137:75–88

    Article  Google Scholar 

  • Calabrese EJ, Baldwin LA (2003) The hormetic dose-response model is more common than the threshold model in toxicology. Toxicol Sci 71:246–250

    Article  Google Scholar 

  • Chiu SJ, Lee MY, Chou WG, Lin LY (2003) Germanium oxide enhances the radiosensitivity of cells. Radiat Res 159:391–400

    Article  Google Scholar 

  • Coen N, Mothersill C, Kadhim M, Wright EG (2001) Heavy metals of relevance to human health induce genomic instability. J Pathol 195:293–299

    Article  Google Scholar 

  • Coen N, Kadhim MA, Wright EG, Case CP, Mothersill CE (2003) Particulate debris from a titanium metal prosthesis induces genomic instability in primary human fibroblast cells. Br J Cancer 88:548–552

    Article  Google Scholar 

  • Copplestone D, Hingston J, Real A (2008) The development and purpose of the FREDERICA radiation effects database. J Environ Radioact 99:1456–1463

    Article  Google Scholar 

  • Dauer LT, Brooks AL, Hoel DG, Morgan WF, Stram D, Tran P (2010) Review and evaluation of updated research on the health effects associated with low-dose ionising radiation. Radiat Prot Dosimetry 140:103–136

    Article  Google Scholar 

  • Ermakov AV, Kon’kova MS, Kostiuk SV, Veĭko NN (2011) DNA-signaling pathway mediating development of a radiation-induced bystander effect in human cells. Radiats Biol Radioecol 51:651–659

    Google Scholar 

  • Figgitt M, Newson R, Leslie IJ, Fisher J, Ingham E, Case CP (2010) The genotoxicity of physiological concentrations of chromium (Cr(III) and Cr(VI)) and cobalt (Co(II)): an in vitro study. Mutat Res 688:53–61

    Article  Google Scholar 

  • Garcia CR, Angelé-Martinez C, Wilkes JA, Wang HC, Battin EE, Brumaghim JL (2012) Prevention of iron- and copper-mediated DNA damage by catecholamine and amino acid neurotransmitters, l-DOPA, and curcumin: metal binding as a general antioxidant mechanism. Dalton Trans 41:6458–6467

    Article  Google Scholar 

  • Garnier-Laplace J, Copplestone D, Gilbin R, Alonzo F, Ciffroy P, Gilek M, Agüero A, Björk M, Oughton DH, Jaworska A, Larsson CM (2008) Issues and practices in the use of effects data from FREDERICA in the ERICA Integrated Approach. J Environ Radioact 99:1474–1483

    Article  Google Scholar 

  • George AM, Sabovljev SA, Hart LE, Cramp WA, Harris G, Hornsey S (1987) DNA quaternary structure in the radiation sensitivity of human lymphocytes–a proposed role of copper. Br J Cancer Suppl 8:141–144

    Google Scholar 

  • Glaviano A, Nayak V, Cabuy E, Baird DM, Yin Z, Newson R, Ladon D, Rubio MA, Slijepcevic P, Lyng F, Mothersill C, Case CP (2006) Effects of hTERT on metal-ion induced genomic instability. Oncogene 25:3424–3435

    Article  Google Scholar 

  • Glaviano A, Mothersill C, Case CP, Rubio MA, Newson R, Lyng F (2009) Effects of hTERT on genomic instability caused by either metal or radiation or combined exposure. Mutagenesis 24:25–33

    Article  Google Scholar 

  • Godon C, Coullet S, Baus B, Alonso B, Davin AH, Delcuze Y, Marchetti C, Hainaut P, Kazmaier M, Quemeneur E (2005) Quantitation of p53 nuclear relocation in response to stress using a yeast functional assay: effects of irradiation and modulation by heavy metal ions. Oncogene 24:6459–6464

    Google Scholar 

  • Grygoryev D, Moskalenko O, Zimbrick JD (2008) Non-linear effects in the formation of DNA damage in medaka fish fibroblast cells caused by combined action of cadmium and ionizing radiation. Dose Response 6:283–298

    Article  Google Scholar 

  • Hadi N, Malik A, Azam S, Khan NU, Iqbal J (2002) Serotonin-Cu(II)-mediated DNA cleavage: mechanism of copper binding by serotonin. Toxicol In Vitro 16:669–674

    Article  Google Scholar 

  • Hamada N, Maeda M, Otsuka K, Tomita M (2011) Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects. Curr Mol Pharmacol 4:79–95

    Article  Google Scholar 

  • Handy RD (2003) Chronic effects of copper exposure versus endocrine toxicity: two sides of the same toxicological process? Comp Biochem Physiol A: Mol Integr Physiol 135:25–38

    Article  Google Scholar 

  • He M, Ye S, Ren R, Dong C, Xie Y, Yuan D, Shao C (2012) Cytochrome-c mediated a bystander response dependent on inducible nitric oxide synthase in irradiated hepatoma cells. Br J Cancer 106:889–895

    Article  Google Scholar 

  • Heier LS, Teien HC, Oughton D, Tollefsen KE, Olsvik PA, Rossel BO, Lind OC, Farmen E, Skipperud L, Salbu B (2013) Sublethal effects in Atlantic salmon (Salmo salar) exposed to mixtures of copper, aluminum and gamma radiation. J Environ Radioact 121:33–42

    Article  Google Scholar 

  • Held KD, Sylvester FC, Hopcia KL, Biaglow JE (1996) Role of Fenton chemistry in thiol-induced toxicity and apoptosis. Radiat Res 145:542–553

    Article  Google Scholar 

  • Hoyes KP, Lord BI, McCann C, Hendry JH, Morris ID (2001) Transgenerational effects of preconception paternal contamination with (55) Fe. Radiat Res 156:488–494

    Article  Google Scholar 

  • International Commission on Radiation Protection (2009) Environmental Protection: the Concept and Use of Reference Animals and Plants. ICRP Publication 108:38–330

    Google Scholar 

  • Jagetia GC, Ganapathi NG (1990) Effect of copper glycinate on the radiation induced micronuclei formation in mice bone marrow. Radiat Environ Biophys 29:115–118

    Article  Google Scholar 

  • Jones C, Gilek M (2004) Overview of programmes for the assessment of risks to the environment from ionising radiation and hazardous chemicals. J Radiol Prot 24(4A): A157–177

    Google Scholar 

  • Keegan GM, Learmonth ID, Case CP (2008) A system comparison of the actual, potential, and theoretical health effects of cobalt and chromium exposures from industry and surgical implants. Crit Rev Toxicol 38:645–674

    Article  Google Scholar 

  • Khan NA, Poisson JP (1999) 5-HT3 receptor-channels coupled with Na + influx in human T cells: role in T cell activation. J Neuroimmunol 99:53–60

    Article  Google Scholar 

  • Lauren DJ, Mcdonald DG (1987) Acclimation to Copper by rainbow trout (Salmo gairdneri)- Physiology. Can J Fish Aquat Sci 44:99–104

    Article  Google Scholar 

  • Law JM, Bull M, Nakamura J, Swenberg JA (1998) Molecular dosimetry of DNA adducts in the medaka small fish model. Carcinogenesis 19:515–518

    Article  Google Scholar 

  • Little EE, Calfee RD, Theodorakos P, Brown ZA, Johnson CA (2007) Toxicity of cobalt-complexed cyanide to Oncorhynchus mykiss, Daphnia magna, and Ceriodaphnia dubia. Potentiation by ultraviolet radiation and attenuation by dissolved organic carbon and adaptive UV tolerance. Environ Sci Pollut Res Int 14:333–337

    Article  Google Scholar 

  • Liu Z, Mothersill CE, McNeill FE, Lyng FM, Byun SH, Seymour CB, Prestwich WV (2006) A dose threshold for a medium transfer bystander effect for a human skin cell line. Radiat Res 166:19–23

    Article  Google Scholar 

  • Lord BI (1999) Transgenerational susceptibility to leukaemia induction resulting from preconception, paternal irradiation. Int J Radiat Biol 75:801–810

    Article  Google Scholar 

  • Lord BI, Woolford LB, Wang L, Stones VA, McDonald D, Lorimore SA, Papworth D, Wright EG, Scott D (1998) Tumour induction by methyl-nitroso-urea following preconceptional paternal contamination with plutonium-239. Br J Cancer 78:301–311

    Article  Google Scholar 

  • Lyng FM, Seymour CB, Mothersill C (2002a) Early events in the apoptotic cascade initiated in cells treated with medium from the progeny of irradiated cells. Radiat Res 153:508–511

    Google Scholar 

  • Lyng FM, Seymour CB, Mothersill C (2002b) Initiation of apoptosis in cells exposed to medium from the progeny of irradiated cells: a possible mechanism for bystander-induced genomic instability? Radiat Res 157:365–370

    Article  Google Scholar 

  • Lyng FM, Maguire P, McClean B, Seymour C, Mothersill C (2006) The involvement of calcium and MAP kinase signaling pathways in the production of radiation-induced bystander effects. Radiat Res 165:400–409

    Article  Google Scholar 

  • Maguire P, Mothersill C, Seymour C, Lyng FM (2005) Medium from irradiated cells induces dose-dependent mitochondrial changes and BCL2 responses in unirradiated human keratinocytes. Radiat Res 163:384–390

    Article  Google Scholar 

  • Mason RP (1993) Membrane interaction of calcium channel antagonists modulated by cholesterol. Implications for drug activity. Biochem Pharmacol 45:2173–2183

    Article  Google Scholar 

  • McGeer JC, Szebedinszky C, McDonald DG, Wood CM (2000) Effects of chronic sublethal exposure to waterborne Cu, Cd or Zn in rainbow trout. 1: iono-regulatory disturbance and metabolic costs. Aquat Toxicol 50:231–243

    Article  Google Scholar 

  • Miller AC, McClain D (2007) A review of depleted uranium biological effects: in vitro and in vivo studies. Rev Environ Health 22:75–89

    Article  Google Scholar 

  • Miller AC, Bonait-Pellie C, Merlot RF, Michel J, Stewart M, Lison PD (2005) Leukemic transformation of hematopoietic cells in mice internally exposed to depleted uranium. Mol Cell Biochem 279:97–104

    Article  Google Scholar 

  • Miller AC, Stewart M, Rivas R (2009) DNA methylation during depleted uranium-induced leukemia. Biochimie 91:1328–1330

    Article  Google Scholar 

  • Mothersill C, Seymour CB (2004) Radiation-induced bystander effects—implications for cancer. Nat Rev Cancer 4:158–164

    Article  Google Scholar 

  • Mothersill C, Seymour CB (2006) Actions of radiation on living cells in the “post-bystander” era. EXS 96:159–177

    Google Scholar 

  • Mothersill C, Seymour C (2009) Communication of ionising radiation signals–a tale of two fish. Int J Radiat Biol 85:909–919

    Article  Google Scholar 

  • Mothersill C, Seymour C (2012a) Are epigenetic mechanisms involved in radiation-induced bystander effects? Front Genet 3:74–80

    Article  Google Scholar 

  • Mothersill C, Seymour C (2012b) Changing paradigms in radiobiology. Mutat Res 750:85–95

    Article  Google Scholar 

  • Mothersill C, Moran G, McNeill F, Gow MD, Denbeigh J, Prestwich W, Seymour CB (2007a) A role for bioelectric effects in the induction of bystander signals by ionizing radiation? Dose Response 5:214–429

    Article  Google Scholar 

  • Mothersill C, Mosse I, Seymour C (2007b) Multiple stressors: a challenge for the future. Springer, Dordrecht

    Book  Google Scholar 

  • Mothersill C, Salbu B, Heier LS, Teien HC, Denbeigh J, Oughton D, Rosseland BO, Seymour CB (2007c) Multiple stressor effects of radiation and metals in salmon (Salmo salar). J Environ Radioact 96:20–31

    Article  Google Scholar 

  • Mourot A, Bamberg E, Rettinger J (2008) Agonist- and competitive antagonist- induced movement of loop 5 of the alpha subunit of the neuronal alpha4beta4 nicotinic acetylcholine receptor. J Neurochem 105:413–424

    Article  Google Scholar 

  • Muqbil I, Beck FW, Bao B, Sarkar FH, Mohammad RM, Hadi SM, Azmi AS (2012) Old wine in a new bottle: the Warburg effect and anticancer mechanisms of resveratrol. Curr Pharm Des 18:1645–1654

    Article  Google Scholar 

  • Niyogi S, Wood CM (2004) Biotic ligand model, a flexible tool for developing site-specific water quality guidelines for metals. Environ Sci Tech 38:6177–6192

    Article  Google Scholar 

  • Norwood WP, Borgmann U, Dixon DG, Wallace A (2003) Effects of metal mixtures on aquatic biota: a review of observations and methods. Hum Ecol Risk Assess 9:795–811

    Article  Google Scholar 

  • Olsvik PA, Heier LS, Rosseland BO, Teien HC, Salbu B (2010) Effects of combined gamma-irradiation and metal (Al + Cd) exposures in Atlantic salmon (Salmo salar L.). J Environ Radioact 101:230–236

    Article  Google Scholar 

  • Pirisi L, Creek KE, Doniger J, DiPaolo JA (1988) Continuous cell lines with altered growth and differentiation properties originate after transfection of human keratinocytes with human papillomavirus type 16 DNA. Carcinogenesis 9:1573–1579

    Article  Google Scholar 

  • Poon RC, Agnihotri N, Seymour C, Mothersill C (2007) Bystander effects of ionizing radiation can be modulated by signaling amines. Environ Res 105:200–211

    Article  Google Scholar 

  • Puck TT, Marcus PI (1956) Action of x-rays on mammalian cells. J Exp Med 103:653–666

    Article  Google Scholar 

  • Real A, Sundell-Bergman S, Knowles JF, Woodhead DS, Zinger I (2004) Effects of ionising radiation exposure on plants, fish and mammals: relevant data for environmental radiation protection. J Radiol Prot 24(4A):123–137

    Google Scholar 

  • Rothkamm K, Löbrich M (2003) Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci USA 100:5057–5062

    Article  ADS  Google Scholar 

  • Sabita Majumdar S, Chatterjee J, Chaudhuri K (1999) Ultrastructural and trace metal studies on radiographers’ hair and nails. Biol Trace Elem Res 67:127–138

    Article  Google Scholar 

  • Salbu B, Rosseland BA, Oughton DH (2005) Multiple stressors: a challenge for the future. J Environ Monit 7:539

    Article  Google Scholar 

  • Salbu B, Denbeigh J, Smith RW, Heier LS, Teien HC, Rosseland BO, Oughton D, Seymour CB, Mothersill C (2008) Environmentally relevant mixed exposures to radiation and heavy metals induce measurable stress responses in Atlantic salmon. Environ Sci Technol 42:3441–3446

    Article  ADS  Google Scholar 

  • Saroya R, Smith R, Seymour C, Mothersill C (2009) Injection of resperpine into zebrafish, prevents fish to fish communication of radiation-induced bystander signals: confirmation in vivo of a role for serotonin in the mechanism. Dose Response 8:317–330

    Article  Google Scholar 

  • Schettino G, Folkard M, Michael BD, Prise KM (2005) Low-dose binary behaviour of bystander cell killing after microbeam irradiation of a single cell with focused c(k) x rays. Radiat Res 163:332–336

    Article  Google Scholar 

  • Seymour CB, Mothersill C (2000) Relative contribution of bystander and targeted cell killing to the low-dose region of the radiation dose-response curve. Radiat Res 153:508–511

    Article  Google Scholar 

  • Shao C, Lyng FM, Folkard M, Prise KM (2006) Calcium fluxes modulate the radiation-induced bystander responses in targeted glioma and fibroblast cells. Radiat Res 163:479–487

    Article  Google Scholar 

  • Sparrow AH, Miksche JP (1961) Correlation of nuclear volume and DNA [deoxyribonucleic acid] content with higher plant tolerance to chronic radiation. Science 134:282–298

    Article  ADS  Google Scholar 

  • Spitzner M, Ousingsawat J, Scheidt K, Kunzelmann K, Schreiber R (2007) Voltage-gated K + channels support proliferation of colonic carcinoma cells. FASEB J 21:35–44

    Article  Google Scholar 

  • Suzuki K, Yamashita S (2012) Low-dose radiation exposure and carcinogenesis. Jpn J Clin Oncol 42:563–568

    Article  Google Scholar 

  • Tilton SC, Foran CM, Benson WH (2003) Effects of cadmium on the reproductive axis of Japanese medaka (Oryzias latipes). Comp Biochem Physiol C: Toxicol Pharmacol 136:265–276

    Google Scholar 

  • Turcu G (1973) Radiobiology of irradiated leukocytes. VI. Respiratory Capacity, Proteolytic Activity and the Level of Microelements. Biophysik 10:293–298

    Article  Google Scholar 

  • Ubels JL, Van Dyken RE, Louters JR, Schotanus MP, Haarsma LD (2011) Potassium ion fluxes in corneal epithelial cells exposed to UVB. Exp Eye Res 92:425–431

    Article  Google Scholar 

  • Ulsh BA (2010) Checking the foundation: recent radiobiology and the linear no-threshold theory. Health Phys 99:747–758

    Article  Google Scholar 

  • Weiss JF, Kumar KS, Walden TL, Neta R, Landauer MR, Clark EP (1990) Advances in radioprotection through the use of combined agent regiments. Int J Radiat Biol 57:709–722

    Article  Google Scholar 

  • Whicker FW, Schultz V (1982) Radioecology: Nuclear energy and the environment. CRC Press, Boca Raton

    Google Scholar 

  • Wise SS, Wise JP Sr (2012) Chromium and genomic stability. Mutat Res 733:78–82

    Article  Google Scholar 

  • Woo S, Yum S, Jung JH, Shim WJ, Lee CH, Lee TK (2006) Heavy metal-induced differential gene expression of metallothionein in Javanese medaka, Oryzias javanicus. Mar Biotechnol 8:654–662

    Article  Google Scholar 

  • Yang H, Magpayo N, Held KD (2011) Targeted and non-targeted effects from combinations of low doses of energetic protons and iron ions in human fibroblasts. Int J Radiat Biol 87:311–319

    Article  Google Scholar 

Download references

Acknowledgments

This work was funded by the Natural Science and Engineering Research Council of Canada andby the Canada Research Council Chairs Program.

Conflict of interest

The authors report no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carmel Mothersill.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mothersill, C., Smith, R.W., Heier, L.S. et al. Radiation-induced bystander effects in the Atlantic salmon (salmo salar L.) following mixed exposure to copper and aluminum combined with low-dose gamma radiation. Radiat Environ Biophys 53, 103–114 (2014). https://doi.org/10.1007/s00411-013-0505-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00411-013-0505-6

Keywords

Navigation