Prolonged maternal amino acid infusion in late-gestation pregnant sheep increases fetal amino acid oxidation

Protein supplementation during human pregnancy does not improve fetal growth and may increase small-for-gestational-age birth rates and mortality. To define possible mechanisms, sheep with twin pregnancies were infused with amino acids (AA group, n = 7) or saline (C group, n = 4) for 4 days during late gestation. In the AA group, fetal plasma leucine, isoleucine, valine, and lysine concentrations were increased (P < 0.05), and threonine was decreased (P < 0.05). In the AA group, fetal arterial pH (7.365 [+ or -] 0.007 day 0 vs. 7.336 [+ or -] 0.012 day 4, P < 0.005), hemoglobin-oxygen saturation (46.2 [+ or -] 2.6 vs. 37.8 [+ or -] 3.6%, P < 0.005), and total oxygen content (3.17 [+ or -] 0.17 vs. 2.49 [+ or -] 0.20 mmol/l, P < 0.0001) were decreased on day 4 compared with day 0. Fetal leucine disposal did not change (9.22 [+ or -] 0.73 vs. 8.09 [+ or -] 0.63 [micro]mol x [min.sup.-1] x [kg.sup.-1], AA vs. C), but the rate of leucine oxidation increased 43% in the AA group (2.63 [+ or -] 0.16 vs. 1.84 [+ or -] 0.24 [micro]mol x [min.sup.-1] x [kg-.sup.1-], P < 0.05). Fetal oxygen utilization tended to be increased in the AA group (327 [+ or -] 23 vs. 250 [+ or -] 29 [micro]mol x [min.sup.-1] x [kg.sup.-1], P = 0.06). Rates of leucine incorporation into fetal protein (5.19 [+ or -] 0.97 vs. 5.47 [+ or -] 0.89 [micro]mol x [min.sup.-1] x [kg.sup.-1], AA vs. C), release from protein breakdown (4.20 [+ or -] 0.95 vs. 4.62 [+ or -] 0.74 [micro]mol x [min.sup.-1] x [kg.sup.-1]), and protein accretion (1.00 [+ or -] 0.30 vs. 0.85 [+ or -] 0.25 [micro]mol x [min.sup.-1] x [kg.sup.-1]) did not change. Consistent with these data, there was no change in the fetal skeletal muscle ubiquitin ligases MaFBx1 or MuRF1 or in the protein synthesis regulators 4E-BP1, eEF2, eIF2[alpha], and [p70.sup.S6K]. Decreased concentrations of certain essential amino acids, increased amino acid oxidation, fetal acidosis, and fetal hypoxia are possible mechanisms to explain fetal toxicity during maternal amino acid supplementation. metabolism; threonine; leucine; oxygen