Elimination of O6-ethylguanine from the DNA of brain, liver, and other rat tissues exposed to ethylnitrosourea at different stages of prenatal development.

ABSTRACT

The magnitude of the neurooncogenic effect of N-ethyl-N-nitrosourea (EtNU) in the BD IX rat is strongly dependent on the developmental stage of the nervous system at the time of carcinogen exposure, with a maximum during late prenatal and early postnatal development. Both with increasing postnatal age and in the direction of early embryonic development (prior to Postnatal Day 15), the yield of neuroectodermal tumors in the brain and peripheral nervous system declines sharply. Using a competitive radioimmunoassay for O6-ethyldeoxyguanosine (O6-EtdGuo), we have ascertained that the initial degree of DNA ethylation in BD IX rat tissues (including brain) is independent of the developmental stage at the time of transplacental (i.v.) exposure to a constant single dose of EtNU over a time range from Prenatal Day 11 to a postnatal age of 102 days. O6-EtdGuo is highly persistent in the DNA of peri- and postnatal rat brain but enzymatically removed from the DNA of other tissues, notably liver. The present analyses by radioimmunoassay indicate that O6-EtdGuo is equally persistent in the DNA of prenatal BD IX rats exposed to EtNU (50 micrograms/g body weight) on the 11th, 13th, or 16th day of gestation but removed enzymatically from other prenatal tissues. The rate of removal from the DNA of liver (Prenatal Day 16) is higher than the corresponding rate in 10-day-old (postnatal) BD IX rats. On Prenatal Day 11 to 12 (when a neurooncogenic effect first became apparent after transplacental exposure of BD IX rats to EtNU; S. Ivankovic and H. Druckrey, Z. Krebsforsch., 71 320-360, 1968), the number of cells per brain is approximately 2 X 10(5). When a limited number of experimental animals are used, and regardless of the incapacity of neural precursor cells to remove O6-EtdGuo from their DNA, this target population size may be incompatible with the manifestation of a rare event such as malignant transformation.