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Toxicol Appl Pharmacol. 2018 Jun 15;349:39-54. doi: 10.1016/j.taap.2018.04.005. Epub 2018 Apr 7.

Antimicrobial agent triclosan disrupts mitochondrial structure, revealed by super-resolution microscopy, and inhibits mast cell signaling via calcium modulation.

Author information

1
Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, USA; Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME, USA.
2
Department of Physics and Astronomy, University of Maine, Orono, ME, USA.
3
Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME, USA.
4
Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
5
Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, USA.
6
Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, USA; Department of Physics and Astronomy, University of Maine, Orono, ME, USA. Electronic address: Samuel.hess@maine.edu.
7
Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, USA; Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME, USA. Electronic address: Julie.gosse@maine.edu.

Abstract

The antimicrobial agent triclosan (TCS) is used in products such as toothpaste and surgical soaps and is readily absorbed into oral mucosa and human skin. These and many other tissues contain mast cells, which are involved in numerous physiologies and diseases. Mast cells release chemical mediators through a process termed degranulation, which is inhibited by TCS. Investigation into the underlying mechanisms led to the finding that TCS is a mitochondrial uncoupler at non-cytotoxic, low-micromolar doses in several cell types and live zebrafish. Our aim was to determine the mechanisms underlying TCS disruption of mitochondrial function and of mast cell signaling. We combined super-resolution (fluorescence photoactivation localization) microscopy and multiple fluorescence-based assays to detail triclosan's effects in living mast cells, fibroblasts, and primary human keratinocytes. TCS disrupts mitochondrial nanostructure, causing mitochondria to undergo fission and to form a toroidal, "donut" shape. TCS increases reactive oxygen species production, decreases mitochondrial membrane potential, and disrupts ER and mitochondrial Ca2+ levels, processes that cause mitochondrial fission. TCS is 60 × more potent than the banned uncoupler 2,4-dinitrophenol. TCS inhibits mast cell degranulation by decreasing mitochondrial membrane potential, disrupting microtubule polymerization, and inhibiting mitochondrial translocation, which reduces Ca2+ influx into the cell. Our findings provide mechanisms for both triclosan's inhibition of mast cell signaling and its universal disruption of mitochondria. These mechanisms provide partial explanations for triclosan's adverse effects on human reproduction, immunology, and development. This study is the first to utilize super-resolution microscopy in the field of toxicology.

KEYWORDS:

Ca(2+); Degranulation; Fluorescence photoactivation localization microscopy (FPALM); Keratinocyte; Mast cell; Membrane potential; Microtubules; Mitochondria; NIH-3T3; RBL-2H3; Reactive oxygen species; Super-resolution microscopy; Triclosan

PMID:
29630968
DOI:
10.1016/j.taap.2018.04.005
[Indexed for MEDLINE]

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