T. Ito1,3,4, H. Saeki2,3, X. Guo3, P. S. Shah6, J. Coulter8, K. Tamashiro7, H. Orita4, K. Sato4, A. Hulbert5, K. Rodgers1, B. Lee1, M. Garner1, N. Fackche1, Y. Mei1, M. V. Brock1, K. Gabrielson3 1The Johns Hopkins University School Of Medicine,Surgery,Baltimore, MD, USA 2The Johns Hopkins University School Of Medicine,Pathology,Baltimore, MD, USA 3The Johns Hopkins University School Of Medicine,Molecular And Comparative Pathobiology,Baltimore, MD, USA 4Juntendo University Shizuoka Hospital,Surgery,Izunokuni-shi, SHIZUOKA, Japan 5University Of Illinois At Chicago,Surgery,Chicago, IL, USA 6The Johns Hopkins University School Of Medicine,Radiology,Baltimore, MD, USA 7The Johns Hopkins University School Of Medicine,Psychiatry And Behavioral Sciences,Baltimore, MD, USA 8The Johns Hopkins University School Of Medicine,Radiation Oncology And Molecular Radiation Sciences,Baltimore, MD, USA
Introduction: Lung cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related death worldwide. Maternal stress during pregnancy has both detrimental effects on both mother and fetus. Although in epidemiology studies, prenatal stress has been associated with an increased risk of cancers in later life, the causal relationship between prenatal stress and tumorigenesis has not been determined. To date, no animal studies linking prenatal stress to tumorigenesis have ever been reported. The purpose of this study is to investigate whether prenatal stress can increase tumor multiplicity in the well-established nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced lung tumor model in AJ mice.
Methods: Pregnant AJ mice were timed-bred and assigned randomly at gestation day (GD) 12.5 to either a prenatal stress (PS) group or a control group. Mice in the PS group were restrained for 2 hours for 5 days through GD16.5. Pups from each group were weaned and housed until 11 weeks of age when all were administered 3 NNK injections of 50mg/kg every other day. All mice were euthanized at 27 weeks of age and examined for hyperplasia and lung tumors. Three different sections of each lung lobe were stained by H&E and examined. Categories of individual proliferation types were defined as follows: C1 for “single layer of hyperplastic alveolar Type II cells lined along alveoli”; C2 for “multiple layers of hyperplastic alveolar Type II cells lined along alveoli”; C3 for “adenoma within hyperplasia”; C4 for “adenoma” and analyzed.
Results: There were significantly more lung proliferative lesions in male and female offspring in the PS group compared to control group [n=16-22, control male group (CM) vs. PS male group (PSM), 9.6 ± 1.0 vs. 12.6 ± 1.0, P=0.021; control female group (CF) vs. PS female group (PSF), 10.3 ± 0.5 vs. 16.9 ± 1.0, P<0.001] (Fig. 1). In both genders, the control group had a significantly higher frequency of C1 lesions in 3 sections of lung compared to PS group. Yet for C2, the opposite was found as the control group had lower frequency of C2 lesions compared to the PS group (CM vs. PSM, C1, 67.9 ± 5.6 vs. 50.4 ± 5.2, %, P=0.041, C2, 28.6 ± 5.5 vs. 46.6 ± 4.6, %, P=0.028; CF vs. PSF, C1, 70.4 ± 5.4 vs. 50.4 ± 5.1, %, P=0.041; C2, 28.8 ± 5.3 vs. 43.5 ± 5.2, %, P=0.068). These results suggest that prenatal stress enhances NNK induced lung tumor pathogenesis.
Conclusion: This is the first report of an animal model that supports the findings in epidemiological studies that prenatal stress may influence lung tumor carcinogenesis.
