Toxicological Sciences, Vol 47, 86-92, Copyright © 1999 by Society of Toxicology
JM Peters, MG Narotsky, G Elizondo, PM Fernandez-Salguero, FJ Gonzalez and BD Abbott
The aryl hydrocarbon receptor (AhR) mediates many of the biological effects
of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and transcriptional
activation of genes encoding a number of xenobiotic metabolizing enzymes.
Prenatal exposure of mice to TCDD causes severe alterations in embryo and
fetal development, 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 micrograms/kg TCDD. Fetuses were examined on GD18
for visceral and skeletal alterations. For non-TCDD-exposed litters, all
developmental endpoints were comparable between genotypes, with the
exception of a lower incidence of large interfrontal bones in (-/-) mice.
For TCDD- exposed litters, (+/+) fetuses had a significantly greater
incidence of cleft palate, hydronephrosis, small kidneys, tortuous ureters
and greater dilation of the renal pelves and ureters compared to (-/-)
fetuses. Interestingly, an increased resorption rate was observed in (- /-)
fetuses exposed to TCDD. Results from this work demonstrate that fetal
development per se is generally unaffected by the absence of 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
teratogenicity. Further, since a higher percentage of resorptions was
observed in (-/-) litters from TCDD-treated dams, it is possible that
AhR-independent mechanisms contribute to TCDD-induced developmental
toxicity.
ARTICLES
Amelioration of TCDD-induced teratogenesis in aryl hydrocarbon receptor (AhR)-null mice
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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