Comparative transplacental carcinogenesis by directly acting and metabolism-dependent alkylating agents in rodents and nonhuman primates

Abstract

Transplacental carcinogenesis by N-ethyl-N-nitrosourea (ENU) was studied in patas (Erythrocebus patas) and rhesus (Macaca mulatta) monkeys. Repeated intravenous injections throughout pregnancy caused gestational choriocarcinoma in female patas monkeys and a variety of non-trophoblastic neoplasms in their offspring. Latent periods for transplacentally induced tumours varied from less than one month to more than ten years. One case of congenital neoplasm was observed. Certain kinds of neoplasms were observed only in transplacentally exposed offspring, and not in monkeys given the same carcinogen during juvenile or adult life. These included a variety of embryonal tumours, especially nephroblastoma, and tumours of the brain, mostly gliomas. Schwannomas of the peripheral nervous system were not observed in patas monkeys given ENU. One embryonal tumour yielded DNA that transformed NIH 3T3 cells in a transfection assay. Similar protocols performed in rhesus monkeys also yielded a variety of tumours in the offspring, including brain tumours; but in this species the most common embryonal tumour was pulmonary blastoma, and no choriocarcinoma was seen in adult females given ENU during pregnancy. Administration of N-nitrosodiethylamine to patas monkeys during pregnancy at first appeared to have had no effect on the offspring, but administration of phenobarbital beginning at four years of age resulted in the rapid appearance of multiple hepatocellular tumours. With regard to potential human risk from prenatal exposure to carcinogens, three conclusions deserve special emphasis: (1) the extreme susceptibility of the fetal primate central nervous system to certain chemical carcinogens, which confirms and reinforces what was previously known from studies in rodents; (2) the prolonged latency of transplacentally initiated epithelial tumours and the importance of subsequent postnatal exposure to promoting agents; and (3) the concurrent risk of transplacental chemical carcinogenesis in offspring and gestational choriocarcinoma in the mother, suggesting that gestational choriocarcinoma with its short latent period may serve as an epidemiologically exploitable marker for human populations in which transplacental carcinogenesis is likely.