Congenital malformations of the central nervous system and transplacental carcinogenesis: modification of ethylnitrosourea-induced brain tumors in rats by pretreatment with methylazoxymethanol

Abstract

X-irradiation of rat fetuses prior to exposing them transplacentally to the neurotropic carcinogen ethylnitrosourea (ENU) greatly reduces the frequency of offspring that develop neurogenic tumors. Since the tumor inhibition may have been related to the teratogenic effects of the irradiation of the fetal brain, it was of interest to learn whether another means of causing such brain damage would also interfere with the development of ENU-induced neurogenic tumors. For this purpose methylazoxymethanol (MAM), known to produce microencephaly, was used. Pregnant Sprague-Dawley rats were injected i.p. with 20 or 30 mg MAM/kg on the 15th day of gestation and 10 mg ENU/kg on the 16th or 20th day of gestation, or with either chemical alone. The offspring were observed during their life-span for the appearance of neurogenic tumors. MAM produced the expected microencephaly, but when administered alone caused no neurogenic tumors. ENU had no effect on brain size; and when administered alone produced high rates of offspring with neurogenic tumors (68 and 72% after treatment on the earlier and later day of gestation, respectively). The combined treatments resulted in significantly reduced frequencies of brain tumors, but did not modify the frequencies of non-brain tumors. The treatments caused relatively little or no excess pre- and postnatal mortality and for the most part had little effect on postnatal growth. Mean time of appearance of neurogenic tumors and mean number of neurogenic tumors per affected animal were unchanged by the dual treatments. There were no sex differences in tumor frequency, latency, or multiplicity. As noted, MAM reduced cerebral hemisphere size, but did not affect spinal cord size. The site of tumor inhibition by MAM thus appears to be correlated with the site of teratogenic damage. Nevertheless, various considerations led us to conclude that reduced number of target cells does not entirely explain the modifications in the frequency of tumors caused by MAM.