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• W2129173694 abstract "Vitamin A (VA) metabolism in neonates is virtually uncharacterized. Our objective was to develop a compartmental model of VA metabolism in unsupplemented and VA-supplemented neonatal rats. On postnatal day 4, pups (n = 3/time) received 11,12-[3H]retinol orally, in either oil (control) or VA combined with retinoic acid (VARA) [VA (∼6 mg/kg body weight) + 10% retinoic acid]. Plasma and tissues were collected at 14 time points up to 14 days after dose administration. VARA supplementation rapidly, but transiently, increased total retinol mass in plasma, liver, and lung. It decreased the peak fraction of the dose in plasma. A multi-compartmental model developed to fit plasma [3H]retinol data predicted more extensive recycling of retinol between plasma and tissues in neonates compared with that reported in adults (144 vs. 12–13 times). In VARA pups, the recycling number for retinol between plasma and tissues (100 times) and the time that retinol spent in plasma were both lower compared with controls; VARA also stimulated the uptake of plasma VA into extravascular tissues. A VARA perturbation model indicated that the effect of VARA in stimulating VA uptake into tissues in neonates is both dramatic and transient. Vitamin A (VA) metabolism in neonates is virtually uncharacterized. Our objective was to develop a compartmental model of VA metabolism in unsupplemented and VA-supplemented neonatal rats. On postnatal day 4, pups (n = 3/time) received 11,12-[3H]retinol orally, in either oil (control) or VA combined with retinoic acid (VARA) [VA (∼6 mg/kg body weight) + 10% retinoic acid]. Plasma and tissues were collected at 14 time points up to 14 days after dose administration. VARA supplementation rapidly, but transiently, increased total retinol mass in plasma, liver, and lung. It decreased the peak fraction of the dose in plasma. A multi-compartmental model developed to fit plasma [3H]retinol data predicted more extensive recycling of retinol between plasma and tissues in neonates compared with that reported in adults (144 vs. 12–13 times). In VARA pups, the recycling number for retinol between plasma and tissues (100 times) and the time that retinol spent in plasma were both lower compared with controls; VARA also stimulated the uptake of plasma VA into extravascular tissues. A VARA perturbation model indicated that the effect of VARA in stimulating VA uptake into tissues in neonates is both dramatic and transient. Very little is currently known about vitamin A (VA) metabolism in neonates in spite of the critical roles that VA plays in neonatal development. Specifically, VA is required for normal embryonic development, hematopoiesis, immune response, metabolism, and growth and differentiation of many types of cells (1Clagett-Dame M. DeLuca H.F. The role of vitamin A in mammalian reproduction and embryonic development.Annu. Rev. Nutr. 2002; 22: 347-381Crossref PubMed Scopus (384) Google Scholar, 2Altucci L. Gronemeyer H. Nuclear receptors in cell life and death.Trends Endocrinol. Metab. 2001; 12: 460-468Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). VA is also necessary for both innate and adaptive immunity (3Palmer A.C. Nutritionally mediated programming of the developing immune system.Adv. Nutr. 2011; 2: 377-395Crossref PubMed Scopus (150) Google Scholar), and VA-deficient infants are at increased risk of mortality and infectious diseases (3Palmer A.C. Nutritionally mediated programming of the developing immune system.Adv. Nutr. 2011; 2: 377-395Crossref PubMed Scopus (150) Google Scholar, 4Ma Y. Ross A.C. The anti-tetanus immune response of neonatal mice is augmented by retinoic acid combined with polyriboinosinic:polyribocytidylic acid.Proc. Natl. Acad. Sci. USA. 2005; 102: 13556-13561Crossref PubMed Scopus (46) Google Scholar, 5Sommer A. West K.P. Vitamin A Deficiency: Health, Survival, and Vision.. Oxford University Press, New York1996Google Scholar). In addition, VA is important for normal postnatal development of the lung (6Biesalski H-K. Vitamin A in lung development and function..in: Sommerburg O. Siems W. Kraemer K. In Carotenoids and Vitamin A in Translational Medicine. CRC Press, Boca Raton, FL.2013: 259-288Crossref Scopus (5) Google Scholar, 7Mactier H. Vitamin A for preterm infants; where are we now?.Semin. Fetal Neonatal Med. 2013; 18: 166-171Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). Studies in neonatal rat lung have indicated a significant accumulation and utilization of retinyl esters during the alveolar stage (8Geevarghese S.K. Chytil F. Depletion of retinyl esters in the lungs coincides with lung prenatal morphological maturation.Biochem. Biophys. Res. Commun. 1994; 200: 529-535Crossref PubMed Scopus (49) Google Scholar, 9Shenai J.P. Chytil F. Vitamin A storage in lungs during perinatal development in the rat.Biol. Neonate. 1990; 57: 126-132Crossref PubMed Scopus (67) Google Scholar) and an increase in retinol and retinoic acid (RA) in lung fibroblasts (10McGowan S.E. Harvey C.S. Jackson S.K. Retinoids, retinoic acid receptors, and cytoplasmic retinoid binding proteins in perinatal rat lung fibroblasts.Am. J. Physiol. 1995; 269: L463-L472PubMed Google Scholar). The levels of retinoid binding proteins, RA receptors, and RA synthesizing enzymes have been shown to peak postnatally (11Maden M. Hind M. Retinoic acid in alveolar development, maintenance and regeneration.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2004; 359: 799-808Crossref PubMed Scopus (100) Google Scholar), suggesting a requirement for RA during alveologenesis. In spite of the involvement of VA in so many physiological and metabolic systems, neonates begin life with low levels of VA (12Ross A.C. et al.Introduction to vitamin A: a nutritional and life cycle perspective..in: Packer L. Kraemer K. Obermμller-Jevic U. In Carotenoids and Retinoids—Molecular Aspects and Health Issues. AOCS Press, Champaign, IL.2005: 23-41Crossref Google Scholar). Comparison of VA levels in plasma, liver, and extrahepatic tissues in newborns with those in adults have consistently shown lower amounts in neonates, even in industrialized countries not known for VA deficiency. Plasma retinol levels in healthy newborns were ∼50% of the levels in the corresponding maternal plasma (13Yeum K-J. Ferland G. Patry J. Russell R.M. Relationship of plasma carotenoids, retinol and tocopherols in mothers and newborn infants.J. Am. Coll. Nutr. 1998; 17: 442-447Crossref PubMed Scopus (88) Google Scholar, 14Godel J.C. Basu T.K. Pabst H.F. Hodges R.S. Hodges P.E. Ng M.L. Perinatal vitamin A (retinol) status of northern Canadian mothers and their infants.Biol. Neonate. 1996; 69: 133-139Crossref PubMed Scopus (46) Google Scholar), and concentrations of retinol-binding protein (RBP) and its cotransport protein transthyretin were also lower in newborns (7Mactier H. Vitamin A for preterm infants; where are we now?.Semin. Fetal Neonatal Med. 2013; 18: 166-171Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 15Vahlquist A. Rask L. Peterson P.A. Berg T. The concentrations of retinol-binding protein, prealbumin, and transferrin in the sera of newly delivered mothers and children of various ages.Scand. J. Clin. Lab. Inv. 1975; 35: 569-575Crossref PubMed Google Scholar). A liver retinol concentration of <10 μg/g tissue was reported in an autopsy study of otherwise healthy infants who died at 0–1 month of age from sudden infant death syndrome, as well as from other causes (16Dahro M. Gunning D. Olson J.A. Variations in liver concentrations of iron and vitamin A as a function of age in young American children dying of the sudden infant death syndrome as well as of other causes.Int. J. Vitam. Nutr. Res. 1983; 53: 13-18PubMed Google Scholar). Such a level is considered VA deficient in older children and adults. Similar values were reported in neonatal rats (17Davila M.E. Norris L. Cleary M.P. Ross A.C. Vitamin A during lactation: relationship of maternal diet to milk vitamin A content and to the vitamin A status of lactating rats and their pups.J. Nutr. 1985; 115: 1033-1041Crossref PubMed Scopus (53) Google Scholar). VA stores are high in fetal lung and decrease toward term, and they are almost depleted in newborns (18Zachman R.D. Role of vitamin A in lung development.J. Nutr. 1995; 125: 1634S-1638SPubMed Google Scholar, 19Zachman R.D. Kakkad B. Chytil F. Perinatal rat lung retinol (vitamin A) and retinyl palmitate.Pediatr. Res. 1984; 18: 1297-1299Crossref PubMed Scopus (39) Google Scholar). Retinol levels are even lower in neonates in developing countries where VA intakes may be low and VA deficiency is a common and significant nutritional problem (20Agarwal K. Dabke A. Phuljhele N. Khandwal O. Factors affecting serum vitamin A levels in matched maternal-cord pairs.Indian J. Pediatr. 2008; 75: 443-446Crossref PubMed Scopus (24) Google Scholar). Lower VA stores and plasma retinol concentrations are present in low birth-weight (LBW) infants and in preterm newborns, and poor VA status may contribute to their greater likelihood of developing chronic lung disease, such as bronchopulmonary dysplasia (21Hustead V.A. Gutcher G.R. Anderson S.A. Zachman R.D. Relationship of vitamin A (retinol) status to lung disease in the preterm infant.J. Pediatr. 1984; 105: 610-615Abstract Full Text PDF PubMed Scopus (151) Google Scholar), a major cause of morbidity in preterm infants. Currently, VA supplementation is included in the WHO/UNICEF Millennium Development Goals (22United Nations International Children's Emergency Fund. Goal: Reduce Child Mortality. Accessed Aug 1, 2013, at http://www.unicef.org/mdg/childmortality.html.Google Scholar) as a strategy to reduce mortality in children aged 6–59 months in parts of the world where VA deficiency is a public health problem (23Aguayo V.M. Garnier D. Baker S.K. Drops of Life: Vitamin A Supplementation for Child Survival..Progress and Lessons Learned in West and Central Africa. UNICEF Regional Office for West and Central Africa. Cold Spring Harbor Lab Press, Cold Spring Harbor2007http://www.unicef.org/wcaro/english/WCARO_Pub_DropsLifeVitA.pdfDate: 2012Date accessed: September 1, 2013Google Scholar), and high-dose bolus VA supplementation has been widely adopted for this age group (24Beaton G.H. Martorell R. Aronson K.A. Edmonston B. McCabe G. Ross A.C. Harvey B. Vitamin A supplementation and child morbidity and mortality in developing countries.Food Nutr. Bull. 1994; 15: 282-289Crossref Scopus (40) Google Scholar). However, studies investigating VA supplementation in 1–5-month-old infants did not show any survival benefits. Also, VA supplementation to newborns (0–28 days of life) has produced mixed results, with reduced mortality in some trials but not in others (25.World Health Organization. 2008. Neonatal vitamin A supplementation research priorities. Report of the WHO technical consultation. Geneva, Switzerland, December 4–5, 2008.Google Scholar), although clinically, VA treatment has shown beneficial effects in elevating VA status, reducing bronchopulmonary dysplasia, and improving outcomes in LBW infants (26Tyson J.E. Wright L.L. Oh W. Kennedy K.A. Mele L. Ehrenkranz R.A. Stoll B.J. Lemons J.A. Stevenson D.K. Bauer C.R. et al.Vitamin A supplementation for extremely-low-birth-weight infants.N. Engl. J. Med. 1999; 340: 1962-1968Crossref PubMed Scopus (448) Google Scholar, 27Shenai J.P. Kennedy K.A. Chytil F. Stahlman M.T. Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia.J. Pediatr. 1987; 111: 269-277Abstract Full Text PDF PubMed Scopus (291) Google Scholar, 28McGowan S.E. Contributions of retinoids to the generation and repair of the pulmonary alveolus.Chest. 2002; 121: 206S-208SAbstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). As a result, the WHO has not yet established a position on VA supplementation in neonates (29World Health Organization,Newborns: reducing mortality..http://www.who.int/mediacentre/factsheets/fs333/en/index.htmlDate: 2012Date accessed: August 1, 2013Google Scholar). New trials are being initiated by WHO in Africa and Asia to determine if neonatal VA supplementation (50,000 IU given within the first days after birth) is effective in reducing morbidity and mortality (25.World Health Organization. 2008. Neonatal vitamin A supplementation research priorities. Report of the WHO technical consultation. Geneva, Switzerland, December 4–5, 2008.Google Scholar). Previously, we reported that oral administration of VA combined with RA (VARA), an admixture of VA and a small proportion (one-tenth) of RA, synergistically stimulates a rapid increase in retinol uptake and esterification in the lung of neonatal rats as compared with either VA alone or RA alone (30Ross A.C. Ambalavanan N. Zolfaghari R. Li N-q. Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in a synergistic manner in neonatal rats.J. Lipid Res. 2006; 47: 1844-1851Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 31Ross A.C. Li N-q. Wu L. The components of VARA, a nutrient-metabolite combination of vitamin A and retinoic acid, act efficiently together and separately to increase retinyl esters in the lungs of neonatal rats.J. Nutr. 2006; 136: 2803-2807Crossref PubMed Scopus (24) Google Scholar). In addition, lung retinyl ester content was 5-fold higher in neonatal rats treated with VARA compared with VA alone, even in dexamethasone-treated neonatal rats (32Ross A.C. Ambalavanan N. Retinoic acid combined with vitamin A synergizes to increase retinyl ester storage in the lungs of newborn and dexamethasone-treated neonatal rats.Neonatology. 2007; 92: 26-32Crossref PubMed Scopus (17) Google Scholar). VARA was found to also partially ameliorate the effect of hyperoxia and attenuate oxygen-induced inflammation in neonatal lungs (33James M.L. Ross A.C. Bulger A. Philips 3rd, J.B. Ambalavanan N. Vitamin A and retinoic acid act synergistically to increase lung retinyl esters during normoxia and reduce hyperoxic lung injury in newborn mice.Pediatr. Res. 2010; 67: 591-597Crossref PubMed Scopus (38) Google Scholar). The use of methods of tracer kinetics and the application of compartmental analysis have led to an enhanced understanding of VA dynamics and metabolism in adult animals and humans, including prediction of extensive recycling of retinol among plasma, liver, and extrahepatic tissues, and estimates of the transit, turnover, storage, and utilization of retinol (34Cifelli C.J. Green J.B. Green M.H. Use of model-based compartmental analysis to study vitamin A kinetics and metabolism.in: Litwack G. In Vitamins and Hormones. Academic Press, San Diego, CA.2007: 161-195Crossref Scopus (41) Google Scholar, 35Cifelli C.J. Green J.B. Green M.H. Dietary retinoic acid alters vitamin A kinetics in both the whole body and in specific organs of rats with low vitamin A status.J. Nutr. 2005; 135: 746-752Crossref PubMed Scopus (27) Google Scholar, 36Gieng S.H. Green M.H. Green J.B. Rosales F.J. Model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats.J. Lipid Res. 2007; 48: 904-913Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 37Green M.H. Uhl L. Green J.B. A multicompartmental model of vitamin A kinetics in rats with marginal liver vitamin A stores.J. Lipid Res. 1985; 26: 806-818Abstract Full Text PDF PubMed Google Scholar, 38Kelley S.K. Green M.H. Plasma retinol is a major determinant of vitamin A utilization in rats.J. Nutr. 1998; 128: 1767-1773Crossref PubMed Scopus (33) Google Scholar, 39Lewis K.C. Green M.H. Green J.B. Zech L.A. Retinol metabolism in rats with low vitamin A status: A compartmental model.J. Lipid Res. 1990; 31: 1535-1548Abstract Full Text PDF PubMed Google Scholar). However, compartmental ana­lysis has not yet been used to model VA metabolism in neonates. This may be in part because of the added challenges of applying this method to organisms that are not in a metabolic steady state. In the present study, we aimed to fill the gap by developing a compartmental model of VA kinetics in neonatal rats under different nutritional conditions (placebo and VARA). Information on the transfer, turnover, storage, and disposal of retinol in neonates was expected from the model as well as insight into the effect of VARA on VA kinetic behavior in a rat model of the neonatal life stage. Animal protocols were approved by the Institutional Animal Care and Use Committee of the Pennsylvania State University. Sprague-Dawley female and male rats were housed with continuous access to food and water and a 12 h light/dark cycle. After mating, and throughout the study period, females were fed a diet with a marginal level of VA (0.35 mg retinol equivalents/kg diet; Research Diets, New Brunswick, NJ) to reduce the transplacental transfer of VA and the concentration of VA present in the dams' colostrum and milk during lactation (17Davila M.E. Norris L. Cleary M.P. Ross A.C. Vitamin A during lactation: relationship of maternal diet to milk vitamin A content and to the vitamin A status of lactating rats and their pups.J. Nutr. 1985; 115: 1033-1041Crossref PubMed Scopus (53) Google Scholar). Rat pups were assigned randomly to two treatments, a control (oil) group treated with canola oil to provide data on the kinetics of retinol in the absence of supplementation, and a VARA group to obtain the effect of acute VA supplementation. Retinoids for the oral dose (all-trans retinyl palmitate and all-trans RA) were purchased from Sigma-Aldrich (St. Louis, MO). The amount of VA in the oral dose [∼6 mg/kg body weight (30Ross A.C. Ambalavanan N. Zolfaghari R. Li N-q. Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in a synergistic manner in neonatal rats.J. Lipid Res. 2006; 47: 1844-1851Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar)] was based on the amount of VA administered to human infants to reduce morbidity and mortality (50,000 IU/∼2.5 kg) (25.World Health Organization. 2008. Neonatal vitamin A supplementation research priorities. Report of the WHO technical consultation. Geneva, Switzerland, December 4–5, 2008.Google Scholar). The amount of RA was determined in previous studies to stimulate retinol uptake and esterification in neonatal lungs (31Ross A.C. Li N-q. Wu L. The components of VARA, a nutrient-metabolite combination of vitamin A and retinoic acid, act efficiently together and separately to increase retinyl esters in the lungs of neonatal rats.J. Nutr. 2006; 136: 2803-2807Crossref PubMed Scopus (24) Google Scholar) and to induce lung septation in neonatal rats (40Massaro G.D. Massaro D. Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats.Am. J. Physiol. 1996; 270: L305-L310Crossref PubMed Google Scholar). VARA was a mixture of the VA dose and the RA dose such that RA equaled 10% of the amount of VA. Canola oil was used as placebo. The VARA mixture, or oil only, was admixed with 11,12-[3H]retinol (Perkin-Elmer, Waltham, MA) so that the radioactivity in the oral dose was 0.2 μCi/μl. A volume of 0.8 μl/g body weight plus 1 μl for potential loss of the dose was given to each pup. The dose was administered on postnatal day 4 (P4), which coincides with the time when alveolar septation begins in rats (41Roth-Kleiner M. Post M. Similarities and dissimilarities of branching and septation during lung development.Pediatr. Pulmonol. 2005; 40: 113-134Crossref PubMed Scopus (85) Google Scholar). The study continued throughout the period of maximum septation (until P14). On P4, each pup received a single oral dose containing 11,12-[3H]retinol, as above. The dose was delivered directly into the mouth via a small micropipette. After dosing, each tip was retained for extraction with hexanes. For pups that had any visible oil left on their muzzle, the muzzle was blotted with a small “chip” of paper towel which was extracted with the pipette tip. An aliquot of hexanes representing undelivered dose for each pup was taken for counting. In this way, the dose delivered to each pup was individually corrected for any losses. Aliquots of each dose preparation were extracted and analyzed for [3H]retinol to determine the value for 100% of the dose. Immediately after dosing, the time was recorded and pups were returned to their mothers. Pups consumed mother's milk throughout the study. Groups of pups (three/time/group) were euthanized at 14 time points after dosing, including several during the initial phase of VA absorption: 1, 2.5, 4, 6, 8, 11, 15, and 24 h, and 2, 4, 6, 8, 11, and 14 days. At these times, pups were weighed and euthanized with isoflurane (Phoenix Pharmaceutical, Saint Joseph, MO). Blood was collected from the vena cava into heparinized syringes, and tissues (liver, lungs, etc.) were excised and rapidly frozen in liquid nitrogen. Plasma was obtained following centrifugation of blood samples and stored at −20°C; tissue samples were stored at −80°C until analysis. An aliquot of each plasma sample (10–60 μl) was transferred into a vial containing 4 ml Scintiverse (Fisher Chemical) and analyzed for tritium content by liquid scintillation spectrometry; counting was done to a 1% counting error (38Kelley S.K. Green M.H. Plasma retinol is a major determinant of vitamin A utilization in rats.J. Nutr. 1998; 128: 1767-1773Crossref PubMed Scopus (33) Google Scholar). Another aliquot of plasma (25–100 μl) was analyzed for total retinol concentration by ultra performance liquid chromatography (UPLC) as previously reported (30Ross A.C. Ambalavanan N. Zolfaghari R. Li N-q. Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in a synergistic manner in neonatal rats.J. Lipid Res. 2006; 47: 1844-1851Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 42Ross A.C. Separation and quantitation of retinyl esters and retinol by high-performance liquid chromatography.Methods Enzymol. 1986; 123: 68-74Crossref PubMed Scopus (63) Google Scholar). The extraction method for tissues was originally developed by Ross and Zilversmit (43Ross A.C. Zilversmit D.B. Chylomicron remnant cholesteryl esters as the major constituent of very low density lipoproteins in plasma of cholesterol-fed rabbits.J. Lipid Res. 1977; 18: 169-181Abstract Full Text PDF PubMed Google Scholar) for lipid extraction and was based on the procedure of Thompson et al. (44Thompson J.N. Erdody P. Brien R. Murray T.K. Fluorometric determination of vitamin A in human blood and liver.Biochem. Med. 1971; 5: 67-89Crossref PubMed Scopus (210) Google Scholar). Briefly, portions of tissue were cut, weighed, and homogenized in 100% ethanol. Tissues were incubated in ethanol for at least 1 h and then lipids were extracted with 6 ml hexanes containing 0.1% butylated hydroxytoluene. After centrifuging, the upper phase was removed into new vials. Solvent was evaporated under argon. The extraction with hexane/butylated hydroxytoluene was repeated and the two extracts were pooled, after which the solvent was removed. A known amount of an internal standard, trimethylmethoxyphenyl-retinol, was added to 1 ml of extract; the samples were dried under argon and reconstituted in 200 μl of methanol for UPLC analysis of total retinol. The fraction of the ingested dose remaining in plasma at each sampling time for each pup was calculated as total radioactivity (dpm) in plasma divided by dpm in the ingested dose as determined for each pup. Total dpm in plasma was calculated from the measured plasma tracer concentration at each time × the estimated plasma volume, where plasma volume was calculated as the pup's body weight × 0.035 ml plasma/g body weight. Radioactivity in the ingested dose was calculated as the dose total dpm minus the dpm remaining in the tip and paper chip combined. Model-based compartmental analysis was applied to the plasma tracer response profiles (the mean fraction of the ingested dose at each time within each group versus time after dose administration) for neonatal rats in both groups using the Windows version of the Simulation, Analysis, and Modeling software (WinSAAM) (45Wastney M.E. Patterson B.H. Linares O.A. Greif P.C. Boston R.C. Investigating Biological Systems Using Modeling. Academic Press, San Diego, CA1999Google Scholar). A proposed multi-compartmental model of VA kinetics (“proposed model” ; see Results) was developed based on a previous model proposed by Cifelli et al. (46Cifelli C.J. Green J.B. Wang Z. Yin S. Russell R.M. Tang G. Green M.H. Kinetic analysis shows that vitamin A disposal rate in humans is positively correlated with vitamin A stores.J. Nutr. 2008; 138: 971-977Crossref PubMed Scopus (43) Google Scholar), which describes the metabolism of orally administered VA in humans, including the absorption phase. Plasma tracer data were analyzed in light of the proposed model using WinSAAM until a satisfactory fit was obtained between observed and model-predicted values. Specifically, model parameters {fractional transfer coefficients [L(I,J)s]; see below} and, when necessary, model structure, were iteratively adjusted until a close fit was obtained, as judged by visual inspection of the simulated tracer data plot and by statistical analysis, including the sum of squares from nonlinear regression analysis and the estimated fractional SD (FSD) for each kinetic parameter. An F-statistic (47Landaw E.M. DiStefano J.J. Multiexponential, multicompartmental, and noncompartmental modeling. II. Data analysis and statistical considerations.Am. J. Physiol. 1984; 246: R665-R677PubMed Google Scholar) and the Akaike information criterion (48Akaike H. A new look at the statistical model identification.IEEE Trans. Automat. Contr. 1974; 19: 716-723Crossref Scopus (36021) Google Scholar) were used to statistically test whether increases in model complexity were justified. The model complexity (and thus the number of pa­rameters) was increased only when it resulted in a significant improvement in the sum of squares as determined by an F-statistic and reduced Akaike information criterion by more than 1–2 units. Once a satisfactory fit was achieved, the final estimates of the L(I,J)s and their statistical uncertainties were generated by nonlinear regression analysis in WinSAAM. For weighting purposes, an FSD of 0.05 was assigned to each datum. Parameters were considered well-identified if their estimated variability (FSD) was less than 0.5. L(I,J) is the fraction of retinol in compartment J transferred to compartment I each day. L(I,J)s are parameters that define the behavior of the system. Although neonatal rats were in a metabolic nonsteady state due to growth, we hypothesized that the fraction of retinol that was transferred between compartments was not changing with time. Thus, we set L(I,J)s to be time-invariant. The following parameters were calculated from model-generated L(I,J)s (49Green M.H. Green J.B. Experimental and kinetic methods for studying vitamin A dynamics in vivo.in: Packer L. In Methods in Enzymology. Academic Press, San Diego, CA1990: 304-317Crossref Scopus (27) Google Scholar): mean transit time [t(I)] or turnover time is the mean of the distribution of times that a retinol molecule entering compartment I spends there during a single transit before leaving reversibly or irreversibly; mean residence time [T(I,J)] is the average of the distribution of times that a retinol molecule spends in compartment I before irreversibly leaving it after entering the system via compartment J; recycling number [ν(I)] is the average number of times a retinol molecule recycles through compartment I before it irreversibly exits from compartment I; fractional catabolic rate (FCR) is the fraction of the retinol pool which is utilized each day; disposal rate (DR) is the rate of irreversible utilization of retinol; traced mass [M(I)] is the amount of retinol in compartment I; and transfer rate [R(I,J)] is the amount of retinol transferred from compartment J to compartment I each day and is calculated as the product of M(I) and L(I,J). Parameters were then compared between the control group and the VARA group. A VARA perturbation model was also developed by applying a nonsteady state solution in WinSAAM to estimate the perturbation that VARA exerts on the system, as further presented in the Results. Data for tissue VA mass and tracer responses are reported as mean ± SEM. Differences among groups, P < 0.05, were determined by two-way ANOVA followed by a Bonferroni post hoc test using Prism software (GraphPad, La Jolla, CA). Compartmental modeling was done using group mean data at each time [“super-pup” model (35Cifelli C.J. Green J.B. Green M.H. Dietary retinoic acid alters vitamin A kinetics in both the whole body and in specific organs of rats with low vitamin A status.J. Nutr. 2005; 135: 746-752Crossref PubMed Scopus (27) Google Scholar)]. For kinetic parameters, L(I,J)s are presented with estimated FSDs. Differences of L(I,J)s between groups, P < 0.05, were determined by using an unpaired t-test. Briefly, t-statistic for each L(I,J) was calculated using the equation (Value1 − Value2)/sqrt(SEM12 + SEM22), which was then applied to the t-table to determine P < 0.05, with df = 60 based on (3 pups/time × 14 times − 12 parameters) × 2 treatments. The body weights of the pups versus time after dosing are shown in Fig. 1A, B. Body weight was relatively constant during the first 2 days after dosing, when pups were 4–6 days old. Pups started to grow robustly 2 days after dosing. VARA treatment did not affect pup body weights. In the control group, plasma retinol concentration (Fig. 1C, D) was relatively constant (0.9–1.5 μM) throughout the study period. Plasma retinol was significantly increased (P < 0.01) in the VARA group at 1 and" @default.
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• W2129173694 title "Retinol kinetics in unsupplemented and vitamin A-retinoic acid supplemented neonatal rats: a preliminary model" @default.
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