Mammary glands of sexually immature rats are more susceptible than those of mature rats to the carcinogenic, lethal, and mutagenic effects of N-nitroso-N-methylurea

Knowing that the prepubertal period is a time of enhanced susceptibility for radiation-induced human breast cancer, we used the Fischer 344 rat model to explore the age-differential susceptibility of the mammary gland to the carcinogenic, lethal, and mutagenic effects of two structurally diverse chemical carcinogens, N-nitroso-N-methylurea (NMU), and 7,12-dimethylbenz(a)anthracene (DMBA). Mammary carcinoma incidences and multiplicities were significantly greater in immature than mature NMU-treated rats while mammary carcinoma incidences and multiplicities were significantly lower in immature than mature DMBA-treated rats. The survival of mammary clonogens of mature NMU-treated rats in limiting dilution transplantation assays was greater than that of the survival of mammary clonogens of immature NMU-treated rats. No differences were found in the survival of mammary cells from immature and mature rats exposed to DMBA. Although there were no mutation spectra differences, mammary epithelial cells of immature NMU-treatecl rats had greater mutation frequencies than those of mature NMU-treated rats. Together these results support the hypothesis that the mammary gland of immature rats is more susceptible to the carcinogenic, lethal, and mutagenic effects of alkylating agents represented by NMU in a carcinogen-class-specific manner. Further, the results suggest the importance of mechanistic and epidemiological studies of the susceptibility of the prepubertal breast to specific carcinogens such as alkylating agents. (c) 2005 Wiley-Liss, Inc.