Mechanism of perinatal tumor induction by neuro-oncogenic alkylnitrosoureas and dialkylaryltriazenes.

Abstract

The methylation by DMPT and MNU of DNA from rat liver and brain was investigated at various developmental stages. Following a single sc injection of [14C]DMPT (100 mg/kg body wt, 15 hr survival time) in pregnant rats (21st day of gestation), the extent of methylation of purine bases was similar in fetal liver and brain. During postnatal growth, this treatment resulted in an increasingly preferential methylation of liver DNA. In 30-day-old BD-IX rats, the concentration of 7-methylguanine in liver was approximately eight times higher than in brain DNA. This suggested that during prenatal development, both liver and brain DNA are transplacentally methylated by a proximate carcinogen produced by maternal organs. After a single ip injection of [3H]MNU (10 mg/kg body wt) to 10-day-old rats, O6-methylguanine was more rapidly removed from hepatic than from cerebral DNA. Within 1 week after the injection, the brain-to-liver ratio for 06-methylguanine increased from 1.4 to 98. These results are compatible with the hypothesis that the deficiency of various organs for repair excision of O6-alkylguanine from DNA correlates with their susceptibility to malignant transformation by monofunctional alkylating carcinogens.