Teratological studies on the TCDD congener 3,3',4,4'-tetrachloroazoxybenzene in sensitive and nonsensitive mouse strains: evidence for direct effect on embryonic tissues.

The teratogenicity of 3,3',4,4'- tetrachloroazoxybenzene ( TCAOB ), a TCDD congener, was studied in Ah-responsive (C57BL and NMRI) and non-responsive (DBA/2J and AKR/ NBom ) strains of mice. In the responsive strains, the TCAOB produced cleft palate and hydronephrosis in 50-90% of the offspring at a dose level of 6-8 mg/kg b.w. in the absence of apparent maternal toxicity. Day 11 was shown to be the day of highest sensitivity (palatal closure occurs at day 14) in the C57BL strain. Higher doses (16 mg/kg b.w.) produced high rate of fetal death both in responsive (C57BL; 60%) and non-responsive (DBA; 40%) strains. These doses induced cleft palate in 95% of the surviving C57BL fetuses but failed to do so in the DBA strain. The non-sensitivity of the DBA and AKR strains appeared to segregate as a dominant trait. Backcrosses between NMRI X DBA F1 generation and NMRI showed an intermediate sensitivity. It was shown that the genotype of the embryo was of ultimate importance for the development of cleft palate. There appeared however to be an additional host (maternal) factor as well, because the offspring of NMRI females mated with NMRI X DBA F1 males showed a higher rate of cleft palate as compared to those of the crossing between NMRI X DBA F1 females and NMRI males. Light and scanning electron microscopy indicated that the apical epithelial cells of the secondary palates failed to follow the normal pattern of programmed cell death, suggesting a similar mechanism of pathogenesis as previously described for TCDD.