Müller R, Rajewsky M F
Cancer Res. 1983 Jun;43(6):2897-904.
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.
N-乙基-N-亚硝基脲（EtNU）对BD IX大鼠的神经致癌作用强度在很大程度上取决于致癌物暴露时神经系统的发育阶段，在产前晚期和产后早期发育阶段达到最大值。随着产后年龄的增加以及朝着早期胚胎发育方向（出生后第15天之前），脑和外周神经系统中神经外胚层肿瘤的发生率急剧下降。通过竞争性放射免疫分析法检测O6-乙基脱氧鸟苷（O6-EtdGuo），我们已确定BD IX大鼠组织（包括脑）中DNA乙基化的初始程度与在产前第11天至出生后102天的时间段内经胎盘（静脉内）暴露于恒定单剂量EtNU时的发育阶段无关。O6-EtdGuo在围产期和产后大鼠脑的DNA中高度持久，但可从其他组织（尤其是肝脏）的DNA中通过酶促作用去除。目前的放射免疫分析表明，在妊娠第11天、第13天或第16天暴露于EtNU（50微克/克体重）的产前BD IX大鼠的DNA中，O6-EtdGuo同样持久，但可从其他产前组织中通过酶促作用去除。从肝脏DNA（产前第16天）中去除的速率高于10日龄（产后）BD IX大鼠中的相应速率。在产前第11天至12天（当BD IX大鼠经胎盘暴露于EtNU后神经致癌作用首次显现时；S. Ivankovic和H. Druckrey，《肿瘤研究杂志》，71: 320 - 360，1968），每只脑的细胞数量约为2×10⁵ 。当使用数量有限的实验动物时，并且无论神经前体细胞无法从其DNA中去除O6-EtdGuo，这种靶细胞群体大小可能与诸如恶性转化等罕见事件的表现不相容。
