Interference of acetoxyalkyl-nitrosamines with limb bud differentiation in organ culture

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Abstract
α-acetoxynitrosamines have been used as model compounds to study biological activity of N-nitrosamines. After hydrolytic cleavage they yield an “active intermediate” (the hydroxynitrosamine) which presumably also arises as metabolite of N-nitrosamines. We tested eight N-nitrosamines mono-substituted at theα-carbon with an acetoxy group for their teratogenic potential in a mouse limb bud culture system. The following results were obtained: The methyl compound (MOAc-MNA) — a derivative of dimethynitrosamine — proved to be the strongest teratogen in this group of chemicals. The tertiary-butyl derivative — releasing a carbonium ion of low chemical reactivity — possessed the lowest activity in our test system. The primaryα-acetates with unbranched side chains (POAc-MNA or BOAc-MNA) were more active than the corresponding derivatives with branched side chains. The secondaryα-acetate (EOAc-ENA) was clearly less active than the primaryα-acetate (EOAc-MNA). A teratogenic potential could also be demonstrated in the organ culture system with the cyclic derivative: N-nitroso-α-acetoxy-pyrrolidine (NAPYR). With the use of limb buds from 12-day-old mouse embryos the explants showed the highest susceptibility to the teratogens on the first day of culture. No effect could be produced if the substances were added to the culture medium at the third day of culture or later. When initiating the culture with limb buds from 11-day-old mouse embryos the concentrations needed to induce typical effects were lower than those tested with 12-day-old explants. Typical and pronounced impairment with morphogenetic differentiation could be induced by MOAc-MNA if the substance was present in the medium for less than 60 min — the shortest period tested was 15 min. A different abnormality pattern could be induced with the various substances tested. This may partly be explained by a quite different stability of the compounds in the test system. N-Nitrosamines must be expected to be highly teratogenic if they can be “activated” in embryonic tissues. Such an activation into potent electrophilic agents does not occur in rodents under normal conditions. It will be interesting to study if such activity can be “induced” in embryonic tissues of rodents or if it is already present in embryonic tissues of primates.

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