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THE IMPACT OF MICRONUTRIENT STATUS ON VITAMIN A METABOLISM AND KINETICS IN RATS
Restricted (Penn State Only)
Doctor of Philosophy
Date of Defense:
October 05, 2018
A. Catharine Ross, Dissertation Advisor
A. Catharine Ross, Committee Chair
Michael H. Green, Committee Member
Laura E. Murray-Kolb, Committee Member
Kevin Harvatine, Outside Member
Gregory Shearer, Committee Member
Vitamin A deficiency has been recognized as a public health issue for decades, affecting the health outcomes of different populations. Specifically, pregnant women and young children are at high risk of becoming vitamin A deficient. Indeed, vitamin A supplementation programs have been implemented in areas with high prevalence of vitamin A to eliminate vitamin A deficiency and its detrimental consequences. Although beneficial effects of vitamin A supplementation to infants more than six months of age were supported by strong scientific evidence, no solid conclusion has been made regarding the impact of vitamin A supplementation to infants younger than six months of age. Applying model-based compartmental analysis, along with tracer kinetic techniques, previous studies conducted in our laboratory have shown that a combination of vitamin A and retinoic acid supplementation to neonatal rats increased total retinoid concentration in their plasma, liver and lung. Subsequent studies have further shown that supplementation with vitamin A alone was capable of stimulating the uptake of vitamin A into the liver, resulting in a significantly elevated liver total retinol concentration. Therefore, in order to distinguish the effects of retinoic acid and vitamin A, we examined the effect of retinoic acid pretreatment, provided prior to a single-dose of vitamin A supplementation, on the vitamin A metabolism and kinetics of neonatal rats. On postnatal day 2 and 3, half of the rat pups received oral supplementation of retinoid acid as the RA-pretreated group, and the remaining half of the pups received canola oil as the oil-pretreated control group. On postnatal day 4, all pups received 3H-labeled retinol dissolved in retinyl palmitate as the vitamin A supplementation. After dose administration, pups were euthanized at 12 chosen time points, and different tissues were collected. Tissue vitamin A mass was quantified, plasma and tissue 3H-tracer levels were determined. Model-based compartmental analysis was applied to the tracer kinetic data of plasma, liver, lung and intestine, compartmental models describing vitamin A kinetics in neonatal rats were developed from a plasma view and from specific-organ level. Neonates receiving retinoic acid pretreatment largely increased vitamin A mass in their lungs, resulting in a significantly higher lung total retinol concentration. Retinoic acid pretreatment also stimulated the uptake of newly ingested vitamin A into lung and intestine, causing a dramatic increase in tissue tracer level compared to oil-pretreated group. Results from compartmental analysis further demonstrated that there was more vitamin A going to extrahepatic tissues in retinoic acid pretreated pups. In conclusion, the distinct effects of retinoid acid on vitamin A metabolism and kinetics were examined in the current study. Retinoic acid pretreatment to neonatal rats may stimulate the uptake of vitamin A into extrahepatic tissues rather than liver, which in turn altering the tissue distribution of vitamin A, and sparing vitamin A in target tissues, which may benefit the postnatal development of these tissues. In addition to vitamin A deficiency, iron deficiency is another public health concern, recognized as the most widespread nutritional disorder in the world. Although vitamin A deficiency and iron deficiency are generally considered as distinct public health issues, there is a highly frequent coexistence of these two micronutrients deficiency. Previous studies conducted in humans and animals have indicated potential interactions between the metabolism of vitamin A and iron. More specifically, using model-based compartment analysis, studies have demonstrated that iron deficiency caused a reduction in plasma retinol and increased liver vitamin A storage, which may be due to decreased liver mobilization of vitamin A with iron deficiency. Thus, in the second study, we investigated the impact of iron repletion on vitamin A kinetics and metabolism in iron deficient rats. Rats were divided into two groups after weaning, either assigned to a vitamin A marginal diet as control group, or to a vitamin A marginal plus iron deficient diet as iron deficient group. After 5 weeks of dietary treatment, four rats from each group were euthanized at the beginning of kinetic study for the baseline measurement. Remaining rats received 3H labeled retinol emulsion via i.v. injection to initiate the kinetic study. At day 21 after dose injection, half of the rats from the iron deficient group started iron repletion by switching the diet to the same vitamin A marginal diet fed to the control rats. Serial blood samples were collected from each rat at 34 chosen time points by nicking the tail vein. At day 92, all the rats were euthanized to determine the final iron and vitamin A status. Iron and vitamin A status at the beginning and conclusion of the kinetic study were determined. Model-based compartmental analysis was applied to plasma tracer response profile, and vitamin A kinetic models were developed for rats from different groups. Rats fed an iron deficient diet developed iron deficiency, and exhibited decreased plasma retinol and relatively higher liver vitamin A storage at the beginning of kinetic study. At the end of study, rats in the iron deficient with iron repletion group (ID+) recovered from iron deficiency. Although iron deficiency continued in the iron deficient without iron repletion rats (ID-), ID- rats showed a significantly higher liver vitamin A storage but relatively lower plasma retinol concentration compared to control rats (CN), whereas the iron deficient with iron repletion rats (ID+) had decreased liver vitamin A storage and increased plasma retinol concentration to a level comparable to CN rats, resulting from increased liver mobilization of vitamin A as revealed in the compartmental model. In summary, the impact of iron repletion on vitamin A kinetics and metabolism was investigated in this study, and multi-compartmental models describing vitamin A kinetics under different iron status were developed. The effects of iron deficiency on vitamin A kinetics were partially reversed by iron repletion, but the pre-existing iron deficiency may have some long-term and irreversible impact on vitamin A metabolism. This study was supported by National Institutes of Health grant #HD006982, and the findings and conclusions do not necessarily reflect the view of the NIH.
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