Teratogenicity in vitro of two deacetylated metabolites of N-hydroxy-2-acetylaminofluorene.

In previous studies [E. Faustman-Watts, J. C. Greenaway, M. J. Namkung, A. G. Fantel, and M. R. Juchau (1983) Teratology 27, 19-28] an embryo culture system was utilized to investigate the role of biotransformation in the embryotoxicity of 2-acetylaminofluorene. For this investigation, the capacity of two deacetylated metabolites of N-hydroxy-2-acetylaminofluorene (N-OH-AAF) to produce malformations in cultured whole rat embryos is reported. The relative capacities of N-hydroxy-2-aminofluorene (N-OH-AF) and 2-nitrosofluorene (NF) to elicit embryotoxic effects, including embryolethality, malformations, growth retardation, and alterations in macromolecular content, were assessed and compared with effects produced by N-OH-AAF and bioactivated 2-acetylaminofluorene (AAF). Qualitatively similar patterns of malformations were produced by NF and N-OH-AF. At initial concentrations greater than 60 microM, both deacetylated compounds caused abnormalities in axial rotation (flexure), decreased viability, and decreases in embryonic DNA and protein content. Both chemicals were active in the absence of a bioactivating system. AAF produced a different spectrum of defects, and was active only in the presence of a complete monooxygenase system. The malformations produced by bioactivated AAF included abnormally open neural tubes; flexure abnormalities were rarely observed. The primary defect elicited by N-OH-AAF was prosencephalic hypoplasia. This chemical was active without an added bioactivating system. Temporal studies demonstrated that exposure of embryos to NF (128 microM) for as little as 2 hr was sufficient to elicit embryotoxic effects. None of the individual metabolites appeared to be solely responsible for the interruptions of neural tube closure produced by bioactivated AAF.