The embryotoxic, mutagenic, and cytotoxic properties of 2-acetylaminofluorene (AAF) and two of its reactive metabolites, N-acetoxy-2-acetylaminofluorene (AAAF) and 2-nitrosofluorene (NF) were assessed in vitro. A combined embryo culture/biotransformation system was used to determine the ability of these compounds to produce embryonic malformations, growth retardation, and/or embryolethality. Salmonella typhimurium auxotrophs (his-) were utilized to measure the mutagenic and cytotoxic potentials of these compounds. The parent compound, AAF, did not produce embryonic malformations or mutagenicity in the absence of an added cytochrome P-450-dependent monooxygenase system. Both metabolites produced each of the measured toxic effects without supplementation of a bioactivation system. However, the three chemicals each elicited a different spectrum of malformations. Bioactivated AAF produced neural tube abnormalities, whereas embryos treated with AAAF primarily exhibited prosencephalic malformations, and NF produced abnormalities of axial rotation or flexure. NF was approximately ten times more potent than AAAF as a direct-acting mutagen but only slightly more active in producing embryonic malformations in vitro. The results indicated that differential effects on the various measured parameters could be produced by these chemicals. The results indicated further that neither NF nor AAAF appeared to be individually responsible for the neural tube abnormalities generated by biotransformed AAF.
2-Acetylaminofluorene (AAF), a highly effective mutagen and carcinogen, was tested as a direct-acting teratogen in an embryo culture system. Concentrations of up to 75 kg/ml (336 kM) of AAF produced no detectable malformations and only minimal decreases in viability and growth of rat embryos explanted on day 10 (11th day of gestation; the day after fertilization was designated as day 0). Inclusion of a microsomal monooxygenase system (prepared from rat liver) in the culture medium, however, resulted in marked changes in viability and growth. All explanted embryos exposed to concentrations of AAF above 60 Fg/ml (269 (LM) plus the microsomal monooxygenase system exhibited readily observable malformations as well as significant decreases in size and macromolecular content. Two metabolites, N-hydroxy-2-acetylaminofluorene (N-OH-AAF) and N-acetoxy-2-acetylaminofluorene (AAAF), each produced malformations in the absence of a monooxygenase system. At concentrations of 25 Fgl ml (105 and 88 FM) approximately 50% of the embryos exposed to these metabolites were malformed. The predominant malformations associated with the metabolites were ventrolateral protrusions and hypoplasia of the prosencephalic region, whereas AAF plus the monooxygenase system produced an interruption of neural tube closure. This suggested the possibility that other metabolites may participate in the AAF-induced malformation syndrome. The addition of the monooxygenase system to cultures containing N-OH-AAF or AAAF increased the frequency of malformations without increasing lethality or decreasing growth.2-Acetylaminofluorene (AAF) is an extremely effective mutagenic and carcinogenic aromatic amine. It is utilized extensively as a
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