Skip to main content

Advertisement

SpringerLink
Log in

Dose-dependent synergistic and antagonistic mutation responses of binary mixtures of the environmental carcinogen benzo[a]pyrene with food-derived carcinogens

  • Regulatory Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Cooking food at high temperatures produces genotoxic chemicals and there is concern about their impact on human health. DNA damage caused by individual chemicals has been investigated but few studies have examined the consequences of exposure to mixtures as found in food. The current study examined the mutagenic response to binary mixtures of benzo[a]pyrene (BaP) with glycidamide (GA), BaP with acrylamide (AC), or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with GA at human-relevant concentrations (sub-nM). The metabolically competent human MCL-5 cells were exposed to these chemicals individually or in mixtures and mutagenicity was assessed at the thymidine kinase (TK) locus. Mixture exposures gave dose–responses that differed from those for the individual chemicals; for the BaP-containing mixtures, an increased mutation frequency (MF) at low concentration combinations that were not mutagenic individually, and decreased MF at higher concentration combinations, compared to the calculated predicted additive MF of the individual chemicals. In contrast, the mixture of PhIP with GA did not increase MF above background levels. These data suggest BaP is driving the mutation response and that metabolic activation plays a role; in mixtures with BaP the increased/decreased MF above/below the expected additive MF the order is PhIP > AC > GA. The increase in MF at some low concentration combinations that include BaP is interesting and supports our previous work showing a similar response for BaP with PhIP, confirming this response is not limited to the BaP/PhIP combination. Moreover, the lack of a mutation response for PhIP with GA relative to the response of the individual chemicals at equivalent doses is interesting and may represent a potential avenue for reducing the risk of exposure to environmental carcinogens; specifically, removal of BaP from the mixture may reduce the mutation effect, although in the context of food this would be significantly challenging.

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

References

  • Abendroth JA, Blankenship EE, Martin AR, Roeth FW (2011) Joint action analysis utilizing concentration addition and independent action models. Weed Technol 25(3):436–446. https://doi.org/10.1614/Wt-D-10-00102.1

    Article  CAS  Google Scholar 

  • Berenbaum MC (1989) What is synergy? Pharmacol Rev 41(2):93–141

    CAS  PubMed  Google Scholar 

  • Busby WF, Penman BW, Crespi CL (1994) Human cell mutagenicity of mono-and dinitropyrenes in metabolically competent MCL-5 cells. Mut Res Genetic Toxicol 322(4):233–242

    Article  CAS  Google Scholar 

  • Chou T-C (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58(3):621–681

    Article  CAS  Google Scholar 

  • Clements J (2000) The mouse lymphoma assay. Mutat Res-Fund Mol M 455(1–2):97–110

    Article  CAS  Google Scholar 

  • Cooper C, Grover P (1990) Chemical carcinogenesis and mutagenesis. Springer, Berlin

    Google Scholar 

  • Crespi CL, Gonzalez FJ, Steimel DT et al (1991) A metabolically competent human cell line expressing five cDNAs encoding procarcinogen-activating enzymes: application to mutagenicity testing. Chem Res Toxicol 4(5):566–572

    Article  CAS  Google Scholar 

  • Danesi CC, Dihl RR, Bellagamba BC et al (2012) Genotoxicity testing of combined treatment with cisplatin, bleomycin, and 5-fluorouracil in somatic cells of Drosophila melanogaster. Mutat Res 747(2):228–233. https://doi.org/10.1016/j.mrgentox.2012.05.009

    Article  CAS  PubMed  Google Scholar 

  • David R, Ebbels T, Gooderham N (2016) Synergistic and antagonistic mutation responses of human MCL-5 cells to mixtures of benzo [a] pyrene and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine: dose-related variation in the joint effects of common dietary carcinogens. Environ Health Perspect 124(1):88

    CAS  PubMed  Google Scholar 

  • Doerge DR, Young JF, McDaniel LP, Twaddle NC, Churchwell MI (2005) Toxicokinetics of acrylamide and glycidamide in B6C3F1 mice. Toxicol Appl Pharmacol 202(3):258–267

    Article  CAS  Google Scholar 

  • EFSA (European Food Safety Authority) (2005) Statement on summary report on Acrylamide in food of the 64th meeting of the joint FAO/WHO expert committee on food additives by the Scientific Panel on contaminants in the food chain (CONTAM). EFSA J 3(4):619

    Article  Google Scholar 

  • Felton JS, Knize MG, Salmon CP, Malfatti MA, Kulp KS (2002) Human exposure to heterocyclic amine food mutagens/carcinogens: relevance to breast cancer. Environ Mol Mutagen 39(2-3):112–118

    Article  CAS  Google Scholar 

  • IARC (International Agency for Research on Cancer) (1994) Some Industrial Chemicals. IARC Monogr Eval Carcinog Risk Hum 60

    Google Scholar 

  • IARC (International Agency for Research on Cancer) (2010) Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures. IARC Monogr Eval Carcinog Risk Hum 92

  • Ito N, Hasegawa R, Sano M et al (1991) A new colon and mammary carcinogen in cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis 12(8):1503–1506

    Article  CAS  Google Scholar 

  • Jamin EL, Riu A, Douki T et al (2013) Combined genotoxic effects of a polycyclic aromatic hydrocarbon (B (a) P) and an heterocyclic amine (PhIP) in relation to colorectal carcinogenesis. PLoS One 8(3):e58591

    Article  CAS  Google Scholar 

  • Johnson GE, Quick EL, Parry EM, Parry JM (2010) Metabolic influences for mutation induction curves after exposure to Sudan-1 and para red. Mutagenesis 25(4):327–333

    Article  CAS  Google Scholar 

  • Knize MG, Kulp KS, Salmon CP, Keating GA, Felton JS (2002) Factors affecting human heterocyclic amine intake and the metabolism of PhIP. Mutat Res 506–507, 153–162

  • Koyama N, Sakamoto H, Sakuraba M et al (2006) Genotoxicity of acrylamide and glycidamide in human lymphoblastoid TK6 cells. Mut Res Genetic Toxicol Environ Mutagen 603(2):151–158

    Article  CAS  Google Scholar 

  • Koyama N, Yasui M, Oda Y et al (2011) Genotoxicity of acrylamide in vitro: acrylamide is not metabolically activated in standard in vitro systems. Environ Mol Mutagen 52(1):11–19. https://doi.org/10.1002/em.20560

    Article  CAS  PubMed  Google Scholar 

  • Lijinski W, Shubik P (1964) Benzoapyrene and other polynuclear hydrocarbons in charcoal-broiled meat. Science 145:53–55

    Article  Google Scholar 

  • Mason D, Benford D (2007) Nutrition and health: current topics 6–7. Nat Bull 33:153–154

    Google Scholar 

  • Murray S, Lynch AM, Knize MG, Gooderham MJ (1993) Quantification of the carcinogens 2-amino-3,8-dimethyl- and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in food using a combined assay based on gas chromatography-negative ion mass spectrometry. J Chromatogr 616(2):211–219

    Article  CAS  Google Scholar 

  • OECD (Organisation for Economic Co-operation and Development) (1997) Test No. 476: In vitro mammalian cell gene mutation test. In: OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris, France

  • Rajapakse N, Ong D, Kortenkamp A (2001) Defining the Impact of Weakly Estrogenic Chemicals on the Action of Steroidal Estrogens. Toxicol Sci 60(2):296–304

    Article  CAS  Google Scholar 

  • Rice JM (2005) The carcinogenicity of acrylamide. Mutat Res 580(1–2):3–20. https://doi.org/10.1016/j.mrgentox.2004.09.008

    Article  CAS  PubMed  Google Scholar 

  • Schlesinger RB, Zelikoff JT, Chen LC, Kinney PL (1992) Assessment of toxicologic interactions resulting from acute inhalation exposure to sulfuric acid and ozone mixtures. Toxicol Appl Pharmacol 115(2):183–190

    Article  CAS  Google Scholar 

  • Sen A, Ozgun O, Arinc E, Arslan S (2012) Diverse action of acrylamide on cytochrome P450 and glutathione S-transferase isozyme activities, mRNA levels and protein levels in human hepatocarcinoma cells. Cell Biol Toxicol 28(3):175–186. https://doi.org/10.1007/s10565-012-9214-1

    Article  CAS  PubMed  Google Scholar 

  • Sinha R, Kulldorff M, Gunter MJ, Strickland P, Rothman N (2005) Dietary benzo[a]pyrene intake and risk of colorectal adenoma. Cancer Epidemiol Biomarkers Prev 14(8):2030–2034. https://doi.org/10.1158/1055-9965.EPI-04-0854

    Article  CAS  PubMed  Google Scholar 

  • Sugimura T (1997) Overview of carcinogenic heterocyclic amines. Mut Res Fund Mol Mech Mutagen 376(1–2):211–219

    Article  CAS  Google Scholar 

  • Tornqvist M (2005) Acrylamide in food: the discovery and its implications: a historical perspective. Adv Exp Biol Med 561:1–19

    Article  Google Scholar 

  • Yadollahi-Farsani M, Gooderham NJ, Davies DS, Boobis AR (1996) Mutational spectra of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) at the Chinese hamsters hprt locus. Carcinogenesis 17:617–624

    Article  CAS  Google Scholar 

  • Zhao K, Murray S, Davies DS, Boobis AR, Gooderham NJ (1994) Metabolism of the food derived mutagen and carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) by human liver microsomes. Carcinogenesis 15(6):1285–1288

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Food Standards Agency UK (T01052).

Funding

Grant: Food Standards Agency UK—T01052.

Author information

Author notes

  1. Rhiannon M. David

    Present address: Genetic Toxicology, MSAS, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK

Authors and Affiliations

  1. Computational and Systems Medicine, Imperial College London, London, UK

    Rhiannon M. David & Nigel J. Gooderham

Authors
  1. Rhiannon M. David
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nigel J. Gooderham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rhiannon M. David.

Ethics declarations

Conflict of interest

The authors disclose no potential conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

David, R.M., Gooderham, N.J. Dose-dependent synergistic and antagonistic mutation responses of binary mixtures of the environmental carcinogen benzo[a]pyrene with food-derived carcinogens. Arch Toxicol 92, 3459–3469 (2018). https://doi.org/10.1007/s00204-018-2319-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-018-2319-4

Keywords

Search

Navigation