In vitro embryotoxicity of N-methyl-N-(7-propoxynaphthalene-2-ethyl)hydroxylamine (QAB): evidence for N-dehydroxylated metabolite as a proximate dysmorphogen.

The rat conceptus biotransforms N-methyl-N-(7-propoxynaphthalene-2-ethyl)hydroxylamine (QAB) in vitro to 7-propoxynaphthalen-2-ylacetic acid (QAA) and six more (M1 to M6) metabolites. Thus far, M4 has been identified as N-demethyl-QAB and M6 as N-desoxy-QAB. We investigated which of these two metabolites might be involved in QAB-embryotoxicity in vitro. Conceptuses were cultured from day 9.5 to 11.5 post-coitum, and were exposed to N-demethyl-QAB or N-desoxy-QAB either in the culture medium or by microinjection directly into the amniotic cavity. When added to the culture medium, N-demethyl-QAB (No Observed Adverse Effect Level, NOAEL, for growth 122 microM and for differentiation 41 microM) was less active than QAB itself (NOAEL for growth and differentiation 12 microM). N-desoxy-QAB caused severe growth retardation and an impairment of differentiation at a concentration of 11 microM (NOAEL 3.6 microM). As regards causing anomalies, the NOAEL of N-demethyl-QAB (41 microM) was 10-fold higher than that of QAB (NOAEL 3.9 microM) and that of N-desoxy-QAB (NOAEL 3.6 microM). At an intraamniotic concentration of 0.7 mM, N-demethyl-QAB caused no effects on growth and differentiation and no increase of anomalies was observed, whereas QAB and N-desoxy-QAB each elicited an increase in dysmorphogenic embryos at equimolar concentrations without affecting growth and differentiation. It is, therefore, concluded that N-desoxy-QAB, but not N-demethyl-QAB, could be a proximate dysmorphogen responsible for the embryotoxicity/teratogenicity of QAB in vitro.