Aflatoxin B1-DNA Adduct Formation and Mutagenicity in Livers of Neonatal Male and Female B6C3F1 Mice
Aflatoxin B1-DNA Adduct Formation and Mutagenicity in Livers of Neonatal Male and Female B6C3F1 Mice
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DOI：
10.1093/toxsci/kfr087
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发表时间：
2011-07-01
影响因子：
3.8
通讯作者：
Wogan, Gerald N.
中科院分区：
文献类型：
--
作者：
Woo, Leslie L.;Egner, Patricia A.;Wogan, Gerald N.
在年轻时暴露于遗传毒性化学物质会增加晚年癌症的发病率。黄曲霉毒素B-1（AFB（1））是一种强效遗传毒素，可诱导许多动物和人类发生肝细胞癌（HCC）。尽管成年小鼠对黄曲霉毒素诱导的致癌作用不敏感，但出生后不久接受AFB（1）治疗的小鼠成年后肝癌发病率很高。此外，在婴儿时期接受治疗的成年雄性小鼠中HCC的发病率远高于雌性小鼠，其原因尚不清楚。在这项研究中，AFB（1）治疗在新生雄性和雌性gpt delta B6 C3 F1小鼠的肝脏中产生了相似水平的DNA损伤和突变。在给予AFB（1）（6 mg/kg）24小时后，雄性和雌性肝脏DNA中存在的高致突变性AFB（1）-FAPY加合物的水平是AFB（1）-N-7-鸟嘌呤水平的两倍。多次给药方案（3 x 2 mg/kg），虽然总剂量相同，但AFB（1）加合物水平较低。肝脏中gpt转基因的突变频率增加了20- 30倍。在AFB（1）处理的小鼠中，最突出的突变是G：C到T：A颠换和G：C到A：T转换。在该21天时间点，雄性和雌性之间的突变频率或突变类型无显著差异。这些结果表明，幼年雄性和雌性B6 C3 F1小鼠经历了相似数量的DNA损伤和AFB（1）突变，可能引发肿瘤过程。在随后的HCC发展中的性别差异突出了阐明调节HCC发展的其他因素的重要性。
Exposure to genotoxic chemicals at a young age increases cancer incidence later in life. Aflatoxin B-1 (AFB(1)) is a potent genotoxin that induces hepatocellular carcinoma (HCC) in many animal species and in humans. Whereas adult mice are insensitive to aflatoxin-induced carcinogenesis, mice treated with AFB(1) shortly after birth develop a high incidence of HCC in adulthood. Furthermore, the incidence of HCC in adult male mice treated as infants is much greater than in females, reasons for which are unclear. In this study, treatment with AFB(1) produced similar levels of DNA damage and mutations in the liver of newborn male and female gpt delta B6C3F1 mice. Twenty-four hours after dosing with AFB(1) (6 mg/kg), the highly mutagenic AFB(1)-FAPY adduct was present at twice the level of AFB(1)-N-7-guanine in liver DNA of males and females. A multiple dose regimen (3 x 2 mg/kg), while delivering the same total dose, resulted in lower AFB(1) adduct levels. Mutation frequencies in the gpt transgene in liver were increased by 20- to 30-fold. The most prominent mutations in AFB(1)-treated mice were G:C to T:A transversions and G:C to A:T transitions. At this 21-day time point, no significant differences were found in mutation frequency or types of mutations between males and females. These results show that infant male and female B6C3F1 mice experience similar amounts of DNA damage and mutation from AFB(1) that may initiate the neoplastic process. The gender difference in the subsequent development of HCC highlights the importance of elucidating additional factors that modulate HCC development.