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Nanoparticles can cause DNA damage across a cellular barrier

Abstract

The increasing use of nanoparticles in medicine has raised concerns over their ability to gain access to privileged sites in the body. Here, we show that cobalt–chromium nanoparticles (29.5 ± 6.3 nm in diameter) can damage human fibroblast cells across an intact cellular barrier without having to cross the barrier. The damage is mediated by a novel mechanism involving transmission of purine nucleotides (such as ATP) and intercellular signalling within the barrier through connexin gap junctions or hemichannels and pannexin channels. The outcome, which includes DNA damage without significant cell death, is different from that observed in cells subjected to direct exposure to nanoparticles. Our results suggest the importance of indirect effects when evaluating the safety of nanoparticles. The potential damage to tissues located behind cellular barriers needs to be considered when using nanoparticles for targeting diseased states.

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Figure 1: CoCr particles and their respective ions cause DNA damage in human fibroblasts.
Figure 2: Behaviour of CoCr particles in the BeWo cell barrier.
Figure 3: Fibroblast DNA damage after indirect exposure through the BeWo barrier is dependent on intercellular signalling through connexin channels within the barrier.
Figure 4: DNA damage caused by either indirect exposure to CoCr nanoparticles or direct exposure to ATP (beneath the barrier) is dependent on pannexin channel signalling.
Figure 5: ATP, transferrin and Co(ii) as signals passing through the barrier.
Figure 6: Schematic of the proposed mechanism by which CoCr nanoparticles cause DNA damage to human fibroblasts across a BeWo cell barrier.

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Acknowledgements

Advice and discussion was kindly provided by A. Poole and A. Halestrap (University of Bristol). Support from the Research Foundation Non-medical Committee of the charitable trusts for the University Hospitals Bristol is acknowledged.

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Authors

Contributions

C.P.C., G.B., A.S., M.S. and L.C. conceived and designed the experiments. G.B., A.S., L.C., B.F., G.L., S.D., L.H., P.V., J.L. and K.H. performed the experiments. C.P.C., G.B., A.S., L.C., M.S., W.H.E., A.-M.S., G.L., S.D., L.H., P.V., J.L. and K.H. analysed the data. M.S., W.H.E., A.M.S. and E.I. contributed materials and analysis tools. C.P.C., G.B., A.S., W.H.E. and S.M. co-wrote the paper.

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Correspondence to Charles Patrick Case.

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Bhabra, G., Sood, A., Fisher, B. et al. Nanoparticles can cause DNA damage across a cellular barrier. Nature Nanotech 4, 876–883 (2009). https://doi.org/10.1038/nnano.2009.313

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