Lung tumorigenicity in A/J and rasH2 transgenic mice following mainstream tobacco smoke inhalation
Lung tumorigenicity in A/J and rasH2 transgenic mice following mainstream tobacco smoke inhalation
复制标题
DOI：
10.1093/toxsci/kfh175
复制
发表时间：
2004-09-01
影响因子：
3.8
通讯作者：
Mosberg, AT
中科院分区：
文献类型：
--
作者：
Curtin, GM;Higuchi, MA;Mosberg, AT
假设它们各自的遗传背景会增加对肺部肿瘤发生的敏感性，评估了选定的啮齿动物模型用于主流烟草烟雾(MTS)吸入测试的可信程度。将品系A/J和rasH2转基因(TG)小鼠暴露于来自肯塔基州1R4F研究卷烟的NITS，采用全身暴露或仅鼻部暴露方案。全身给药方案包括20周[0.200 mg湿总颗粒物/升(WTPM/L)，6小时/天，5天/周]；仅鼻腔给药28周[0.040，0.125或0.400 mg湿总颗粒物/L，3小时/天，5天/周]。这两种方案都包括16周的恢复期。肺的大体和显微镜检查被用来评估肿瘤的形成，实验结果支持以下结论：1.基于大体评估和显微镜确认对MTS诱导的致瘤性的评估提供了截然不同的结果，表明连续切片对于明确评估肺肿瘤是必要的。虽然所使用的剂量方案不允许进行明确的比较，但与仅鼻部照射相比，全身照射似乎更有效地诱导肿瘤多发性和发病率的统计变化。暴露相关的压力，被证明为体重增加和背景肿瘤形成的减少，是吸入测试NITS致瘤性的一个潜在的混杂因素，有必要进行额外的研究来验证暴露相关反应的特异性。A/J和rasH2转基因小鼠之间的比较结果表明，前者可能对暴露相关的压力过于敏感，潜在地影响致瘤反应。
Hypothesizing that their respective genetic backgrounds would confer an increased sensitivity to lung tumorigenesis, the plausibility of selected rodent models for the inhalation testing of mainstream tobacco smoke (MTS) was evaluated. Strain A/J and rasH2 transgenic (Tg) mice were exposed to NITS from Kentucky 1R4F research cigarettes using either a whole-body or nose-only exposure regimen. The whole-body regimen consisted of a 20-week exposure period [0.200 mg wet total particulate matter/liter (WTPM/l), 6 h/day, 5 days/week]; nose-only dosing proceeded for 28 weeks [0.040, 0.125, or 0.400 mg WTPM/l, 3 h/day, 5 days/week]. Both regimens included a 16-week recovery period. Gross and microscopic examinations of the lungs were used to evaluate tumor formation, with experimental results supporting the following conclusions:1. Evaluation of MTS-induced tumorigenicity based on gross evaluation versus microscopic confirmation provides strikingly disparate results, indicating that serial sectioning is necessary for a definitive assessment of lung tumors.2. While the dosing regimens employed do not allow for a definitive comparison, whole-body exposure appeared to be more effective for inducing statistical changes in tumor multiplicity and incidence compared to nose-only exposure.3. Exposure-related stress, evidenced as reductions in both body weight gain and background tumor formation, represents a potential confounder during inhalation testing of NITS tumorigenicity, with additional investigation warranted to validate the specificity of exposure-related responses.4. Comparative findings between A/J and rasH2 Tg mice suggest that the former may be overly sensitive to exposure-related stress, potentially influencing tumorigenic responses.