Williams Gary M, Kobets Tetyana, Duan Jian-Dong, Iatropoulos Michael J
Chemical Safety Program, Department of Pathology, New York Medical College , Valhalla, New York 10595, United States.
Chem Res Toxicol. 2017 Jul 17;30(7):1470-1480. doi: 10.1021/acs.chemrestox.7b00105. Epub 2017 Jun 29.
Exposure to acrylonitrile induces formation of tumors at multiple sites in rats, with females being more sensitive. The present study assessed possible mechanisms of acrylonitrile tumorigenicity, covalent DNA binding, DNA breakage, and oxidative DNA damage, in two target tissues, the brain and Zymbal's glands, of sensitive female Fischer (F344) and Sprague-Dawley (SD) rats. One group received acrylonitrile in drinking water at 100 ppm for 28 days. Two other groups were administered either acrylonitrile in drinking water at 100 ppm or drinking water alone for 27 days, followed by a single oral gavage dose of 11 mg/kg bw C-acrylonitrile on day 28. A positive control group received a single dose of 5 mg/kg bw of 7-C-benzo[a]pyrene, on day 27 following the administration of drinking water for 26 days. Using liquid scintillation counting, no association of radiolabeled acrylonitrile with brain DNA was found. In accelerator mass spectrometry analysis, the association of C of acrylonitrile with DNA in brains was detected and was similar in both strains, which may reflect acrylonitrile binding to protein as well as to DNA. Nucleotide P-postlabeling assay analysis of brain samples from rats of both strains yielded no evidence of acrylonitrile DNA adducts. Negative conventional comet assay results indicate the absence of direct DNA strand breaks in the brain and Zymbal's gland in both strains of rats dosed with acrylonitrile. In both rat strains, positive results in an enhanced comet assay were found only in brain samples digested with formamidopyrimidine-DNA glycosylase but not with human 8-hydroxyguanine-DNA glycosylase, indicating possible oxidative DNA damage, other than 8-oxodG formation. In conclusion, definitive evidence of DNA binding of acrylonitrile in the brain and Zymbal's gland was not obtained under the test conditions. A role for oxidative stress in tumorigenesis in the brain but not Zymbal's gland may exist.
接触丙烯腈会在大鼠的多个部位诱发肿瘤，雌性更为敏感。本研究评估了敏感雌性Fischer（F344）和Sprague-Dawley（SD）大鼠的两个靶组织——脑和齐默尔氏腺中，丙烯腈致瘤性、共价DNA结合、DNA断裂及氧化性DNA损伤的可能机制。一组大鼠饮用含100 ppm丙烯腈的水28天。另外两组大鼠饮用含100 ppm丙烯腈的水或仅饮用普通水27天，然后在第28天经口单次灌胃给予11 mg/kg体重的C-丙烯腈。阳性对照组在饮用26天普通水后，于第27天经口单次给予5 mg/kg体重的7-C-苯并[a]芘。采用液体闪烁计数法，未发现放射性标记的丙烯腈与脑DNA有相关性。在加速器质谱分析中，检测到丙烯腈的C与脑中DNA的相关性，且在两个品系中相似，这可能反映了丙烯腈与蛋白质以及DNA的结合。对两个品系大鼠脑样本进行核苷酸P后标记分析，未发现丙烯腈DNA加合物的证据。常规彗星试验结果为阴性，表明在给予丙烯腈的两个品系大鼠中，脑和齐默尔氏腺均未出现直接的DNA链断裂。在两个大鼠品系中，仅在用甲酰胺嘧啶-DNA糖基化酶消化的脑样本中，增强彗星试验呈阳性，而用人8-羟基鸟嘌呤-DNA糖基化酶消化的样本则无阳性结果，这表明除8-氧代脱氧鸟苷形成外，可能存在氧化性DNA损伤。总之，在试验条件下未获得丙烯腈在脑和齐默尔氏腺中与DNA结合的确切证据。氧化应激可能在脑肿瘤发生中起作用，但在齐默尔氏腺中不起作用。
