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

Abstract

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-treated 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.

Noticing pesticide spray drift from agricultural pesticide application areas and breast cancer: a case‐control study

“…These findings are consistent with animal studies that showed that effects of environmental exposure depended on whether exposure occurs during specific times of the mammary gland development. 22,27 Epidemiological human studies also propose similar periods of susceptibility of the breast to carcinogenesis early in a woman's life. For example, increases in breast cancer risk were observed in women who survived the atomic bomb in Hiroshima and Nagasaki when aged less than 20 years, whereas no increase in risk was observed among women older than 35 years at the time of the bombing.…”

“…21 Results from animal models suggest there is a time window of increased susceptibility to mammary carcinogens in early life. 22,23 Breast tissues undergo terminal differentiation at first full-term birth and before that time the breast tissue is still developing. Hence, taken together, these findings suggest that environmental exposures during younger ages, compared with those that occur at older ages, may be more likely to affect breast cancer risk.…”

Reversibility of pre-malignant estrogen-induced epigenetic changes

“…The ACI rat shares a common genetic etiology remarkably similar to human breast cancer, with the developing mammary gland of a young adult being the most susceptible for chemical and physical agents to exert their carcinogenic potential. 28,29 By examining the influence of estrogen exposure on epigenetic mechanisms that parallel the histological progression of pre-malignant changes in the mammary gland, we hope to characterize the sequence of early epigenetic markers that can be detected prior to tumor development. Furthermore, we hypothesized that the removal of the promoting agent will lead to regression of pre-malignant alterations that may be related to "redifferentiation" and remodeling of the epignomic landscape.…”

Inducible tumor difference between rapid and slow rat Nat2 congenic Fischer 344 rats administered methyl-nitrosourea.

“…MNU is a simple alkylating agent, which places a methyl group on oxygen and nitrogen of macromolecules, like DNA. It has been shown previously that sexually immature F344 rats (at 3 weeks of age) are more susceptible to mammary carcinogenic effects from MNU than mature rats (8 weeks of age) [45].…”

“…MNU is a direct acting DNA alkylating agent that does not need biotransformation before forming DNA adducts. It has been previously shown that sexually immature F344 rats (at 3 weeks of age) are more susceptible to mammary carcinogenic effects from MNU than mature rats (8 weeks of age) [45]. Developmental studies on the rats over time can be done to see if O 6 -alkyguanine-DNA alkyltransferase, also known as O 6 -methylguanine DNA methyltransferase, the only enzyme shown to have a chemopreventive role in MNU toxicity varies between rapid and slow Nat2 congenic rats [51].…”