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Pregnant rats near term were injected iv with creatine-l-14C or creatinine-1-14C and the distribution of radioactivity was studied in maternal and fetal blood as well as in the visceral yolk sacs and chorio-allantoic placentae. After injection of crea-tine-l-14C into the dam, the level of radioactivity in fetal blood was somewhat higher than that in maternal blood at 30 min, reached maximal levels after 30 min, and remained essentially constant for at least 4 hr. The radioactivity in the labyrinth and junctional zone portions of the chorioal-lantoic placenta and the yolk sac was maximal after 30-60 min and was always considerably higher than that in the fetal and maternal blood. Furthermore, the level of radioactivity in the labyrinth was several times higher than that in the junctional zone portion of the chorioallantoic placenta and the yolk sac in which the radioactivity remained essentially constant after 1 hr. On the other hand, the radioactivity in the labyrinth declined rapidly after the first hour and reached levels which were about one-third of the maximal value after 4 hr. When labeled creatine was injected into the dam, 99% of the radioactivity present in the fetal blood and chorioallantoic placenta was found in free creatine as shown by paper chromatography in three different systems. Ancillary studies showed that the creatine concentration in fetal blood was several times higher than that in the maternal blood on the 21st-22nd day of gestation. Creatine concentration in both portions of the chorioallantoic placenta as well as the visceral yolk sac was higher than that in the fetal blood, indicating that a downhill concentration gradient existed between creatine in placental tissues and that in the fetal circulation. When creatinine-l-14C was injected iv into pregnant rats, the level of radioactivity in fetal blood rose to a maximum after 5-15 min, but the radioactivity in the maternal blood was considerably higher than that in either the fetal blood or the chorioallantoic placenta and yolk sac. These studies indicate that creatine is actively accumulated and released by the placental unit to the growing rat fetus, while creatinine is passively transported from mother to conceptus across the placentae, at least during the later stages of rat gestation.We are indebted to Drs. Richard K. Miller and Barbara Davis for their constructive criticism of the manuscript and to Carole L. Andrew for her excellent technical assistance.

The uptake of labeled creatine by skeletal muscle was enhanced in rats treated with 2 units of NPH insulin on each of two successive days and then injected ip with creatine-1-14C. While the uptake of labeled creatine by muscle was impaired in rats exposed to an X-ray dose of 500 rads, this impairment was relieved by treatment with insulin after X-irradiation. The level of radioactivity and the creatine concentration in whole blood was lower in insulin-treated rats injected ip with creatine-1-14C than in untreated controls. In contrast, X-irradiated rats injected ip with labeled creatine exhibited higher levels of radioactivity and a higher creatine concentration in blood than did the sham-irradiated controls. When X-irradiated rats were treated with insulin, the amount of radioactivity and the creatine concentration in the blood 1 hr after the injection of labeled creatine was not significantly different from that in the sham-irradiated controls. These observations are consistent with the view that insulin enhances the transfer of creatine from the circulation into skeletal muscle in normal as well as in X-irradiated rats.

When guanido-L-arginine-14C was injected directly into rat testis, both guanidoacetic acid and creatine were significantly labeled in the testis after 30 min. About 7% of the total dose of radioactivity injected was recovered in creatine while 8% of the dose was recovered in guanidoacetic acid. Similarly, guanidoacetic acid-2-14C injected into the testis was converted to labeled creatine; 3% of the total dose of radioactivity injected was found in creatine after 15 min. These data, along with the specific activity relationships observed among arginine, guanidoacetic acid, and creatine support the existence of the classical pathway for creatine biosynthesis in rat testis, namely, creatine.

The plasma and urinary amino nitrogen content was studied in dogs exposed to an L. D. 50 (and pair-fed non-irradiated controls) and to an L. D. 100 of x-rays. No significant abnormalities were noted in contrast to the pronounced aminoaciduria reported to occur in man exposed even to small doses of total body radiation.

The synthesis of creatine from glycocyamine was studied in the perfused liver of normal and whole body x-irradiated rats. No significant difference was found in the ability of the perfused liver to synthesize creatine when normal and x-irradiated rats were compared. It is postulated that radiation-induced creatinuria does not result from an increased synthesis of creatine by the liver, but rather from a decreased utilization of creatine by skeletal muscle.