Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA.
Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA; Department of Chemistry, Federal University of Lavras (UFLA), Minas Gerais, Brazil.
Sci Total Environ. 2024 Jun 10;928:172377. doi: 10.1016/j.scitotenv.2024.172377. Epub 2024 Apr 10.
Antineoplastic medications are present in aquatic environments and are measured at relatively high concentrations in hospital sewage effluent. Thus, it is important to characterize risk associated with waterborne exposures to anticancer drugs. The drug 5-fluorouracil (5-FU) is used to treat several types of cancers, acting to inhibit cell division and cellular metabolism. The objectives of this study were to determine the effects of 5-FU on developmental endpoints and lipid composition in zebrafish. 5-FU did not negatively affect development nor survival in developing zebrafish at concentrations up to 1000 μg/L. However, 5-FU increased neutral lipid content in zebrafish larvae, indicating potential for lipid dysregulation. To further discern effects on lipids, lipidomics was conducted and a total of 164 lipids belonging to 14 lipid classes were identified. Significant changes (false discovery rate < 0.05) in abundance were detected for 19 lipids including some ceramides, ether-linked phosphatidylethanolamines, and sphingomyelins among others. We also measured the expression levels of 14 lipid-related enzymes and transporters (e.g., acox3, dgat1, fads2, fasn, elovl2) using real-time PCR; however, mRNA abundance levels were not affected, suggesting transcriptional changes may not be a primary mechanism underlying lipid dysregulation. Locomotor activity was measured in zebrafish as lipids are needed for swimming activity in larvae. Exposure to 5-FU did not affect locomotor activity up to 1000 μg/L. We conclude that lipids accumulate in larval zebrafish with exposure to 5-FU, which can subsequently affect lipid composition. These data reveal potential lipid signatures of 5-FU exposure and contribute to risk assessments for antineoplastic exposure in aquatic environments.
抗肿瘤药物存在于水生环境中，在医院污水废水中的浓度相对较高。因此，描述与水接触抗癌药物相关的风险非常重要。药物 5-氟尿嘧啶（5-FU）用于治疗多种癌症，通过抑制细胞分裂和细胞代谢起作用。本研究的目的是确定 5-FU 对斑马鱼发育终点和脂质组成的影响。在浓度高达 1000μg/L 的情况下，5-FU 并未对发育中的斑马鱼的发育和生存产生负面影响。然而，5-FU 增加了斑马鱼幼虫的中性脂质含量，表明可能存在脂质失调。为了进一步区分对脂质的影响，进行了脂质组学分析，共鉴定出 14 种脂质类别的 164 种脂质。检测到 19 种脂质的丰度发生了显著变化（错误发现率 < 0.05），包括一些神经酰胺、醚连接的磷脂酰乙醇胺和鞘磷脂等。我们还使用实时 PCR 测量了 14 种与脂质相关的酶和转运蛋白（如 acox3、dgat1、fads2、fasn、elovl2）的表达水平；然而，mRNA 丰度水平没有受到影响，这表明转录变化可能不是脂质失调的主要机制。在斑马鱼中测量了运动活性，因为在幼虫中游泳活动需要脂质。在高达 1000μg/L 的浓度下，5-FU 暴露不会影响运动活性。我们得出结论，暴露于 5-FU 会导致幼虫斑马鱼的脂质积累，进而影响脂质组成。这些数据揭示了 5-FU 暴露的潜在脂质特征，并为水生环境中抗肿瘤暴露的风险评估做出了贡献。
