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Quantum dot-induced epigenetic and genotoxic changes in human breast cancer cells

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Abstract

The staggering array of nanotechnological products, found in our environment and those applicable in medicine, has stimulated a growing interest in examining their long-term impact on genetic and epigenetic processes. We examined here the epigenomic and genotoxic response to cadmium telluride quantum dots (QDs) in human breast carcinoma cells. QD treatment induced global hypoacetylation implying a global epigenomic response. The ubiquitous responder to genotoxic stress, p53, was activated by QD challenge resulting in translocation of p53, with subsequent upregulation of downstream targets Puma and Noxa. Consequential decrease in cell viability was in part prevented by the p53 inhibitor pifithrin-α, suggesting that p53 translocation contributes to QD-induced cytotoxicity. These findings suggest three levels of nanoparticle-induced cellular changes: non-genomic, genomic and epigenetic. Epigenetic changes may have long-term effects on gene expression programming long after the initial signal has been removed, and if these changes remain undetected, it could lead to long-term untoward effects in biological systems. These studies suggest that aside from genotoxic effects, nanoparticles could cause more subtle epigenetic changes which merit thorough examination of environmental nanoparticles and novel candidate nanomaterials for medical applications.

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Acknowledgements

The authors would like to thank Jacynthe Laliberté for her help with the confocal microscopy and Jeannie Mui for her help with the electron microscopy. Also, the authors would like to thank Dr. Alain Niveleau for providing the anti-5-methyl-cytosine antibody and Dr. Jasmina Lovriç for scientific discussions. SEB is supported by a Doctoral Research Award from CIHR. These studies were supported by grants from the NCIC awarded to MS and grants from CIHR and JDRF awarded to DM.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William-Osler, McIntyre Medical Sciences Building, Montreal, H3G 1Y6, Canada

    Angela O. Choi, Shelley E. Brown, Moshe Szyf & Dusica Maysinger

Authors
  1. Angela O. Choi
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  2. Shelley E. Brown
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  3. Moshe Szyf
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  4. Dusica Maysinger
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Corresponding author

Correspondence to Dusica Maysinger.

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Angela O. Choi and Shelley E. Brown contributed equally to the manuscript

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Table 1

Table of primers used for RT-PCR (DOC 32.5 kb)

SFig. 1

QDs induce multiple types of cell death in MCF-7 cells. Viability of MCF-7 cells untreated (Ctrl) and treated with CdTe g(−) QDs for 24 h (5 μg/ml) (QD) was confirmed with three assays: cell counting with Trypan blue (a), lactate dehydrogenase (LDH) assay (b), and mitochondrial metabolic activity with MTT assay (c). All values represent means ± SEM from triplicate measurements obtained from two to three independent experiments (*p < 0.05) (DOC 67.5 kb)

SFig. 2

QDs induce changes in mitochondrial membrane potential in MCF-7. Mitochondrial depolarization of untreated (Ctrl) and QD-treated (24 h; 5 μg/ml) MCF-7 cells was determined using the fluorescent JC-1 dye (15 μM, 30 min, Molecular Probes T3168; monomer: λ ex 485 nm, λ em 530 nm; aggregate: λ ex 535 nm, λ em 590 nm) and confocal microscopy (Zeiss LSM 510 NLO inverted microscope, Zeiss, Canada). The potential-sensitive color shift was monitored using Argon 488 nm and LP 520 nm, and HeNe 543 nm and LP 560 filter. Note strong red fluorescence (aggregated JC-1) in untreated control cells (Ctrl) and a significant increase in green fluorescence (JC-1 monomers) in QD treated cells (DOC 300 kb)

SFig. 3

Small concentrations of cadmium ions released from QDs are not toxic to MCF-7 cells and do not induce hypoacetylation as assessed by Western blot analyses. a Histones extracted from untreated (Ctrl) and CdCl2-treated (35 and 300 nM; 24 h) MCF-7 cells were assayed by Western blot with an antibody directed against acetylated histone 3 (α-Ac-H3; top panel). The membrane was stripped and re-probed with an antibody directed against histone 3 as a loading control (α-H3; bottom panel). b MCF-7 cells were untreated (Ctrl) or treated with 300 nM of CdCl2, with or without 50 or 300 nM TSA, for 24 h. Extracted histones from these cells were assayed by Western blot with antibodies as in (a), and cell viability was assessed using the MTT assay (c) and verified with cell counts. Values represent means ± SEM from triplicate measurements obtained from two independent experiments. ***p < 0.001 where significance was found between the Cd and the Cd+TSA groups (DOC 82.5 kb)

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Choi, A.O., Brown, S.E., Szyf, M. et al. Quantum dot-induced epigenetic and genotoxic changes in human breast cancer cells. J Mol Med 86, 291–302 (2008). https://doi.org/10.1007/s00109-007-0274-2

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  • DOI: https://doi.org/10.1007/s00109-007-0274-2

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