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Gadolinium induced effects on mammalian cell motility, adherence and chromatin structure

  • The many ways of apoptotic cell death
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Abstract

The toxicity of gadolinium is reduced by chelating agents that render this heavy metal into contrast complexes used for medical magnetic resonance imaging. However, the dissociation of gadolinium chelates is known to generate Gd3+ ions, the cellular toxicity of which has not been tested in details. The cytotoxic effects of Gd(III) ions were evaluated by monitoring the proliferation, measuring the cellular motility and following chromatin changes in various cell lines upon Gd3+ treatment. Measurements applied long-term scanning microscopy and a perfusion platform that replaced the medium with test solutions, bypassed physical contact with the cell culture during experiments, and provided uninterrupted high time-resolution time-lapse photomicrography for an extended period of time. Genotoxicity specific chromatin changes characteristic to Gd(III) were distinguished in human skin keratinocytes (HaCaT), human limbal stem cells (HuLi), colorectal adenocarcinoma (CaCO2), murine squamous carcinoma (SCC) and Indian muntjac (IM) cell lines. Characteristic features of Gd(III) toxicity were: loss of cellular motility, irreversible attachment of cells to the growth surface and cell death. Injury-specific chromatin changes manifested at micromolar Gd3+ concentrations as premature chromatin condensation and highly condensed sticky chromatin patches. Gd(III) concentration- and cell type-dependent reduction of normal adherence, as well as premature chromatin condensation confirmed apoptosis. The risk related to the release of toxic Gd3+ ions from gadolinium complexes and their effects on mono- and multi-layer cellular barriers have to be reconsidered when these chelated complexes are used as contrasting agents especially in relation to possible blood–brain barrier damages.

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Abbreviations

CaCO2 :

Colorectal adenocarcinoma cell line

CAD:

Caspase-activated DNase

DAPI:

2,6-Diamino-2-phenylindole

DMEM:

Dulbecco’s modified Eagle’s medium

EDTA:

Ethylenediaminotetraacetic acid

EGTA:

Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid

DTPA:

Diethylenetriaminepentaacetic acid

Gd(III):

Gadolinium(III), Gd3+ ions

HaCaT:

Human skin keratinocyte line

HuLi:

Human limbal stem cell line

IM:

Indian muntjac cell line

MRI:

Magnetic resonance imaging

PBS:

Phosphate Buffered Saline

RPMI-1640:

Roswell Park Memorial Institute (RPMI) 1640 Medium

SCC:

Squamous carcinoma cell line

SSC:

Scanning Shadow Camera

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Acknowledgments

This research was sponsored by TAMOP 4.2.4. A/2-11-1-2012-0001 grant to GN.

Author contributions

Gaspar Banfalvi has written the manuscript. No other assistance was utilized in the production of this manuscript.

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    Authors and Affiliations

    1. Department of Biotechnology and Microbiology, University of Debrecen, 1 Egyetem Square, Debrecen, 4010, Hungary

      Gabor Nagy, Viktoria Baksa, Alexandra Kiss, Melinda Turani & Gaspar Banfalvi

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    1. Gabor Nagy
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    2. Viktoria Baksa
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    3. Alexandra Kiss
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    4. Melinda Turani
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    5. Gaspar Banfalvi
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    Correspondence to Gabor Nagy.

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    Viktoria Baksa and Alexandra Kiss have contributed equally to this study.

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    Nagy, G., Baksa, V., Kiss, A. et al. Gadolinium induced effects on mammalian cell motility, adherence and chromatin structure. Apoptosis 22, 188–199 (2017). https://doi.org/10.1007/s10495-016-1311-9

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    • DOI: https://doi.org/10.1007/s10495-016-1311-9

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