Early life exposure of a biocide, CMIT/MIT causes metabolic toxicity via the O-GlcNAc transferase pathway in the nematode C. elegans
Early life exposure of a biocide, CMIT/MIT causes metabolic toxicity via the O-GlcNAc transferase pathway in the nematode C. elegans
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DOI：
10.1016/j.taap.2019.05.012
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发表时间：
2019-08-01
影响因子：
3.8
通讯作者：
Choi, Jinhee
中科院分区：
文献类型：
--
作者：
Kim, Youngho;Choi, Jinhee
2006 年至 2011 年，韩国儿童报告了一些不寻常的致命肺损伤病例，后来确定是由于接触用作加湿器消毒剂的化学品所致。这导致对加湿器消毒剂化学品的肺部毒性进行了大量研究，以确定接触与肺部疾病之间的因果关系。然而，前者的全身毒性和肺部疾病以外的健康影响尚未完全了解。在这里，我们通过暴露场景比较，研究了事故中使用的加湿器消毒剂中的 5-氯-2-甲基-4-异噻唑啉-3-酮和 2-甲基-4-异噻唑啉-3-酮 (CMIT/MIT) 对模型生物秀丽隐杆线虫代谢毒性发展的影响。我们使用线虫 oga-1(ok1207) 和 ogt-1(ok1474) 突变体筛选了 CMIT/MIT 诱导代谢毒性的潜力。我们还基于线虫转录因子 RNAi 库筛选进行了通路分析，以确定潜在的毒性机制。最后，为了了解代谢毒性的关键暴露窗口，比较了蠕虫生命周期不同时期对暴露的反应。我们确定 CMIT/MIT 可以通过 O-连接的 N-乙酰氨基葡萄糖转移酶诱导代谢毒性，并且生命早期似乎是接触该物质代谢毒性的关键窗口。 O-连接的 N-乙酰氨基葡萄糖转移酶途径从蠕虫到人类都是保守的；因此，我们的结果暗示，生命早期接触 CMIT/MIT 可能会导致人类成年后出现代谢健康问题。因此，我们建议应考虑采用全身毒性方法来全面了解加湿器消毒剂滥用对健康的不利影响。
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.