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Mass spectrometric identification of isocyanate-induced modifications of keratins in human skin

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Author: Hulst, A.G. · Verstappen, D.R.W. · Riet-van Oeveren, D. van der · Vermeulen, N.P.E. · Noort, D.
Publisher: Elsevier Ireland Ltd
Source:Chemico-Biological Interactions, 237, 141-150
Identifier: 527063
doi: doi:10.1016/j.cbi.2015.06.008
Keywords: Adducts · Biomarkers · Exposure assessment · Isocyanates · Keratin · Skin · 2 methacryloyloxethyl isocyanate · 2 nitrophenylisocyanate · 2,6 toluene diisocyanate · 4 bromophenylisocyanate · Allylisocyanate · Biological marker · Elastin · Isocyanic acid derivative · Keratin · Lysine · Methylene diphenyl diisocyanate · Phenethylisocyanate · Pronase · Unclassified drug · Antigenicity · Asthma · Callus · Exposure · Human · Human tissue · Mass spectrometry · Protein analysis · Protein isolation · Protein modification · Skin sensitization · Observation, Weapon & Protection Systems · CBRN - CBRN Protection · TS - Technical Sciences


In the current paper we show that exposure of human callus to isocyanates leads to covalent modifications within keratin proteins. Mass spectrometric analyses of pronase digests of keratin isolated from exposed callus show that both mono- and di-adducts (for di-isocyanates) are predominantly formed on the ε-amino group of lysine. In addition, numerous modified tryptic keratin fragments were identified, demonstrating rather random lysine modification. Interestingly, preliminary experiments demonstrate that in case of MDI a similar lysine di-adduct was formed with lung elastin. Our data support the hypothesis that skin sensitization through antigenic modifications of skin proteins by isocyanates could play a role in occupational isocyanate-induced asthma. It is further envisaged that the elucidated adducts will also have great potential for use as biomarkers to assess skin exposure to isocyanates. Advantageously, the various lysine adducts display the presence of a characteristic daughter fragment at m/z 173.1 [lysine-NCO]+, enabling generic and rapid screening for exposure to isocyanates. © 2015 Elsevier Ireland Ltd. All rights reserved.