A chance insight into phosgene toxicity

Abstract

It has long been known that phosgene, a war gas and an industrial reagent, causes intense oxidative stress, but how it does so remains unclear. Here we report an accidental discovery: Electron spin resonance spectroscopy (ESR) of live fruit flies reveals that phosgene exposure results in a distinctive manganese (II) hyperfine structure. After exposure to phosgene, every batch of flies consistently displays the Mn (II) signal. Regardless of the aftercare provided, these flies inevitably perish, making the signal a diagnostic of phosgene poisoning in flies. The intensity of the signal is dependent on both exposure time and concentration, resembling the kinetics of phosgene poisoning. The signal of Mn (II) correlates with the presence of a functional superoxide dismutase Sod2. After exposure, heterozygous Sod2 mutants have a markedly lower intensity of Mn (II) in their ESR spectrum. We suggest that phosgene disturbs Mn redox cycling between ESR-silent Mn (III) and ESR-active Mn (II) that is required for superoxide dismutation. Accordingly, mitochondria of phosgene-treated flies show reduced rates of hydrogen peroxide production, and severely compromised complex I-linked respiration. It is likely that phosgene damages mitochondria through MnSOD and complex I, which contributes to its toxicity. This work uses Drosophila melanogaster for the first time in phosgene research.