The effects of ethylene glycol monoethyl ether (EGEE) were determined on development in utero. Pregnant New Zealand White rabbits were exposed to air or 160 or 617 ppm EGEE for 7 hr/day from 1 to 18 days of gestation (dg). Virgin Wistar rats were exposed to 150 or 649 ppm EGEE or air 5 days/week for the 3 weeks immediately preceding their breeding. Sperm-positive rats were subsequently exposed to air or 202 or 767 ppm EGEE for 7 hr/day from 1 to 19 dg. Group sizes were 29 to 38 per concentration for both species.Pregestational exposure of rats had no effect on mating success, and there was no effect of EGEE exposure on establishment of pregnancy in either species. Rabbits exposed to the both concentrations had decreased food intake and depressed weight gain. Exposure-related mortality occurred in the 617 ppm EGEE group of rabbits. The only toxic sign seen in rats was reduced weight gain after exposure to 767 ppm EGEE. Exposure induced high embryomortality at maternal toxic concentrations in rats and rabbits, while lower levels induced fetal growth retardation in rats but not in rabbits. Gestational exposure increased the incidence of anomalies and variations; these were primarily of soft tissues in rabbits and of skeleton in rats. Thus, significant evidence of terata, fetal growth retardation and embryomortality were induced in rabbits and rats at levels that were below or similar to those that induced maternal manifestation of toxicity. These data implicate EGEE as a teratogen.

Abstract. A study was undertaken to elucidate the molecular mechanisms by which glucocorticoids induce cleft palate in mice. It was hypothesized that a compound such as triamcinolone acetonide inhibits m-RNA synthesis; that this results later in depressed protein synthesis; and that the latter is ultimately responsible for slowed palate formation and cleft palate. Support for the model derives from the fact that the palatine shelves rise and fuse 3-4 days after the most sensitive time of administration of steroid; RNA synthesis was markedly inhibited 6-24 hr after its administration; and coadministration of cycloheximide partially reversed the tendency toward cleft palate formation.Prenatally administered cortisone produces cleft palate in mice1' 2 and has been reported to inhibit mucopolysaccharide synthesis in the fetal mouse palate.3 4 Larsson3 postulated that the cleft palate was due to the block in the synthesis of mucopolysaccharides (supposedly responsible for the "internal shelf force" that raises the secondary palatine shelf from the horizontal position to the vertical). Alternative explanations are oligohydramnios,5 excessive hydration of palatine tissue,6 and protein catabolism.7To try to clarify the mechanism by which glucocorticoids cause cleft palate in mice, an alternative approach to the problem was taken. The model proposed was predicated on the known inhibition of RNA synthesis by glucocorticoids, responsible for growth suppression in certain target cells in vivo8 and in vitro.9 It was postulated that such an inhibition of mRNA synthesis in the fetal palate would lead to a later inhibition of protein synthesis and hence cleft palate; i.e., protein and RNA synthesis would be out of phase due to the sequential synthesis of mRNA molecules during the 3-4 day period of time that the glucocorticoid was administered and the time that the palatine shelves rise.Experiments were undertaken to test the model with triamcinolone acetonide, 10 since a single dose of extremely small quantities of this glucocorticoid causes cleft palate in mice.11 It was shown that triamcinolone acetonide (hereafter referred to as triamcinolone) inhibits RNA synthesis in mouse embryos within 6 hr of administration, and furthermore that cycloheximide partly prevents induction of the cleft palate.Materials and Methods. The inbred mouse strain C3H/An (Cumberland View Farms, Clinton, Tenn.) was used. Vaginal plugs on the morning following overnight 779

Medroxyprogesterone acetate (MPA) has been shown to be teratogenic in rabbits but not in rats or mice (Andrew and Staples, '77). Since normal steroid action appears to be mediated, in large part, through interaction with specific steroid receptors, we postulated that the species difference in teratogenicity might be due to a difference in the interaction of MPA with target cells. A primary event in steroid-cell interaction is the binding of a steroid to intracellular receptors. Studies were initiated to measure the specific nature of MPA binding to glucocorticoid and progestin receptors in appropriate rat and rabbit target tissues. The competition of MPA with 3H-dexamethasone binding in liver cytosol (glucocorticoid receptor) and with 3H-progesterone binding in uterine cytosol (progesterone receptor) was determined. In rabbit liver cytosol MPA was as effective at competing for specific dexamethasone binding as the natural glucocorticoids and considerably more effective than the nonspecific steroids. In rat liver cytosol MPA was only 10% as effective as the natural glucocorticoids, and the competition could not be distinguished from that of nonspecific steroids. A similar species difference was not seen in uterine cytosol; MPA competed with progesterone in a similar fashion in both rat and rabbit. These data demonstrate a distinct species difference in the competitive nature of MPA for the glucocorticoid receptor but not for the progestin receptor. The results suggest that MPA, or possibly a metabolite, may be teratogenic in rabbits by binding with specific glucocorticoid receptors to inhibit or alter normal steroidal function in embryo-fetal development.Medroxyprogesterone acetate (MPA, 6a-