Carcinogenic Responses of Transgenic Heterozygous p53 Knockout Mice to Inhaled 239 PuO 2 or Metallic Beryllium

Abstract

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 μg). Additional wild-type p53 ^+/- mice were exposed by inhalation to either 500 Bq of ²³⁹PuO₂ or 60 μg 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 53 ^+/- 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.

Keywords

Inhalation exposure acute exposure lung pulmonary neoplasm cancer incidence latency carcinogenesis survival mice transgenic p53 tumor suppressor gene

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