Recent epidemiological studies have suggested, but not proven, that intake of high levels of vitamin A during early pregnancy may pose a teratogenic risk. Recent studies carried out in the cynomolgus monkey (Macaca fascicularis) contribute new information regarding the possible association of birth defects with hypervitaminosis A in a species closely related to humans. Moreover, this species is a well-documented model for teratogenicity associated with the vitamin A analog, isotretinoin (Accutane). The malformation syndrome, as well as teratogenic dose and sensitive period, is very similar in the monkey to the retinoid syndrome in human infants. Current studies in the monkey model involved oral exposure to excessive doses of vitamin A (retinyl palmitate, AROVIT) administered at 7,500 lU/kg (n=20), 20,000 lU/kg (n=26), 40,000 lU/kg (n=8). and 80,000 IU/kg (n=29) during early pregnancy (gestation day 16-27). The results indicated a dose-related increase in abortions and malformations which affected typical retinoid target tissues, including the craniofacial region (external ear, mandible, zygomatic process, and tympanic ring), heart (transposition of great vessels), and thymus (hypoplasia). These malformations involve structures derived from the cranial neural crest and are similar to those observed after in utero exposure to isotretinoin in both the human and monkey. The NOAEL and LOAEL determined from these studies were 7,500 lU/kg and 20,000 lU/kg, respectively. Based on the known similarities in teratogenic susceptibility to isotretinoin, this monkey data can be used to extrapolate a hypothetical safe dose of the parent compound to humans.
|Original language||English (US)|
|State||Published - 1997|
ASJC Scopus subject areas
- Agricultural and Biological Sciences (miscellaneous)
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology