Zhejiang Province Key Laboratory for Food Safety, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China.
College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
Sci Total Environ. 2022 Jan 20;805:150454. doi: 10.1016/j.scitotenv.2021.150454. Epub 2021 Sep 20.
Difenoconazole is a commonly used triazole fungicide that consists of four stereoisomers [(2S,4S)-, (2S,4R)-, (2R,4R)-, and (2R,4S)-isomers] with different bioactivity. For example, the toxicity of the (2R,4S)-isomer to fish is approximately seven times higher than that of the (2S,4S)-isomer. However, the stereoselective toxic effects of difenoconazole stereoisomers on mammals have received little attention. In the present study, adult male mice were orally treated with a mixture of the four stereoisomers or each stereoisomer individually (0, 30, or 100 mg/kg/d) by gavage for 28 days. Pathological staining of the liver sections showed that the (2R,4R)-isomer caused lipid droplet accumulation. The mixture or each individual stereoisomers decreased the levels of amino acids and acyl-carnitine in serum. Moreover, the (2S,4R)-, (2R,4R)-, and (2R,4S)-isomers affected intestinal permeability, causing decreases in mucus secretion and tight junction protein expression in colon. Analysis of the gut microbiota composition showed that the stereoisomers caused decreases of OTU numbers and observed species at different levels. Interestingly, difenoconazole and its four stereoisomers reduced the relative abundance of Bacteroidetes at the phylum level and some short-chain fatty acid (SCFA)-producing bacteria. Taking the findings together, 2R-difenoconazole with strong bioactivity against pathogenic fungi also had significant effects in mammals, disrupting hepatic lipid metabolism, intestinal permeability, and gut microbiota. It is concluded that the health risks of the four difenoconazole stereoisomers to mammals should not be overlooked.
苯醚甲环唑是一种常用的三唑类杀菌剂，由四个立体异构体[(2S,4S)-、(2S,4R)-、(2R,4R)-和(2R,4S)-异构体]组成，具有不同的生物活性。例如，(2R,4S)-异构体对鱼类的毒性大约是(2S,4S)-异构体的 7 倍。然而，苯醚甲环唑立体异构体对哺乳动物的立体选择性毒性作用却很少受到关注。在本研究中，成年雄性小鼠通过灌胃接受四种立体异构体混合物或每种立体异构体（0、30 或 100mg/kg/d）单独处理 28 天。肝组织切片的病理染色显示，(2R,4R)-异构体引起脂质滴积累。混合物或每个单独的立体异构体降低了血清中氨基酸和酰基肉碱的水平。此外，(2S,4R)-、(2R,4R)-和(2R,4S)-异构体影响肠道通透性，导致结肠粘液分泌减少和紧密连接蛋白表达降低。肠道微生物群落组成分析表明，立体异构体在不同水平上引起 OTU 数量和观察到的物种减少。有趣的是，苯醚甲环唑及其四个立体异构体降低了门水平的拟杆菌门的相对丰度和一些产生短链脂肪酸（SCFA）的细菌。综合这些结果，对病原真菌具有强生物活性的 2R-苯醚甲环唑在哺乳动物中也具有显著的作用，扰乱了肝脂质代谢、肠道通透性和肠道微生物群。因此，不应忽视四种苯醚甲环唑立体异构体对哺乳动物的健康风险。
