The effect of teratogens on maternal corticosterone levels and cleft incidence in A/J mice.
It is unknown whether orofacial clefting, one consequence of teratogenic exposure, results from a direct interaction between the teratogen and the embryonic palate, or indirectly from maternal alterations caused by the teratogen. In the current study pregnant A/J mice were exposed to one of three cleft-inducing agents in order to examine the relationship between drug-induced clefting and the response of maternal plasma corticosterone to drug administration. The agents used, haloperidol (HAL), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), or phenytoin (PHT), were administered in teratogenic doses between 0800 and 0930 on gestational day 10 (GD 10). For corticosterone determinations, mice were dosed on GD 10, and blood was collected at 1, 4, 24, or 48 hr after dosing. For fetal evaluation of cleft lip and/or cleft palate, mice were dosed on GD 10 and killed on GD 18. Phenytoin was the most potent inducer of cleft lip and palate and induced a sustained elevation of plasma corticosterone in maternal animals. The other treatments, in order of decreasing potency to induce clefting and/or cause an elevation of corticosterone in plasma were 2,4,5-T > HAL > controls. Correlations between maternal corticosterone levels and clefting incidence were very high at all time points examined; total exposure (area under the curve) was also highly correlated. A linear relationship between drug-induced increases in maternal corticosterone levels and the incidence of clefting in A/J mice was evident. Based on these findings, we believe that increased maternal corticosterone levels may play a role in orofacial clefting in A/J mice.
Sullivan-Jones
P
P
Division of Reproductive and Developmental Toxicology, Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.
Hansen
D K
DK
Sheehan
D M
DM
Holson
R R
RR
D015085:2,4,5-Trichlorophenoxyacetic Acid / Q000633:toxicity; D000818:Animals; D002971:Cleft Lip / Q000139:chemically induced*; D002972:Cleft Palate / Q000139:chemically induced*; D003345:Corticosterone / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006220:Haloperidol / Q000633:toxicity; D008431:Maternal-Fetal Exchange; D051379:Mice; D008805:Mice, Inbred A; D010672:Phenytoin / Q000633:toxicity; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood*; D013723:Teratogens; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects
D013723:Teratogens; D010672:Phenytoin; D015085:2,4,5-Trichlorophenoxyacetic Acid; D006220:Haloperidol; D003345:Corticosterone