Specific Carcinogenic and Teratogenic Effects of ‘Indirect’ Alkylating Methyl and Ethyl compounds, and their Dependency on Stages of Ontogenic Developments

Abstract

1. Three groups of ‘indirect’ carcinogens, namely dialkylnitrosamines, 1,2-dialkylhydrazines, azo- and azoxy-alkanes, and 1-aryl-3,3-dialkyltriazenes have been comparatively tested for organotropic and transplacental carcinogenicity, and for teratogenicity in BD-rats. It is demonstrated that enzymic dealkylation (probably initiated by α-C-hydroxylation) and subsequent degradation of the resulting monoalkyl-compounds, eventually yielding the respective alkyl-diazonium as ‘proximate’ alkylating carcinogen or teratogen, is a common feature of these three groups.

12. Despite the similarity of metabolic activation, striking differences of the biological effects between the groups, and particularly between their methyl and ethyl derivatives, were observed. The results indicate that the enzymes involved are probably highly specific and that de-ethylation, in contrast to demethylation, is possible at an early stage of prenatal development.

13. In transplacental experiments, hydrazo-, azo- and azoxy-ethane, as well as diethyl-aryltriazenes, proved to be highly carcinogenic to the foetus and induced malignant tumours exclusively of the brain and nervous system in almost all offspring even at a very low single dose. The sensitivity of the foetal nervous system to malignant transformation, however, was demonstrable only after the eleventh day. After administration of the ethyl-compounds at the tenth day partial or complete inhibition of the development of the optic nerves and eyes, mostly associated by hydrocephalus internus, was observed with regularity. The dimethyl homologues and various dialkylnitrosamines were not carcinogenic to the foetus except at the last day of gestation. After birth all compounds revealed their respective organotropic effects, and the induction of, for example, oesophageal or colonic cancer by a single dose was possible in newborn rats.

14. Since the primary carcinogenic effects at the molecular level are to be attributed to the induction or production of irreversible and ‘inheritable’ damage of the genetic apparatus of somatic cells, the potential importance of ‘genotoxic’ substances in the etiology of other degenerative diseases is briefly discussed.