Amelioration of TCDD-induced teratogenesis in aryl hydrocarbon receptor (AhR)-Null mice

The aryl hydrocarbon receptor (AhR) mediates many of the biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and transcriptional activati on of genes encoding a number of xenobiotic metabolizing enzymes. Prenatal exposure of mice to TCDD causes severe alterations in embryo and fetal deve lopment, including hydronephrosis and cleft palate. However, the mechanisms underlying these effects are unclear. In this work, the teratogenicity of TCDD in AhR-null mice was evaluated to determine if this effect is mediated by the AhR. Homozygous wild-type (+/+) or AhR-null (-/-) female mice were mated with males of the same genotype overnight. On gestation day (GD)-10, mice were intubated orally with either corn oil (vehicle control) or 25 mu g/kg TCDD. Fetuses were examined on GD18 for visceral and skeletal alterati ons. For non-TCDD-exposed litters, all developmental endpoints were compara ble between genotypes, with the exception of a lower incidence of large int erfrontal bones in (-/-) mice. For TCDD-exposed litters, (+/+) fetuses had a significantly greater incidence of cleft palate, hydronephrosis, small ki dneys, tortuous ureters and greater dilation of the renal pelves and ureter s compared to (-/-) fetuses. Interestingly, an increased resorption rate wa s observed in (-/-) fetuses exposed to TCDD. Results from this work demonst rate that fetal development per se is generally unaffected by the absence o f the AhR or that other genes may have compensated for the loss of the AhR. More importantly, these data indicate that the AhR mediates TCDD-induced t eratogenicity. Further, since a higher percentage of resorptions was observ ed in (-/-) litters from TCDD-treated dams, it is possible that AhR-indepen dent mechanisms contribute to TCDD-induced developmental toxicity.