Direct and indirect vitamin A supplementation strategies result in different plasma and tissue retinol kinetics in neonatal rats

Abstract

Many questions remain regarding vitamin A (VA) supplementation of infants. Herein we compared direct oral VA supplementation of the neonate and indirect treatment through maternal dietary VA (M-VA) treatment on VA status and kinetics in neonatal rats. Treatments included direct VA combined with retinoic acid (RA) [D-VARA; VA (6 mg/kg) + 10% RA, given orally to neonates on postnatal day (P)2 and P3] and indirect VA supplementation through increased M-VA, compared with each other and oil-treated neonates. [(3)H]retinol was administered orally to all neonates on P4. Plasma and tissue [(3)H]retinol kinetics were determined from 1 h to 14 days post-dosing. D-VARA versus placebo dramatically increased liver and lung retinol, but only in the first 8-10 days. In M-VA neonates, liver and lung VA increased progressively throughout the study. Compartmental modeling of plasma [(3)H]retinol showed that both D-VARA and indirect M-VA reduced retinol recycling between plasma and tissues. Compartmental models of individual tissues predicted that D-VARA stimulated the uptake of VA in chylomicrons to extrahepatic tissues, especially intestine, while the uptake was not observed in M-VA neonates. In conclusion, indirect maternal supplementation had a greater sustained effect than D-VARA on neonatal VA status, while also differentially affecting plasma and tissue retinol kinetics.

Keywords: WinSAAM; compartmental model; maternal dietary vitamin A; neonate.

Fig. 1.

Concentrations of total retinol in plasma (A, B), liver (C, D), lung (E, F), and milk separated from neonatal stomach (G, H) versus time (days) after administration of [³H]retinol in oil to neonatal rats. Plots of data from the first 24 h after dose administration, expanded from panels (B), (D), and (F), are shown in panels (A), (C), and (E). Points shown are means ± SEM, n = 3 per time per group. *Significant differences between the treated groups and the control group at the same time point as indicated (P < 0.05). In panels (G) and (H), ⁺ indicates significant differences between the two treated groups at the same time point as indicated (P < 0.05).

Fig. 2.

Mean observed fraction of administered dose in plasma (A), liver (B), lung (C), kidney (D), carcass (E), stomach (F), and intestine (G) versus time (days) after administration of [³H]retinol to neonatal rats. Each point represents the mean of n = 3 pups.

Fig. 3.

Proposed multi-compartmental model for VA metabolism as viewed from plasma space in neonatal rats after administration of [³H]retinol. A: Compartments are represented as circles; interconnectivities between compartments correspond to L(I,J)s, or the fraction of retinol in compartment J transferred to compartment I per day. Components 3 and 15 are delay elements. Compartments/component 1–3 represent VA digestion and absorption. Compartments/component 10, 15, and 4 represent CM metabolism, the uptake of CM remnants, and the processing of VA in extravascular tissues. Compartment 5 represents plasma retinol bound to RBP; this retinol exchanges with VA in one extravascular pool (compartment 6). The asterisk represents the site of input of [³H]retinol in the oral dose and is also the site of input of dietary VA. B: Mean observed (symbols) and model-predicted fraction of administered dose (lines) in plasma versus time (days) after administration of [³H]retinol to neonatal rats. Each point represents the mean of n = 3 pups.

Fig. 4.

Proposed models with forcing function for VA metabolism in liver (A), lung (B), carcass (C), and intestine (D) in neonatal rats administered [³H]retinol based on the tissue tracer response data. Compartments are represented as circles; interconnectivities between compartments correspond to L(I,J)s, or the fraction of retinol in compartment J transferred to compartment I per day. The squares represent plasma forcing functions. Compartment 10 describes the profile of plasma tracer in CM/CM remnants retinyl ester. Compartment 1 describes the profile of plasma tracer in retinol. Compartments 12, 13, and 15 represent retinyl ester that is taken up from plasma CM/CM remnants by liver, lung, and carcass, respectively. Compartments 2, 3, 5, and 7 represent VA in liver, lung, kidney, carcass, and intestine, respectively, that exchanges with plasma retinol. Compartment 17 represents the processing of newly ingested VA in intestine and retinyl ester that are taken up from plasma CM/CM remnants by intestine. Initial condition (IC)(17) represents the newly ingested dose that enters the intestine. E–H: Mean observed (symbols) and model-predicted fraction of administered dose (lines) in liver (E), lung (F), carcass (G), and intestine (H) versus time (days) after administration of [³H]retinol to neonatal rats. Each point represents the mean of n = 3 pups.