Reduced placental amino acid transport in response to maternal nutrient restriction in the baboon

Abstract

Intrauterine growth restriction increases the risk of perinatal complications and predisposes the infant to diabetes and cardiovascular disease in later life. Mechanisms by which maternal nutrient restriction (MNR) reduces fetal growth are poorly understood. We hypothesized that MNR decreases placental amino acid (AA) transporter activity, leading to reduced transplacental transfer of AAs. Pregnant baboons were fed either a control (ad libitum, n = 7), or MNR diet (70% of control diet, n = 7) from gestational day (GD) 30. At GD 165 (0.9 gestation), placentas (n = 7 in each group) were collected, and microvillous plasma membrane vesicles (MVM) isolated. MVM system A and system L AA transport was determined in vitro using radiolabeled substrates and rapid filtration techniques. In vivo transplacental AA transport was assessed by infusing nine (13)C- or (2)H-labeled essential AA as a bolus into the maternal circulation (n = 5 control, n = 4 MNR) at cesarean section. A fetal vein-to-maternal artery mole percent excess ratio for each essential AA was calculated. Fetal and placental weights were significantly reduced in the MNR group compared with controls (P < 0.01). The activity of system A and system L was markedly reduced by 73 and 84%, respectively, in MVM isolated from baboon placentas at GD 165 following MNR (P < 0.01). In vivo, the fetal vein-to-maternal artery mole percent excess ratio was significantly reduced for leucine, isoleucine, methionine, phenylalanine, threonine, and tryptophan in MNR baboons (P < 0.05). This is the first study to investigate placental AA transport in a nonhuman primate model of MNR. We demonstrate that the downregulation of system A and system L activity in syncytiotrophoblast MVM in MNR leads to decreased transplacental AA transport and, consequently, reduced circulating fetal AA concentrations, a potential mechanism linking maternal undernutrition to reduced fetal growth.

Keywords: fetal growth restriction; maternal-fetal exchange; nonhuman primate.

Fig. 1.

Relationship between placental and fetal weights. Fetal weights were positively correlated to placental weights in the control and maternal nutrient restriction (MNR) groups in the baboon at gestational day (GD) 165. Individual Spearman's rank correlation coefficients were calculated for each slope in control and MNR baboons (control, r² = 0.65; MNR, r² = 0.65, P < 0.05, n = 7 in each group).

Fig. 2.

Decreased microvillous plasma membrane vesicles (MVM) system A activity in MNR. Mediated methylaminoisobutyric acid (MeAIB) uptake into MVM isolated from control and MNR placentas of baboons at GD 165 are shown. Control and MNR groups were compared using the t-test (n = 7 in each group). Values are means ± SE. **P < 0.05.

Fig. 3.

Decreased MVM system L activity in MNR. Mediated l-leucine uptake into MVM isolated from control and MNR placentas of baboons at GD 165 are shown. Control and MNR groups were compared using the t-test (n = 7 in each group). Values are means ± SE. **P < 0.05.

Fig. 4.

In vivo transplacental transfer of essential amino acids (EAAs). A: mole percent excess (MPE) ratios of stable isotope labeled leucine (Leu) and lysine (Lys) in maternal arterial blood after intravenous injection of a mixture of labeled EAAs to the pregnant baboon at GD 165 (n = 5). B: fetal vein/maternal artery (Fv/M) MPE ratios of nine EAAs in baboons (n = 5) and pregnant women (n = 5–7). Ile, isoleucine; Met, methionine; Phe, phenylalanine; Thr, threonine; His, histidine; Val, valine; Trp, tryptophan. C: Fv/M MPE ratios of nine EAAs in MNR baboons (n = 4) compared with controls (n = 5) at GD 165. Values are means ± SE. *P < 0.01.