CLOACAL AND UROGENITAL ABNORMALITIES INDUCED BY ETRETINATE IN MICE

Etretinate, a synthetic retinoid, is a potent teratogen. It has previo usly been shown that acute exposure of gestational day 8 (equivalent t o human week 4 post-fertilization) C57BL/6J mouse embryos to this reti noid results in a spectrum of abnormalities that are recognized as con stituting caudal regression (dysgenesis). These defects, which include spina bifida, imperforate anus, genitourinary anomalies, omphalocele and limb anomalies, result from a major insult to the primitive streak , that is the gastrulation process. Developmental stages present early on gestational day 9 in mice represent the final stages during which the primitive streak contributes to the trunk of the embryo and, there fore, the last opportunity for abnormalities within the realm of cauda l regression to be induced. In fact, acute etretinate exposure on gest ational day 9 resulted in anal and urethral atresia, bladder and urete ral dilatation, and tail deficiencies as observed in 251 near-term fet uses in this study. To examine in further detail the gestational day 9 etretinate induced urogenital and anal abnormalities and their pathog enetic basis, analyses were conducted using scanning electron microsco py, light microscopy, antegrade cystourethrograms and a vital staining technique as early as 6 hours following maternal drug administration. It appears that diminution of the caudal cell populations, including those of and those surrounding the cloaca, at this critical stage of e mbryogenesis accounts for the observed phenotype. We propose that anal and urethral atresia temporally represents the end of the caudal regr ession (dysgenesis) syndrome.