Cloacal and Urogenital Abnormalities Induced by Etretinate in Mice

Abstract

Etretinate, a synthetic retinoid, is a potent teratogen. It has previously been shown that acute exposure of gestational day 8 (equivalent to human week 4 post-fertilization) C57BL/6J mouse embryos to this retinoid results in a spectrum of abnormalities that are recognized as constituting 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, therefore, the last opportunity for abnormalities within the realm of caudal regression to be induced. In fact, acute etretinate exposure on gestational day 9 resulted in anal and urethral atresia, bladder and ureteral dilatation, and tail deficiencies as observed in 251 near-term fetuses in this study. To examine in further detail the gestational day 9 etretinate induced urogenital and anal abnormalities and their pathogenetic basis, analyses were conducted using scanning electron microscopy, light microscopy, antegrade cystourethrograms and a vital staining technique as early as 6hours 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 embryogenesis accounts for the observed phenotype. We propose that anal and urethral atresia temporally represents the end of the caudal regression (dysgenesis) syndrome.