Department of Pathology, University of Vermont, Burlington, VT 05404, USA.
Chem Biol Interact. 2010 Mar 19;184(1-2):77-85. doi: 10.1016/j.cbi.2009.12.019. Epub 2009 Dec 24.
Hprt mutant frequency and p53 gene status were assessed in wild-type and p53 heterozygous (p53+/-) mice exposed chronically by inhalation to benzene. Benzene exposures to 100 ppm for 6h on Monday-Friday, 100 ppm for 10h on Monday-Wednesday-Friday, or 200 ppm for 5h on Monday-Wednesday-Friday yielded the same total exposures (concentration x time) of 3000 ppm x h/week. Hprt mutations in splenic T-lymphocytes were significantly increased in all benzene groups, ranging from 3.8- to 8.0-fold greater than control values. Wild-type and p53+/- mice were equally susceptible to benzene mutagenesis. Hprt wild-type and mutant isolates from control and exposed animals were examined for TCR gene rearrangements (as markers of in vivo clonality) and for loss of p53 wild-type or mutant alleles. Moderate clonal amplifications were observed among the Hprt mutant but not Hprt wild-type isolates but was not sufficient to account for the increases in Hprt mutant frequencies. Most isolates, whether Hprt wild-type or mutant, retained both p53 alleles in the benzene-exposed p53+/- animals (54% and 63%, respectively, for the Hprt wild-type and mutants). However, 37% of the Hprt wild-type isolates and 46% of the Hprt mutant isolates lost the p53 mutant allele. Only a small percentage of either type of isolate lost the p53 wild-type allele, and this was always in isolates that that previously lost the p53 mutant allele. Loss of the p53 mutant allele was independent of benzene exposure, Hprt status, or 6-thioguanine selection. These findings contrast with the p53 status of thymic lymphomas that had preferentially lost the wild-type p53 allele in some of these same mice. Possible reasons for loss of the mutant p53 allele in the Hprt mutant and wild-type isolates are discussed.
在慢性吸入苯的情况下，评估了野生型和 p53 杂合子（p53+/-）小鼠的 Hprt 突变频率和 p53 基因状态。每周一至周五暴露于 100ppm 苯 6 小时，每周一、三、五暴露于 100ppm 苯 10 小时，或每周一、三、五暴露于 200ppm 苯 5 小时，得到相同的总暴露量（浓度 x 时间）3000ppm x h/周。所有苯组的脾 T 淋巴细胞 Hprt 突变均显著增加，比对照值高 3.8-8.0 倍。野生型和 p53+/- 小鼠对苯致突变均敏感。检查了来自对照和暴露动物的 Hprt 野生型和突变分离物的 TCR 基因重排（作为体内克隆性的标志物）以及 p53 野生型或突变等位基因的丢失。在 Hprt 突变体中观察到适度的克隆扩增，但在 Hprt 野生型分离物中没有观察到这种扩增，但不足以解释 Hprt 突变体频率的增加。大多数分离物，无论是 Hprt 野生型还是突变型，在苯暴露的 p53+/- 动物中均保留了两个 p53 等位基因（分别为 Hprt 野生型和突变体的 54%和 63%）。然而，37%的 Hprt 野生型分离物和 46%的 Hprt 突变型分离物丢失了 p53 突变型等位基因。只有一小部分分离物丢失了 p53 野生型等位基因，而且总是在先前丢失 p53 突变型等位基因的分离物中。p53 突变型等位基因的丢失与苯暴露、Hprt 状态或 6-硫鸟嘌呤选择无关。这些发现与这些小鼠中一些胸腺淋巴瘤的 p53 状态形成对比，这些胸腺淋巴瘤优先丢失了野生型 p53 等位基因。讨论了 Hprt 突变体和野生型分离物中丢失突变型 p53 等位基因的可能原因。
