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First published on December 14, 2005; DOI: 10.1124/mol.105.019760

0026-895X/06/6903-770-775$20.00
Mol Pharmacol 69:770-775, 2006

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The Teratogenic Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Is Modified by a Locus on Mouse Chromosome 3

Tami L. Thomae, Emily A. Stevens, Adam L. Liss, Norman R. Drinkwater, and Christopher A. Bradfield

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

In an effort to understand how genetics can influence individual sensitivity to environmentally induced disease, we performed a linkage analysis to identify murine loci in addition to the Ahr locus that influence the incidence of cleft palate and hydronephrosis in developing mice exposed to the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). Administration of 64 µg/kg dioxin to C57BL/6J (B6) dams at embryonic day 9 (E9) led to palatal clefting and hydronephrosis in nearly 100% of embryos by E17. In contrast, similar exposure of CBA/J (CBA) dams led to cleft palate in only 8% and hydronephrosis in 69% of embryos. To determine the genetic basis for this strain-dependent sensitivity, linkage analyses on the progeny of a B6CBAF1 intercross and a CBAxB6CBAF1 backcross were performed. The incidences of cleft palate and hydronephrosis were assessed and genomic DNA from embryos was analyzed at informative simple sequence length polymorphism (SSLP) markers. One locus segregating with dioxin-induced cleft palate was identified (p < 0.01) and designated as chemically mediated teratogenesis number 1 (Cmt1). The Cmt1 locus is located on chromosome 3.

Received October 10, 2005; accepted December 14, 2005

Address correspondence to: Christopher A. Bradfield, McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, WI 53706-1599. E-mail: bradfield{at}oncology.wisc.edu






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