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J. Biol. Chem., Vol. 279, Issue 29, 30189-30194, July 16, 2004

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A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis^*

Tami L. Thomae, Edward Glover, and Christopher A. Bradfield

From the McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706

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.

Received for publication, April 2, 2004 , and in revised form, May 10, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should addressed: McArdle Laboratory for Cancer Research, 1400 University Ave., Madison, WI 53706-1599. Tel.: 608-262-2024; Fax: 608-262-2824; E-mail: Bradfield{at}oncology.wisc.edu.

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