Identification of molecular targets for toxic action by persulfate, an industrial sulfur compound.Neurotoxicology. 2019 05; 72:29-37.N
Persulfate salts are broadly used as industrial chemicals and exposure to them causes occupational asthma, occupational rhinitis and contact dermatitis. However, the mechanisms underlying these toxic actions are not fully elucidated. Transient receptor potential (TRP) vanilloid 1 (V1), ankyrin 1 (A1) and melastatin 8 (M8) are non-selective cation channels preferentially expressing sensory neurons. These channels are known to be involved in respiratory and skin diseases. In the present study, we investigated the effects of sodium persulfate on these TRP channels. In wild-type mouse sensory neurons, persulfate evoked [Ca2+]i increases that were inhibited by removal of extracellular Ca2+ or blockers of TRPA1 but not by those of TRPV1 and TRPM8. Persulfate failed to evoke [Ca2+]i responses in neurons from TRPA1(-/-) mice, but did evoke them in neurons from TRPV1(-/-) mice. In HEK 293 cells expressing mouse TRPA1 (mTRPA1-HEK), persulfate induced [Ca2+]i increases. Moreover, in HEK 293 cells expressing mouse TRPV1 (mTRPV1-HEK), a high concentration of persulfate also evoked [Ca2+]i increases. Similar [Ca2+]i responses were observed in HEK 293 cells expressing human TRPA1 and human TRPV1. Current responses were also elicited by persulfate in mTRPA1- and mTRPV1-HEK. Analysis using mutated channels revealed that persulfate acted on electrophilic agonist-sensitive cysteine residues of TRPA1, and it indirectly activated TRPV1 due to the external acidification, because of the disappearance of [Ca2+]i responses in acid-insensitive mTRPV1 mutant. These results demonstrate that persulfate activates nociceptive TRPA1 and TRPV1 channels. It is suggested that activation of these nociceptive channels may be involved in respiratory and skin injuries caused by exposure to this industrial sulfur compound. Thus, selective TRPA1 and TRPV1 channel blockers may be effective to remedy persulfate-induced toxic actions.