Minko Irina G, Vartanian Vladimir L, Luzadder Michael M, Wang Yingming, Fedorov Lev M, McCullough Amanda K, Lloyd R Stephen
Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, Oregon, USA.
Transgenic Mouse Models Shared Resource, Oregon Health and Science University, Portland, Oregon, USA.
Environ Mol Mutagen. 2025 Apr;66(4):144-154. doi: 10.1002/em.70014. Epub 2025 May 8.
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-associated mortality, correlating with obesity, alcohol consumption, hepatitis B and C infections, and dietary exposure to aflatoxin B (AFB). The etiology of AFB-induced HCC involves the formation of highly mutagenic guanine lesions that can be repaired by a branch of the base excision repair pathway initiated by the DNA glycosylase, NEIL1. In a murine model, NEIL1 deficiency results in increased AFB-induced mutagenesis and carcinogenesis. Previous analyses identified several defective NEIL1 variants in human populations, including the temperature-sensitive A51V and glycosylase-deficient G83D variants. Herein, we report AFB-induced mutagenesis in mice expressing the A51V and G83D NEIL1 variants. Cohorts of 6-day-old Neil1 and Neil1 homozygous mice were injected with a single dose of AFB, and frequencies and spectra of mutations were assessed in liver genomes 2.5 months post-exposure using duplex sequencing. Comparisons of these data with previously generated data on AFB-induced mutagenesis in wild-type (WT) and Neil1 mice revealed that although mutation frequencies in Neil1 and Neil1 animals were comparable to those measured in WT, elevated proportions of base substitutions at A/T sites were consistent with NEIL1 deficiency in both of these models. These findings suggest that individuals carrying these NEIL1 variants could be at an elevated risk for the development of AFB-induced HCC.
肝细胞癌（HCC）仍然是癌症相关死亡的主要原因之一，与肥胖、饮酒、乙型和丙型肝炎感染以及饮食中接触黄曲霉毒素B（AFB）有关。AFB诱导的HCC的病因涉及形成高度诱变的鸟嘌呤损伤，这些损伤可由DNA糖基化酶NEIL1启动的碱基切除修复途径的一个分支进行修复。在小鼠模型中，NEIL1缺陷会导致AFB诱导的诱变和致癌作用增加。先前的分析在人群中鉴定出了几种有缺陷的NEIL1变体，包括温度敏感的A51V和糖基化酶缺陷的G83D变体。在此，我们报告了在表达A51V和G83D NEIL1变体的小鼠中AFB诱导的诱变情况。对6日龄Neil1和Neil1纯合小鼠群体注射单剂量AFB，并在暴露后2.5个月使用双链测序评估肝脏基因组中的突变频率和谱。将这些数据与先前生成的关于野生型（WT）和Neil1小鼠中AFB诱导的诱变数据进行比较，结果显示，尽管Neil1和Neil1动物中的突变频率与WT中测得的频率相当，但在这两种模型中，A/T位点的碱基替换比例升高与NEIL1缺陷一致。这些发现表明，携带这些NEIL1变体的个体发生AFB诱导的HCC的风险可能会升高。
