Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Toxicology. 2024 Nov;508:153927. doi: 10.1016/j.tox.2024.153927. Epub 2024 Aug 14.
There is an increasing incidence and prevalence of fatty liver disease in the western world, with steatosis as the most prevalent variant. Known causes of steatosis include exposure to food-borne chemicals, and overconsumption of alcohol, carbohydrates and fat, and it is a well-known side effect of certain pharmaceuticals such as tetracycline, amiodarone and tamoxifen (drug-induced hepatic steatosis). Mechanistic knowledge on chemical-induced steatosis has greatly evolved and has been organized into adverse outcome pathways (AOPs) describing the chain of events from first molecular interaction of a substance with a biological system to the adverse outcome, intrahepatic lipid accumulation. In this study, three known steatosis-inducing pesticides (imazalil, clothianidin, and thiacloprid) were tested for their ability to induce hepatic triglyceride accumulation in the zebrafish (Danio rerio) embryo (ZFE) at 5 days post fertilization, both as single compounds and equipotent binary mixtures. The results indicate that the ZFE is very well applicable as a higher tier testing model to confirm effects in downstream key events in AOPs, that is, chemically-induced triglyceride accumulation in the whole organism and production of visible steatosis. Moreover, dose addition could be concluded for binary mixtures of substances with similar and with dissimilar modes of action.
在西方世界，脂肪肝疾病的发病率和患病率不断上升，其中以脂肪变性最为普遍。脂肪变性的已知病因包括接触食物源化学物质、过度摄入酒精、碳水化合物和脂肪，并且它也是某些药物（如四环素、胺碘酮和他莫昔芬）的已知副作用（药物性肝脂肪变性）。化学诱导性脂肪变性的机制知识已经有了很大的发展，并已组织成描述从物质与生物系统的第一次分子相互作用到肝内脂质积累的不良后果的途径（AOP）。在这项研究中，三种已知的致脂肪变性农药（咪鲜胺、噻虫啉和噻虫嗪）在受精后 5 天的斑马鱼（Danio rerio）胚胎（ZFE）中被测试其诱导肝内三酰甘油积累的能力，无论是作为单一化合物还是等效力的二元混合物。结果表明，ZFE 非常适用于作为更高层次的测试模型，以确认 AOP 中下游关键事件的效应，即化学诱导的整个生物体中的三酰甘油积累和可见脂肪变性的产生。此外，可以推断出具有相似和不同作用模式的物质的二元混合物的剂量相加。
