Effect of salicylamide on skeletal glycosaminoglycan sulfation and calcification in fetal rat limbs

It has been shown that the non-narcotic analgesic salicylamide is teratogenic for rats. When this drug is administered to rats during gestation, sulfate incorporation into the fetal skeleton is reduced. Aims of studies reported here were to examine the effect of salicylamide on the incorporation of radiosulfate into glycosaminoglycans (GAGs) and the biosynthesis of chondroitin 4-sulfate (Ch-4-S) and chondroitin 6-sulfate (Ch-6-S) in fetal rat limbs was studied. Pregnant rats were fed 25% casein diet with or without 2% salicylamide from day 6 to day 17 or day 19 of gestation. The dams were killed on day 17 or day 19 of gestation, 24 hours following an intramuscular injection of sodium 35S-sulfate. Salicylamide administration decreased the levels of radiosulfate in maternal serum and placenta, and impaired the incorporation of radiosulfate into fetal skeletal GAGs. The incorporation of radiosulfate into fetal skeletal GAGs was significantly affected by maternal serum 35S-sulfate, placental 35S-sulfate, litter size, placental weight and fetal weight. After adjusting for these variables, salicylamide administration still had a significant effect, suggesting that salicylamide may have a primary effect in impairing the incorporation of sulfate into fetal skeletal GAGs. Salicylamide administration was found to have no significant effect on the amount of radiosulfate incorporated into Ch-4-S relative to that incorporated into Ch-6-S. The results showed that with increasing gestational age, there was an increase in synthesis of Ch-4-S with a concomitant decrease in synthesis of Ch-6-S. The effect of salicylamide on the calcification of fetal skeletons was studied. Salicylamide administration resulted in a decrease in the calcium content of fetal limb bones, but had no significant effect on maternal serum calcium. The calcium content of fetal limb bones was greatly affected by fetal weight. After adjusting for the fetal weight effect, salicylamide still had a significant effect on the calcium content of fetal limb bones. These results suggest that the degree of sulfation of fetal skeletal GAGs affects the calcification of fetal skeletons.