Rand Amy A, Rooney John P, Butt Craig M, Meyer Joel N, Mabury Scott A
Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
Chem Res Toxicol. 2014 Jan 21;27(1):42-50. doi: 10.1021/tx400317p. Epub 2013 Dec 17.
The biotransformation of fluorotelomer based compounds yields saturated and unsaturated fluorotelomer aldehydes (FTALs and FTUALs, respectively) and carboxylic acids (FTCAs and FTUCAs, respectively) as intermediate metabolites that subsequently transform to perfluorinated carboxylic acids (PFCAs). Previous studies have demonstrated that the FTCAs and FTUCAs are 1 to 5 orders of magnitude more toxic than PFCAs after exposure to aquatic organisms. Additionally, FTUALs have demonstrated reactivity with proteins, which may be associated with toxicity through the inhibition of protein function. The purpose of this study was to carry out a comprehensive assessment of the relative toxicity between PFCAs and their intermediate precursor metabolites: the FTALs, FTUALs, FTCAs, and FTUCAs. Analytes were separately incubated with human liver epithelial (THLE-2) cells to assess how varying the functional group and the fluorinated chain length affects cell viability. For each analyte, dose-response EC50 values were calculated. The EC50 values for FTUCAs and FTCAs were similar, with values ranging from 22 ± 9 and 24 ± 9 μM for the 10:2 congeners to 1004 ± 20 and 1004 ± 24 μM for the 4:2 congeners, respectively. The EC50 values for the PFCAs ranged from 65 ± 41 (PFDA) to 1361 ± 146 (PFBA) μM. The range of toxicity between PFCAs and their acid precursors were similar. However, the comparative toxicity between the 6:2 and 8:2 congeners and their corresponding PFCA had toxicity thresholds that varied depending on the functional headgroup, where FTUALs ≥ FTALs > FTUCAs ≥ FTCAs > PFCAs. For all PFCAs and acid precursors, toxicity depended on the length of the fluorinated chain, where the longer chain lengths yielded greater bioaccumulation and enhanced toxicity, results which agreed with those previously reported. By contrast, FTALs and FTUALs were the most toxic of all the analytes examined, where toxicity was enhanced at shorter chain lengths, with EC50 values of 7 ± 1 μM (6:2 FTUAL) and 8.6 ± 0.8 μM (6:2 FTAL). DNA adducts were not detectable for the aldehyde precursors, using a quantitative long-range PCR method. Our data provide the first evidence that aldehyde intermediates have demonstrated toxicity in cellular systems that is more significant than PFCAs and their corresponding acid intermediates.
基于氟调聚物的化合物的生物转化产生饱和和不饱和氟调聚物醛（分别为FTALs和FTUALs）以及羧酸（分别为FTCAs和FTUCAs）作为中间代谢产物，这些中间代谢产物随后转化为全氟羧酸（PFCA）。先前的研究表明，FTCAs和FTUCAs在暴露于水生生物后比PFCAs的毒性高1至5个数量级。此外，FTUALs已证明与蛋白质具有反应性，这可能通过抑制蛋白质功能而与毒性相关。本研究的目的是对PFCA与其中间前体代谢产物（FTALs、FTUALs、FTCAs和FTUCAs）之间的相对毒性进行全面评估。将分析物分别与人肝上皮（THLE-2）细胞孵育，以评估官能团和氟化链长度的变化如何影响细胞活力。对于每种分析物，计算剂量-反应EC50值。FTUCAs和FTCAs的EC50值相似，10:2同系物的值分别为22±9和24±9μM，4:2同系物的值分别为1004±20和1004±24μM。PFCA的EC50值范围为65±41（PFDA）至1361±146（PFBA）μM。PFCA与其酸前体之间的毒性范围相似。然而，6:2和8:2同系物与其相应PFCA之间的比较毒性具有取决于官能团头的毒性阈值，其中FTUALs≥FTALs>FTUCAs≥FTCAs>PFCAs。对于所有PFCA和酸前体，毒性取决于氟化链的长度，链越长生物累积性越高且毒性增强，结果与先前报道的一致。相比之下，FTALs和FTUALs是所有检测分析物中毒性最大的，在较短链长度时毒性增强，EC50值分别为7±1μM（6:2 FTUAL）和8.6±0.8μM（6:2 FTAL）。使用定量长程PCR方法未检测到醛前体的DNA加合物。我们的数据首次证明醛中间体在细胞系统中表现出比PFCA及其相应酸中间体更显著的毒性。
