Mechanisms involved in A/J mouse lung tumorigenesis induced by inhalation of an environmental tobacco smoke surrogate.
Lung tumors have been reproducibly induced in A/J mice exposed to a surrogate for experimental environmental tobacco smoke (ETSS) in a 5-mo inhalation period followed by 4 mo without further exposure. In order to increase our mechanistic understanding of this model, male mice were whole-body exposed for 6 h/d, 5 d/wk to ETSS with a particulate matter concentration of 100 mg/m(3). Food restriction regimens were included to model or exceed the ETSS-related impairment of body weight development. Half of the mice were pretreated with a single ip injection of urethane to study the effect of the above treatments on lung tumor development induced by this substance. At 5 mo, the tumor response was statistically the same for all groups of non-pretreated mice; however, the expected urethane-induced lung tumorigenesis was significantly inhibited by approximately 25% by ETSS and food restriction. This inhibition was accompanied by a threefold increase in blood corticosterone as a common stress marker for both ETSS and food restriction. At 9 mo, in mice not pretreated, the lung tumor incidence and multiplicity were significantly increased by twofold in the ETSS group; in the urethane-treated groups, the same high tumor multiplicity was reached regardless of previous treatment. The predominant tumor type in all groups was bronchiolo-alveolar adenoma. There was no induction of a specific K-ras mutation pattern by ETSS exposure. These data suggest a stress-induced inhibition of lung tumorigenesis in this model, explaining the need for the posttreatment period.
Stinn
W
W
Philip Morris Research Laboratories GmbH, Cologne, Germany. walter.stinn@pmintl.com
Teredesai
A
A
Kuhl
P
P
Knörr-Wittmann
C
C
Kindt
R
R
Coggins
C
C
Haussmann
H-J
HJ
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000139:chemically induced* / Q000235:genetics / Q000401:mortality; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002263:Carboxyhemoglobin / Q000032:analysis; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D019570:Inhalation Exposure / Q000009:adverse effects*; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000166:cytology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009929:Organ Size / Q000187:drug effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects* / Q000032:analysis; D018675:Toxicity Tests / Q000379:methods; D014520:Urethane / Q000009:adverse effects / Q000032:analysis
D014028:Tobacco Smoke Pollution; D014520:Urethane; D002263:Carboxyhemoglobin; D003345:Corticosterone