In vivo genotoxicity of furan in F344 rats at cancer bioassay doses
In vivo genotoxicity of furan in F344 rats at cancer bioassay doses
复制标题
DOI：
10.1016/j.taap.2012.03.021
复制
发表时间：
2012-06-01
影响因子：
3.8
通讯作者：
Heflich, Robert H.
中科院分区：
文献类型：
--
作者：
Ding, Wei;Petibone, Dayton M.;Heflich, Robert H.
呋喃是一种有效的啮齿动物肝脏致癌物，存在于许多熟食中，因此代表了人类癌症风险。采用体内彗星试验和微核试验，结合组织病理学和基因表达变化分析，研究了呋喃对雄性F344大鼠的致癌机制。此外，监测甲酰胺基嘧啶DNA糖基化酶（Fpg）和核酸内切酶III（EndoIII）敏感的DNA损伤作为氧化性DNA损伤的量度。连续四天用2、4和8 mg/kg bw呋喃（在2年癌症生物测定中具有致瘤性的剂量）和两个更高剂量（12和16 mg/kg）对大鼠进行灌胃给药。在最后一次给药后3小时处死大鼠，该时间被确定为在呋喃处理的大鼠肝脏中产生最大水平的DNA损伤。肝脏彗星试验表明，DNA链断裂和氧化嘌呤和嘧啶以接近线性的剂量反应方式增加，在癌症生物测定剂量下检测到统计学显著增加。在骨髓（癌症的非靶组织）中未检测到DNA损伤，外周血微核试验为阴性。对暴露于呋喃的动物的肝脏进行组织学评价，发现了炎症、单细胞坏死、细胞凋亡和细胞增殖的证据。此外，与细胞凋亡，细胞周期检查点和DNA修复相关的基因在呋喃处理的肝脏中表达水平略低。虽然不能排除涉及直接DNA结合的混合作用模式，但数据表明呋喃主要通过涉及氧化应激的继发性遗传毒性机制诱导大鼠肝脏癌症，并伴有炎症、细胞增殖和毒性。爱思唯尔公司出版
Furan, a potent rodent liver carcinogen, is found in many cooked food items and thus represents a human cancer risk. Mechanisms for furan carcinogenicity were investigated in male F344 rats using the in vivo Comet and micronucleus assays, combined with analysis of histopathological and gene expression changes. In addition, formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III (EndoIII)-sensitive DNA damage was monitored as a measure of oxidative DNA damage. Rats were treated by gavage on four consecutive days with 2, 4, and 8 mg/kg bw furan, doses that were tumorigenic in 2-year cancer bioassays, and with two higher doses, 12 and 16 mg/kg. Rats were killed 3 h after the last dose, a time established as producing maximum levels of DNA damage in livers of furan-treated rats. Liver Comet assays indicated that both DNA strand breaks and oxidized purines and pyrimidines increased in a near-linear dose-responsive fashion, with statistically significant increases detected at cancer bioassay doses. No DNA damage was detected in bone marrow, a non-target tissue for cancer, and peripheral blood micronucleus assays were negative. Histopathological evaluation of liver from furan-exposed animals produced evidence of inflammation, single-cell necrosis, apoptosis, and cell proliferation. In addition, genes related to apoptosis, cell-cycle checkpoints, and DNA-repair were expressed at a slightly lower level in the furan-treated livers. Although a mixed mode of action involving direct DNA binding cannot be ruled out, the data suggest that furan induces cancer in rat livers mainly through a secondary genotoxic mechanism involving oxidative stress, accompanied by inflammation, cell proliferation, and toxicity. Published by Elsevier Inc.