Vitamin A (VA) is known to be essential for the postnatal growth and development of immature organ systems and establishment of immunity, yet VA metabolism in neonates is virtually unstudied. Currently, the World Health Organization (WHO) promotes VA supplementation of young children >6 months of age in low-income countries where VA deficiency is still a public health problem, as a means to reduce young child mortality and improve global health. However, VA supplementation of neonates (infants < 6 mo of age) is controversial and WHO has not established a policy for this age group. Our goal is to use a cost-efficient and well-validated animal model to learn, in depth, how VA, when provided either at non-supplemental or supplemental doses, is absorbed and trafficked throughout the body. We will use two different protocols, direct VA supplementation of neonates and indirect supplementation through addition of VA to the maternal diet, to test our central hypothesis, namely: Direct VA supplementation of neonates, through oral VA supplementation, and indirect VA supplementation, through increased maternal dietary VA, will be significantly, but differently, alter whole-body retinol kinetics in neonates. Moreover, we believe based on our preliminary studies that these routes of administration will differ. Our goal is to provide fundamental new knowledge on retinol absorption, trafficking, and tissue distribution in a neonatal rat model using a whole-body approach that is based on 3H-retinol kinetic analysis and mathematical modeling. Because our results from the previous grant period have suggested the importance of extrahepatic tissues in the clearance of newly absorbed VA carried in chylomicrons (CM), we will focus on CM VA metabolism and on its transport from the intestine and uptake by extrahepatic tissues as well as by the liver. We also have obtained preliminary evidence that retinoic acid (RA), the most active metabolite of retinol, may drive retinol into these extrahepati organs. Therefore, in aim 1.1 we will conduct a study using 3H-retinol tracer kinetics and mathematical modeling studies of neonates that have been supplemented directly with VA, given at a dose what resembles that which has been administered to young children, compared to an oil placebo. Both male and female neonates will be included in the design.
Aim 1. 2 will also address the importance of RA in determining whole-body VA kinetics in neonates.
Aim 2 will address retinol kinetics in the neonate after indirect supplementation through addition of VA to the diet of the mother, whose milk VA concentration will be augmented. By conducting these two aims, we will gain fundamental new information that could inform future policies regarding VA supplementation in human neonates. Since VA supplementation is a practical, low-cost nutritional intervention, if positive results are obtained from our research they could be readily translated into clinical trials.

Public Health Relevance

Vitamin A (VA, retinol) is necessary for neonatal growth and development but several fundamental aspects of its absorption, uptake by extrahepatic organs and liver, and the recycling of retinol to plasma are unknown; moreover, it is unclear how VA supplementation affects retinol kinetics in neonates. Our research in the neonatal rat will investigate retinol kinetics using mathematical modeling and compartmental analysis, in situations of 1) direct oral VA supplementation, or 2) indirect VA supplementation by increasing VA in the mother's diet. Our results will be translational for the most effective use of VA in human infants as a means to improve global health.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Higgins, Rosemary
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Pennsylvania State University
Sch Allied Health Professions
University Park
United States
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Hodges, Joanna K; Tan, Libo; Green, Michael H et al. (2017) Vitamin A supplementation redirects the flow of retinyl esters from peripheral to central organs of neonatal rats raised under vitamin A-marginal conditions. Am J Clin Nutr 105:1110-1121
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Hodges, Joanna K; Tan, Libo; Green, Michael H et al. (2017) Vitamin A and retinoic acid combined have a more potent effect compared to vitamin A alone on the uptake of retinol into extrahepatic tissues of neonatal rats raised under vitamin A-marginal conditions. Curr Dev Nutr 1:
Hodges, Joanna K; Tan, Libo; Green, Michael H et al. (2016) Vitamin A Supplementation Transiently Increases Retinol Concentrations in Extrahepatic Organs of Neonatal Rats Raised under Vitamin A-Marginal Conditions. J Nutr 146:1953-1960
Hodges, Joanna K; Tan, Libo; Green, Michael H et al. (2016) Vitamin A Supplementation Increases the Uptake of Chylomicron Retinyl Esters into the Brain of Neonatal Rats Raised under Vitamin A-Marginal Conditions. J Nutr 146:1677-83
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