Finch G L, March T H, Hahn F F, Barr E B, Belinsky S A, Hoover M D, Lechner J F, Nikula K J, Hobbs C H
Inhalation Toxicology Laboratory, Lovelace Biomedical and Environmental Research Institute, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185, USA.
Toxicol Pathol. 1998 Jul-Aug;26(4):484-91. doi: 10.1177/019262339802600404.
The transgenic heterozygous p53+/- knockout mouse has been a model for assessing the tumorigenicity of selected carcinogens administered by noninhalation routes of exposure. The sensitivity of the model for predicting cancer by inhaled chemicals has not been examined. This study addresses this issue by acutely exposing p53+/- mice of both sexes by nose-only inhalation to either air (controls), or to 1 of 2 levels of 239PuO2 (500 or 100 Bq 239Pu) or beryllium (Be) metal (60 or 15 micrograms). Additional wild-type p53+/+ mice were exposed by inhalation to either 500 Bq of 239PuO2 or 60 micrograms of Be metal. These carcinogens were selected because they operate by differing mechanisms and because of their use in other pulmonary carcinogenesis studies in our laboratory. Four or 5 of the 15 mice per sex from each group were sacrificed 6 mo after exposure, and only 2 pulmonary neoplasms were observed. The remainder of the mice were held for life-span observation and euthanasia as they became moribund. Survival of the p53+/- knockout mice was reduced compared to the p53+/+ wild-type mice. No lung neoplasms were observed in p53+/- mice exposed to air alone. Eleven of the p53+/- mice inhaling 239PuO2 developed pulmonary neoplasms. Seven p53+/+ mice exposed to 239PuO2 also developed pulmonary neoplasms, but the latency period for pulmonary neoplasia was significantly shorter in the p53+/ mice. Four pulmonary neoplasms were observed in p53+/- mice exposed to the higher dose of Be, whereas none were observed in the wild-type mice or in the heterozygous mice exposed to the lower dose of Be. Thus, both p53+/- and p53+/+ mice were susceptible to 239Pu-induced carcinogenesis, whereas the p53+/- but not the p53+/+ mice were susceptible to Be-induced carcinogenesis. However, only 2 pulmonary neoplasms (1 in each of the 239PuO2 exposure groups) were observed in the 59 p53+/ mice that were sacrificed or euthanatized within 9 mo after exposure, indicating that the p53+/- knockout mouse might not be appropriate for a 6-mo model of carcinogenesis for these inhaled carcinogens.
转基因杂合p53+/-基因敲除小鼠一直是用于评估通过非吸入暴露途径给予特定致癌物的致瘤性的模型。该模型对预测吸入性化学物质致癌作用的敏感性尚未得到检验。本研究通过仅经鼻吸入方式，将雌雄p53+/-小鼠急性暴露于空气（对照组）、239PuO2的2个剂量水平之一（500或100 Bq 239Pu）或铍（Be）金属（60或15微克）中来解决这一问题。另外，将野生型p53+/+小鼠经吸入暴露于500 Bq的239PuO2或60微克的Be金属。选择这些致癌物是因为它们的作用机制不同，以及它们在我们实验室的其他肺癌发生研究中的应用。每组每种性别的15只小鼠中有4或5只在暴露后6个月被处死，仅观察到2个肺肿瘤。其余小鼠进行终生观察，并在濒死时实施安乐死。与p53+/+野生型小鼠相比，p53+/-基因敲除小鼠的存活率降低。单独暴露于空气的p53+/-小鼠未观察到肺肿瘤。吸入239PuO2的11只p53+/-小鼠发生了肺肿瘤。7只暴露于239PuO2的p53+/+小鼠也发生了肺肿瘤，但p53+/-小鼠发生肺肿瘤的潜伏期明显更短。暴露于较高剂量Be的p53+/-小鼠中观察到4个肺肿瘤，而野生型小鼠或暴露于较低剂量Be的杂合小鼠中未观察到肺肿瘤。因此，p53+/-和p53+/+小鼠均对239Pu诱导的致癌作用敏感，而p53+/-小鼠而非p53+/+小鼠对Be诱导的致癌作用敏感。然而，在暴露后9个月内被处死或实施安乐死的59只p53+/-小鼠中，仅观察到2个肺肿瘤（239PuO2暴露组各1个），这表明p53+/-基因敲除小鼠可能不适用于这些吸入性致癌物的6个月致癌模型。
