Formaldehyde and
formaldehyde releasers are widely used preservatives and represent an important group of skin sensitizers.
Formaldehyde is very often suspected to be the sensitizing agent of
formaldehyde-releasers; however, many reported clinical cases of contact
allergy to these molecules such as
bronopol (2-bromo-2-nitropropane-1,3-diol) indicate negative skin reactions to
formaldehyde suggesting a more complex mechanism. The aim of this study was to compare the chemical reactivity and
biological activity of
formaldehyde with those of two
formaldehyde releasers:
2-bromo-2-nitropropane-1,3-diol and
1,3-dimethylol-5,5-dimethylhydantoin. A key step in the sensitization to chemicals is the formation of the
hapten-
protein antigenic complex via covalent binding between the chemical sensitizer and
amino acids in
proteins. The chemical reactivity of the three compounds was thus addressed using (13)C NMR analysis of adduct formation upon incubation with a set of nucleophilic
amino acids. The
biological activity was measured in two in vitro models based on dendritic cells and a monocytic cell line (CD34-DC and THP-1 model) through monitoring of a panel of
biomarkers. The results obtained show that
2-bromo-2-nitropropane-1,3-diol produces low amount of free
formaldehyde in physiological
buffers but that its degradation generates various molecules including
2-bromoethanol. In addition,
2-bromo-2-nitropropane-1,3-diol also generates adducts with
amino acids, not observed with
formaldehyde alone, that could be explained by the reactivity of
2-bromoethanol. In parallel, in a cellular approach using the human monocytic THP-1 cell line,
2-bromo-2-nitropropane-1,3-diol activates THP-1 cells at concentrations that are not correlated to simple
formaldehyde release. This observation is confirmed in the more physiological model CD34-DC. Moreover, in the THP-1 model, the expression profiles of several
biomarkers are specific to
2-bromo-2-nitropropane-1,3-diol. Finally, the use in the cellular model of the pure degradation products identified by NMR reveals the reactivity of
bromonitromethane. In contrast,
1,3-dimethylol-5,5-dimethylhydantoin presents chemical and
biological reactivities similar to those of
formaldehyde. Taken together, these data suggest that
2-bromo-2-nitropropane-1,3-diol is an atypical
formaldehyde releaser, releasing low amounts of
formaldehyde at physiological conditions but producing multiple degradation products among which
2-bromoethanol and
bromonitromethane are potential candidates for explaining the specific
allergic reactions to
2-bromo-2-nitropropane-1,3-diol.