Abstract
We have hypothesized that the teratogenic mechanism of glucocorticoids involves the same biochemical pathway as the mechanism of their anti-inflammatory hormonal action, i.e., inhibition of arachidonic acid release and of prostaglandin (PG) and thromboxane (TX) production. Arachidonic acid reversed the production of cleft palate in rats by dexamethasone and this reversal was blocked by indomethacin, an inhibitor of PG and TX synthesis (cyclo-oxygenase) (Fed. Proc. 3616:955, 1980). Pregnant rats were treated with dexamethasone 3.75mg/kg or vehicle on days 12 to 15 of pregnancy, a regimen giving about 80% cleft palate. Three hours after the last dose of steroid on day 15 fetuses were removed by c-section and palates from each litter were dissected, pooled, sonicated, and incubated at 37°C for 3 hours. 100μl aliquots were removed at 1 hr. and 3 hrs. and the reaction stopped with lml ethanol. Aliquots of the ethanol extracts were measured for PG and TX by radioimmunoassay. PG and TX synthesis was proportional to time of incubation. Dexamethasone inhibited significantly the production of F2α, E2, 6-keto F1α, and TX B2 by fetal palates to about 50% of control values. Thus, evidence has been presented for the precise biochemical mechanism of glucocorticoid-induced cleft palate.
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