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MANDIBULAR REPATTERNING RESULTS FROM IN UTERO ANTAGONISM OF ENDOTHELIN RECEPTORS IN MICE
Citation:
Brannen, K. C., E S. Hunter III, M B. Rosen, AND J M. Rogers. MANDIBULAR REPATTERNING RESULTS FROM IN UTERO ANTAGONISM OF ENDOTHELIN RECEPTORS IN MICE. Presented at Teratology Society Meeting, Montreal, Quebec, Canada, June 23-28, 2001.
Description:
BRANNEN, K.C.1,2, E.S. HUNTER1,2, M.B. ROSEN2, and J.M. ROGERS1,2. 1Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 2Reproductive Toxicology Division, NHEERL, U.S. EPA, Research Triangle Park, North Carolina. Mandibular repatterning results from in utero antagonism of endothelin receptors in mice.
Through knockout mice (Kurihara et al., Nature 368:703, 1994; Clouthier et al., Development 125:813, 1998) and receptor antagonism in rats (Spence et al., Reprod Toxicol 13:15, 1999), it has been shown that signaling between endothelin-1 (ET-1) and the endothelin-A receptor (ET-A) is critical for development of neural crest derived pharyngeal arch structures. We previously demonstrated that ET-A antagonism affects first arch development in mouse embryo culture. Here we characterized the effects of in utero exposure to L-754,142 (Merck), an ET-A /ET-B receptor antagonist, in mice. CD-1 mice were dosed orally with the antagonist on gestation day (gd) 8.0 at 1000 or 1250 mg/kg; controls received distilled water. The most striking effects of this single-day exposure in gd 18 fetuses were mandible and ear defects. Mandibles exhibited median cleft, ectopic vibrissal rows, reduced size, and additional bones. Ears of treated fetuses tended to be small with detached pinnae. In most treated fetuses, the mandibular side of the oral cavity was abnormal, exhibiting a pair of tissue swellings with anatomical similarity to palatal shelves, lateral to a hypoplastic tongue. Some lower dose treated fetuses displayed milder micrognathia, microtia, and microglossia, but lacked mandibular vibrissal rows, additional bones, and excess oral tissue. However, the presence of ectopic, but highly organized, vibrissae, a median cleft, altered skeletal structure, and similarities between the tissues lateral to the tongue and palatal shelves in most treated fetuses suggests a patterning change of the mandible to a more maxillary phenotype. Based on these data, it appears that ET-1/ET-A signaling is involved in patterning mandibular versus maxillary processes of the first pharyngeal arch, and production of the defects with a single gd 8 dose indicates that early neural crest cell development is involved. This abstract does not reflect EPA policy. KCB supported by EPA CT827206, NIEHS ES07126.