A maternal Ahr null genotype sensitizes embryos to chemical teratogenesis.
The aryl hydrocarbon receptor (encoded by the Ahr locus) is a ligand-activated transcription factor that mediates the toxicology and teratology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). In an effort to understand the role of the maternal compartment in dioxin teratology, we designed a breeding strategy that allowed us to compare the teratogenic response in embryos from Ahr(-/-) (null) and Ahr(+/+) (wild-type) dams. Using this strategy, we demonstrate that embryos from the Ahr(-/-) dams are 5-fold more sensitive to dioxin-induced cleft palate and hydronephrosis as compared with embryos from an Ahr(+/+) dam. Moreover, this increased teratogenic sensitivity extends beyond dioxin, because embryos from Ahr(-/-) dams exhibited a 9-fold increase in their sensitivity to the fetotoxic effects of the glucocorticoid, dexamethasone. In searching for an explanation for this increased sensitivity, we found that more dioxin and dexamethasone reached the embryos from Ahr(-/-) dams as compared with embryos from Ahr(+/+) dams. We propose that increased deposition of teratogens/fetotoxicants to the embryonic compartment is the result of porto-systemic shunting and/or blocked P4501A induction in Ahr(-/-) dams. In addition to demonstrating the importance of maternal AHR in teratogenesis, these data may have implications that reach beyond the mechanism of action of dioxin. In this regard, the Ahr(-/-) mouse may provide a system that allows pharmacological agents and toxicants to be more easily studied in a model where first pass clearance is a significant obstacle.
Thomae
Tami L
TL
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
Glover
Edward
E
Bradfield
Christopher A
CA
D000818:Animals; D002845:Chromatography; D002972:Cleft Palate / Q000139:chemically induced; D003907:Dexamethasone / Q000494:pharmacology; D004147:Dioxins; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006869:Hydronephrosis / Q000139:chemically induced; D008297:Male; D013058:Mass Spectrometry; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009035:Mothers; D010375:Pedigree; D011247:Pregnancy; D011270:Pregnancy, Animal; D011874:Radiometry; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D013723:Teratogens; D013997:Time Factors; D014018:Tissue Distribution
D004147:Dioxins; D018336:Receptors, Aryl Hydrocarbon; D013723:Teratogens; D003907:Dexamethasone