Evaluation of the Transplacental Tumorigenicity of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-l-(3-pyridyl)-l-butanone in Mice

The transplacental tumorigenicity of the tobacco-specific carcinogen 4-(methylnitrosamino)-l -(3-pyridy 1)–1 -butanone (NNK) was assessed in three strains of mice: A/J; C3H/He x C57BL/6 F, (hereafter called C3B6F,); and Swiss outbred |Cr:NIH(S)|. NNK (100 mg/kg) was administered i.p. on Days 14,16, and 18 of gestation to A/J and C3H/He mice and on Days 15, 17, and 19 of gestation to the Swiss mice. The effects of postnatal treatment with tumor-promoting agents, including 0.05% sodium barbital in the drinking water until death or a single dose of Arodor 1254 (a mixture of polychlorinated biphenyls, PCB) given on Postnatal Day 8 or 56, were also examined. Progeny were sacrificed at age 24 wk (A/J) or 72 wk (C3B6F, and Swiss). Significant incidences of tumors occurred in the lungs of strain A/J progeny and in the livers of male G3B6F| and Swiss progeny. Lung tumor incidence was 8 of 34 (24%) in the female offspring of the A/J mice treated with NNK, compared with 1 of 39 (3%) in controls (P < 0.05). A 2-fold difference in lung tumor incidence in male offspring of NNK-treated (4 of 23,13%) versus control (3 of 48,6%) A/J mice was not of statistical significance. However, the incidence of lung tumors in NNK-exposed progeny A/J mice in both sexes combined (12 of 66, 18%) was also significantly greater than in controls (4 of 87, 5%). The incidence of liver tumors in the male C3B6F, mice exposed transplacentally to NNK was 12 of 30 (40%) compared to 8 of 46 (17%) in controls (P < 0.05). No effects of postnatal sodium barbital or PCB were observed on transplacental NNK tumorigenidty in C3B6F, mice. The combined incidence of liver carcinoma in male mice in all NNK-treated groups (13 of 141, 9%) was significantly greater (P < 0.05) than in controls (5 of 144,3%). In male Swiss mice exposed transplacentally to NNK, the incidence of liver tumors was 3 of 57 (5%) compared to 0 of 35 controls, and postnatal treatment with PCB on Day 56 caused a significant increase (5 of 26, 19%) (P < 0.05) in the incidence of NNK-induced liver tumors. The combined incidence of liver tumors in the male offspring of the Swiss mice treated with NNK, with or without PCB, was 8 of 83 (10%) which was significantly greater (P < 0.05) than in controls (0 of 66). The mothers in all NNK-treated groups of all three strains developed lung tumors in high incidence and multiplicity, and C3H mothers also presented a significant number of liver tumors. Taken together, the results of this study demonstrate that NNK is a transplacental tumorigen in the mouse, with activity that is relatively weak compared with the adult and is demonstrable only in fetal target organs of high sensitivity.