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Abstract：
The interactions between pharmaceuticals and nanomaterials and its potentially resulting toxicological effects in living systems are only insufficiently investigated. In this study, two model compounds, acetaminophen, a pharmaceutical, and cerium dioxide, a manufactured nanomaterial, were investigated in combination and individually. Upon inhalation, cerium dioxide nanomaterials were shown to systemically translocate into other organs, such as the liver. Therefore we picked the human liver cell line HuH-7 cells as an in vitro system to investigate liver toxicity. Possible synergistic or antagonistic metabolic changes after co-exposure scenarios were investigated. Toxicological data of the water soluble tetrazolium (WST-1) assay for cell proliferation and genotoxicity assessment using the Comet assay were combined with an untargeted as well as a targeted lipidomics approach. We found an attenuated cytotoxicity and an altered metabolic profile in co-exposure experiments with cerium dioxide, indicating an interaction of both compounds at these endpoints. Single exposure against cerium dioxide showed a genotoxic effect in the Comet assay. Conversely, acetaminophen exhibited no genotoxic effect. Comet assay data do not indicate an enhancement of genotoxicity after co-exposure. The results obtained in this study highlight the advantage of investigating co-exposure scenarios, especially for bioactive substances.
摘要：
药物与纳米材料之间的相互作用及其在生命系统中可能产生的毒理学作用尚未得到充分研究。在这项研究中,两个模型化合物，对乙酰氨基酚,一种药物，和二氧化铈,一种人造纳米材料，进行了组合和单独研究。吸入后，二氧化铈纳米材料被证明可以系统性地转移到其他器官中，比如肝脏。因此，我们选择了人肝细胞系HuH-7细胞作为体外系统来研究肝毒性。研究了共同暴露方案后可能的协同或拮抗代谢变化。使用Comet测定进行细胞增殖和遗传毒性评估的水溶性四唑（WST-1）测定的毒理学数据与非靶向以及靶向脂质组学方法组合。我们在与二氧化铈的共同暴露实验中发现了减弱的细胞毒性和改变的代谢谱，表明两种化合物在这些端点的相互作用。在彗星测定中，对二氧化铈的单次暴露显示出遗传毒性作用。相反，对乙酰氨基酚没有遗传毒性作用。彗星测定数据不表明共同暴露后遗传毒性的增强。在这项研究中获得的结果突出了调查共同暴露场景的优势，特别是生物活性物质。
