Susceptibility of Fetal Lung to Transplacental 1-Ethyl-1-nitrosourea: Its Relation to Epithelial Proliferation 2

Abstract

The relationship between the age-dependence of the number of lung adenomas produced by exposure of fetal mouse lung to 1-ethyl-1-nitrosourea (ENU) and changes in the number of epithelial cells within the population that are in the cell cycle on different gestation days was studied. The epithelial cells lining peripheral tubules of growing lung were counted by morphometric methods, and, based on previous studies, their distribution in various phases of the cell cycle was estimated. The curve of multiplicity of adenomas was biphasic, with the maximum number in fetuses exposed on days 16 and 17 and the minimum in those exposed on day 19. The number of epithelial cells in the proliferative cycle followed a similar pattern. A linear regression curve relating the number of cells in the cell cycle to the number of adenomas produced 16 weeks after exposure to ENU showed a correlation coefficient of 0.82. The number of adenomas was more highly correlated with the number of cells in the G₁ phase at carcinogen exposure than with the number of cells in either the S phase or the G₂ phase and mitosis. The incidence of adenomas per 10⁶ cells in cycle was greatest when fetuses were exposed to ENU on day 15, and tumors induced on this day grew to a significantly larger size by 16 weeks after birth than did those induced on days 17, 18, or 19. Factors of possible significance in this age-related response may have been the high growth fraction in fetal lung epithelium on day 15, the short cell-cycle time, and the longer period available for cell proliferation between tumor initiation and birth.