TERATOGENICITY OF LOW-DOSES OF ALL-TRANS-RETINOIC ACID IN PERSOMITE MOUSE EMBRYOS

This study was designed to examine the developmental dose response for all-trans retinoic acid (TRA) administered at presomite stages in mouse embryos. Previous studies using hamsters [Shenefelt (1972) Teratology 5:103-118] have shown that developmental stages corresponding to those present early on gestational day (GD) 7 in mice are most sensitive to retinoid-induced teratogenesis. Our preliminary studies showed that at this treatment time, gavage dosages of 7.5 mg/kg maternal body weight administered to C57B1/6N mice, an inbred strain, resulted in severe craniofacial malformations representing the holoprosencephaly, aprosencephaly spectrum. Additionally, in an outbred mouse strain, CD-1, exencephaly was induced by dosages of 2.5 mg/kg TRA and above. Readily detectable abnormalities of the eyes, including anophthalmia and severe microphthalmia and iridial colobomata, were induced by even lower doses of TRA in the C57B1/6N strain. Incidences of micro/anophthalmia were 6.7%, 8.1%, 12.9%, and 32.4% at 0, 0.313, 0.625, and 1.25 mg/kg, respectively. The dosages required to induce significant incidences of exencephaly (2.5 mg/kg) and severe ocular abnormalities (1.25 mg/kg) on GD 7 in mice are approximately 50-100-fold less than those that are commonly used to examine the teratogenicity of this compound at later developmental stages in this species. The trend toward an increase in the incidence of severe ocular malformations at the lowest dose examined and the fact that subtle ocular malformations were not taken into account for this study suggest that even lower dosages may be effective. Practical implications of this study include 1) the obvious need to conduct threshold dose determination studies at the most sensitive developmental stage in a senstive strain/species, and 2) the need for careful surveillance of human populations for brain and ocular malformations (not necessarily those falling within the realm of retinoic acid embryopathy) following retinoid exposure during early stages of pregnancy. (C) 1995 Wiley-Liss, Inc.