Model predicting the teratogenic potential of retinyl palmitate, using a combined in vivo/in vitro approach

Effect of co‐administration of retinoids on rat embryo development in vitro

“…Serum concentrations of a number of teratogenic retinoids are raised above endogenous levels. In vivo studies (Buss et al, 1994; Tembe et al, 1996; Ritchie et al, 1998) have concluded, however, that the maternal serum concentrations of only one metabolite e.g., tRA, may not appropriately predict teratogenic risk. The finding that, if present in certain combinations, RP metabolites can induce malformations even when present below threshold concentrations can assist in assessing the teratogenic potential of a large oral dose of vitamin A.…”

“…The method has earlier been validated in the rat (Ritchie et al, 1998). In that experiment, HPLC was used to determine the serum concentrations of RP and its metabolites and rat embryos were then cultured in this serum ie.…”

“…HPLC of serum collected after a teratogenic oral dose of retinyl palmitate in the rat revealed the presence of suprathreshold concentrations of only some of these metabolites ie. retinol, tRA and 4otRA (Ritchie et al, 1998). Rat embryos were grown in this dosed serum and as expected, many were abnormal confirming the presence of teratogenic compounds.…”

“…Each of the retinoids is teratogenic in vitro at different concentrations. tRA and 4otRA are the most potent, followed by 9cRA, then 13cRA, 4o13cRA and retinol (Morriss and Steele, 1974; Webster et al, 1986; Creech Kraft and Juchau, 1993; Ritchie et al, 1998).…”

“…The endpoint of particular interest is the induction of malformations of the second visceral arch (a predominately neural crest derived structure). This structure has been shown to be peculiarly sensitive to retinoids (Ritchie et al, 1998).…”