Early life exposure of a biocide, CMIT/MIT causes metabolic toxicity via the O-GlcNAc transferase pathway in the nematode C. elegans

Unusual cases of fatal lung injury, later determined to be a result of exposure to chemicals used as humidifier disinfectants, were reported among Korean children from 2006 to 2011. This resulted in considerable study of the pulmonary toxicity of humidifier disinfectant chemicals to establish the causal relationship between exposure and lung disease. However, the systemic toxicity of the former and health effects other than lung disease are not fully understood. Here, we investigated the effect of 5-chloro-2-methyl-4-isothiazoline-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT), among the humidifier disinfectants used in the accidents, on the development of metabolic toxicity in the model organism, Caenorhabditis elegans using an exposure scenario comparison. We screened the potential of CMIT/MIT to induce metabolic toxicity using C. elegans oga-1(ok1207) and ogt-1(ok1474) mutants. We also performed a pathway analysis based on C. elegans transcription factor RNAi library screening to identify the underlying toxicity mechanisms. Finally, to understand the critical window of exposure for metabolic toxicity, responses to exposure during different periods in the life cycles of the worms were compared. We determined that CMIT/MIT could induce metabolic toxicity through O-linked N-acetylglucosamine transferase and early life seems to be the critical window for exposure for metabolic toxicity for this substance. The O-linked N-acetylglucosamine transferase pathway is conserved from worms to humans; our results thus insinuate that early-life exposure to CMIT/MIT could cause metabolic health problems during adult life in humans. We therefore suggest that a systemic toxicity approach should be considered to comprehensively understand the adverse health effects of humidifier disinfectant misuse.