da Cunha de Medeiros P, Nunes E A, Barcelos G R M, Perobelli J E
Laboratory of Experimental Toxicology - LATOEX, Universidade Federal de São Paulo, Instituto do Mar, Carvalho de Mendonça, 144, Santos 11070-100, SP, Brazil.
Department of Biosciences, Laboratory of Gene-Environmental Interactions in Toxicology - GENINTOX, Universidade Federal de São Paulo, XV de novembro 195, sala 614, Santos 11.010-151, SP, Brazil.
Toxicol Res (Camb). 2024 Mar 24;13(2):tfae049. doi: 10.1093/toxres/tfae049. eCollection 2024 Apr.
5-fluorouracil (5-FU) and methotrexate (MTX) are the antineoplastic drugs most commonly used worldwide. Considered cytotoxic, these pharmaceuticals exhibit low specificity, causing damage not only to cancer cells but also to healthy cells in organisms. After being consumed and metabolized, these drugs are excreted through urine and feces, followed by wastewater treatment. However, conventional treatments do not have the capacity to completely remove these substances, risking their introduction into freshwater systems. This could pose a risk to human health even at low concentrations.
Thus, the present study aimed to investigate the genotoxicity, cytotoxicity, and mutagenicity of 5-FU and MTX at environmentally relevant concentrations after a long-term exposure, using adult male rats as an experimental model.
Male Wistar rats (70 days old) were distributed into 4 groups ( = 10/group): control, received only vehicle; MTX, received methotrexate at 10ngL; 5-FU received 5-fluorouracil at 10ngL; and MTX + 5-FU, received a combination of MTX and 5-FU at 10ngL each. The period of exposure was from postnatal day (PND) 70 to PND 160, through drinking water. After that, the animals were euthanized and the samples (liver, testis, femoral bone marrow, and peripheral blood) were obtained.
Increased DNA fragmentation was observed in the peripheral blood, liver, and testis, altering the parameters of the tail moment and tail intensity in the Comet assay. Besides, the change in the ratio between PCE and NCE indicates bone marrow suppression.
These findings warn the adverse effects for the general population worldwide chronically exposed to these drugs at trace concentration unintentionally.
5-氟尿嘧啶（5-FU）和甲氨蝶呤（MTX）是全球最常用的抗肿瘤药物。这些药物具有细胞毒性，特异性较低，不仅会对癌细胞造成损害，还会对机体中的健康细胞产生损伤。药物经摄入和代谢后，通过尿液和粪便排出，随后进入废水处理环节。然而，传统处理方法无法完全去除这些物质，存在它们进入淡水系统的风险。即便浓度很低，这也可能对人类健康构成威胁。
因此，本研究旨在以成年雄性大鼠为实验模型，研究长期暴露于环境相关浓度的5-FU和MTX后的遗传毒性、细胞毒性和致突变性。
将70日龄的雄性Wistar大鼠分为4组（每组n = 10）：对照组，仅接受赋形剂；MTX组，接受10ng/L的甲氨蝶呤；5-FU组，接受10ng/L的5-氟尿嘧啶；MTX + 5-FU组，接受10ng/L的甲氨蝶呤和5-氟尿嘧啶的组合。暴露期从出生后第70天（PND）至第160天，通过饮用水进行。之后，对动物实施安乐死并获取样本（肝脏、睾丸、股骨骨髓和外周血）。
在外周血、肝脏和睾丸中观察到DNA片段化增加，在彗星试验中改变了尾矩和尾强度参数。此外，嗜多染红细胞（PCE）与正常红细胞（NCE）比例的变化表明骨髓受到抑制。
这些发现警示全球普通人群长期无意暴露于痕量浓度的这些药物会产生不良影响。
