Progress 10/01/99 to 09/30/04
Outputs
Developed and validated a method to measure exogenous zinc absorption by using small doses of 65Zn and its urinary excretion. This method opens the possibility of measuring zinc absorption in populations. Double stable zinc isotopic methods are applicable only for clinical studies. Developed a method to measure total hemoglobin (Hb) mass and blood volume by inhalation of a measured small dose of carbon monoxide. This method will be used in studies of conditions where Hb concentration varies because of dilution with plasma (i.e. in pregnancy and possibly in the elderly). In collaboration with Mexican and Argentinean colleagues, have determined the advantages and safety of delaying cord clamping by providing additional iron to the newborn resulting in significantly greater iron stores at 6 months of age. This practice should be adopted as routine perinatal care to prevent iron deficiency during the first year of life. In collaboration with the Mexican National Institute of
Perinatology, we have shown that routine administration of daily iron-folic acid supplements to pregnant women produces oxidative stress using the method we developed to measure breath ethane, TBARS, and hemoconcentration, starting soon after supplementation is started in a significant proportion of pregnant women. These conditions result in increased risk of low birth weight and prematurity. Data on the effect of total supplemental iron ingested during pregnancy in Indonesia confirm the above effect of iron on hemoconcentration. These undesirable effects are not observed when iron-folic acid is administered only every week, while having the desirable preventive effect on the development of gestational anemia. Infants at age six months born from mothers who received daily supplements had delayed brain transmission of auditory stimulus compared to infants born from mothers that received weekly supplements, suggesting defective myelinization in the former group of infants. These results
provide the scientific basis for interventions to reduce oxidative stress during gestation. Field studies on the interactions of zinc and iron supplementation in pregnancy (conducted at WHNRC at UC Davis) and in non-pregnant women consuming diets representative of Mexican urban and rural diets, in collaboration with the Mexican National Institute of Public Health have been finished. We used only stable zinc and iron isotopes. Analytical results are in progress in collaboration with Dr. R. Roehl from the California Department of Public Health. Iron absorption varies little between rural and urban diets. Zinc absorption is being measured. These studies provide information on interactions between zinc and iron on the regulation of their absorption in pregnancy. Bioavailability of zinc and iron from beans selected for being rich in these metals has shown that only total zinc absorption is improved. This has practical as well as basic information to be considered on the possible benefits
from genetically modified beans. Studies on the mechanisms affecting the bioavailability of metals are in progress using in vitro digestions and dialysis, and Caco 2 cells. Chelation with EDTA improves both.
Impacts
These studies have strengthened the concept that preventive iron supplementation administered on a weekly dose rather than daily is as effective, more efficient and safer, based on oxidative stress measurements. Now there are several countries that are adopting this strategy and WHO is recommending this preventive strategy for infants, children and women of childbearing age. We have developed methods that will foster the measurements of zinc absorption in population groups and that will clarify the significance of low hemoglobin levels when hemodilution takes place. We have explored the interactions between iron and zinc absorption and metabolism in pregnancy and when diets vary, including the bioavailability of iron and zinc from bean cultivars that are rich in iron and zinc, stressing the importance of bioavailability measurements in order to evaluate the nutritional impact of such species.
Publications
- Gonzalez, H.F., Perez, N.B., Malpeli, A., Martinez, M.I., Del Buono, B. and Viteri, F.E. 2005. Nutritional and immunological status in long-term follow-up of children with short bowel syndrome. J. Parenter. Enteral Nutr. 29:186-191.
- Viteri, F.E. and Berger, J. 2005. Importance of pre-pregnancy and pregnancy iron status: can long term weekly preventive iron and folic acid supplementation achieve desirable and safe status? Nutr. Rev., In Press.
- Berger, J., Than, H.K., Cavalli-Sforza, T., Suttilak, S., Khan, N.C., Hoa, P.T., Quang, N.D. and Viteri, F.E. 2005. Community mobilization and social marketing to promote weekly iron-folate supplementation in women of reproductive age in vietnam: impact on anemia and iron status. Nutr. Rev., In Press.
- Cavalli-Sforza, L.T., Berger, J., Smitasiri, S. and Viteri, F.E. 2005. Weekly iron-folic acid supplementation of women of reproductive age: impact overview, lessons learned, expansion plans and contributions toward achievement of the millennium development goals. Nutr. Rev., In Press.
- Pena-Rosas, J.P., Nesheim, M.C., Garcia-Casal, M.N., Crompton, D.W., Sanjur, D., Viteri, F.E., Frongillo, E.A. and Lorenzana, P. 2004. Intermittent iron supplementation regimens are able to maintain safe maternal hemoglobin concentrations during pregnancy in Venezuela. J. Nutr. 134:1099-1104
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Progress 01/01/03 to 12/31/03
Outputs
The model to determine zinc nutritional status by the ratio of retained radioactive/excreted zinc after a minute dose of radioactive zinc is promising. Further studies in animals and humans are set-up to evaluate its sensitivity and precision. We have been successful in setting up a simple method to measure total circulating hemoglobin and total blood volume after the inhalation of a safe dose of carbon monoxide. Both volumes have high correlations with lean body mass and their variation in repeated measurements in adult men is less than 3% and 6% in women during diverse menstrual phases. This method, together with other biochemical and hematological measurements, is allowing us to clarify the meaning of 'low hemoglobin' and 'anemia' in these physiological states where blood dilution is normal, and will also allow us to recommend effective and safe use of iron and other nutrients for the prevention and treatment of anemia without inducing oxidative stress. We have
further shown that the addition of a chelate (EDTA) to different iron compounds markedly improves their dialysability compared to ascorbic acid in an in-vitro digestion system, especially in the presence of phytic acid. We are proceeding to study EDTA's effect on other divalent metals, including zinc. The regulation of absorption and metabolism of these chelate-exposed metals is being studied in human intestinal cell cultures made iron-deficient or slightly overloaded. We have been successful in setting up all the necessary methodology for these studies and experiments are already going. These studies are aimed at explaining metal-metal interactions as those we have recently observed in the various population studies that follow: Daily iron supplementation to pregnant women, besides increasing the risk of low birth weight, reduces zinc absorption late in pregnancy, increases oxidative stress indicators, reduces serum copper concentrations and several of the infants from this group of
mothers show mild defects in neurological development. These last three effects were not observed in intermittently supplemented pregnant women in our collaborative studies in Mexico. In collaboration with Drs. JC King and C. Donangelo we have found that iron bioavailability of beans selected for their high iron and zinc content is low and total absorbed iron is similar to that from common beans but total zinc absorption is higher in the high zinc varieties. Continuing with our interest on the efficacy and safety of iron-folic acid supplementation, we have set up our methodology trained a biochemist for measuring exhaled ethane as indicator of body lipid peroxidation in Mexico. We are gathering data in iron-supplemented women that will further substantiate which methods of preventive supplementation are safer. We have found unexpected elevations in red-cell folates after weekly compared to daily folic acid doses and are studying this process. Using both an epidemiological approach in
France and an animal model at UC Davis, in collaboration with Drs. P Havel and JC King, we are studying if mild-moderate deficiencies of micronutrients affect appetite and increase the risk of obesity.
Impacts
We have continued to prove that daily iron supplementation as currently recommended to pregnant women is not innocuous, and that the intermittent administration of iron supplements is safer and effective. Further study on the mechanisms of 'anemia' in pregnancy and the elderly are progressing in order to provide a functional understanding of observed low hemoglobin levels. Our studies are providing in depth scientific evidence on which to base agricultural genetic modifications, mineral supplementation and fortification policies and are opening new areas of micro and macro nutrient interactions with emphasis on obesity.
Publications
- Viteri, F.E. and Warren, R.W. 2003. Why and how to use radioisotopes in human nutrition research. In: Modern Aspects of Nutrition, Present Knowledge and Future Perspectives. I. Elmadfa, E.A. Ispra and J. Konig, Eds. Forum of Nutrition (Formerly "Bibiotheca Nutritio et Dieta") 56:307-309.
- Casanueva, E., and Viteri, F.E. 2003. Iron and oxidative stress in pregnancy. J. Nutr. 133:1700S-1708S.
- Donangelo, C.M., Woodhouse, L.R., King, S.M., Toffolo, G., Shames, D.M., Viteri, F.E., Cheng, Z., Welch, R.M. and King, J.C. 2003. Iron and zinc absorption from two bean (phaseolus vulgaris l.) genotypes in young women. J. Ag. Food Chem. 51:5137-5143.
- Morasso, MdC., Molero, J., Vinocur, P., Acosta, L., Paccussi, N., Rasselli, S., Falivene, G. and Viteri, F.E. 2003. Deficiencias de hierro y de vitamina A y prevalencia de anemia en ninos y ninas de 6 a 24 meses de edad en Chaco, Argentina. Arch. Latinoam. Nutr. 53:21-27.
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Progress 01/01/02 to 12/31/02
Outputs
We have begun a series of studies exploring the bioavailability of different iron chelates using in-vitro dialysis techniques after simulation of gastric and intestinal digestion phases as well as using intestinal cell cultures and intestinal loop perfusions in rats. So far our results indicate that NaFeEDTA is the preferred iron chelate regarding iron absorption. We have conducted a study on daily iron supplements administered together or separate from zinc supplements in pregnant and lactating women, measuring both iron and zinc absorptions and metabolism by means of stable iron and zinc isotopes. This work is in collaboration with Dr. Janet C. King from the WHNRC/USDA center at UC Davis. The objective of the study is to determine the effects of iron supplements on iron and zinc metabolism. We have finished the clinical phase of this study and are proceeding to complete all biochemical analyses. Our active collaboration with B.N. Ames, P. W. Walter and D. Killilea
from Molecular and Cell Biology has continued during 2002 in the study of iron-induced oxidative stress and oxidative damage following our human and animal experimental models of daily and intermittent iron supplementation. We have finished analyzing mitochondrial DNA breakages using real-time PCR and 8-oxo DG determinations by HPLC in DNA isolated from buffy-coat from the human studies we have performed comparing daily and weekly iron administration. Results: women receiving weekly iron as well as controls not receiving iron show the same degree of DNA breakage. Women receiving daily iron show very variable levels of DNA damage probably because of possible defects in sample storage and problems with DNA isolation. We will repeat a group of women on daily iron supplementation. We have continued our collaboration with Dr. E. Casanueva at the Instituto Nacional de Perinatologia in Mexico City on the relative effectiveness and safety of weekly and daily iron supplementation to pregnant
women. The administration of 60 mg of iron daily to non-anemic women results in elevated hemoglobin levels associated with a higher prevalence low birth weights and premature deliveries. These undesirable effects are rare in women receiving weekly supplementation. We have repeated the study administering iron twice weekly. Results are similar as with weekly supplements. The infants of the mothers in this study are being followed for up to 6 months of age to determine their developmental characteristics. Lastly, we continue our collaboration with Drs. J.M. Ceriani, R. Schwarcz, C. Lomuto, G. Carroli and M.dC. Morasso in Argentina. We conducted a study on 3.738 deliveries to determine the practice of cord ligation. The average time for cord clamping is 25 seconds, but obstetric services that have read our publication on this matter have a significantly longer time of cord clamping benefiting the infants.
Impacts
We have continued to prove that daily iron supplementation as currently recommended is not innocuous, and that the intermittent administration of iron supplements is safer and as effective as daily supplement administration. We have also continued to explore in depth iron-zinc supplementation in pregnancy and the choices of iron compounds for food fortification of populations. These studies may open new avenues for overcoming iron deficiency safely, including changing the practice of umbilical cord ligation for the benefit of infants' iron nutrition.
Publications
- Donangelo, C.M., Woodhouse, L.R., King, S.M., Viteri, F.E. and King, J.C. 2002. Supplemental zinc lowers measures of iron status in young women with low iron reserves. J. Nutr. 132:1860-1864.
- Casanueva, E., Mares-Galindo, M., Meza, C., Schnaas, L., Gutierrez-Valenzuela, V. and Viteri, F.E. 2002. Intermittent iron supplementation in non-anaemic pregnant women as an effective and safe alternative to daily supplementation. SCN News 25:37-38.
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Progress 01/01/01 to 12/31/01
Outputs
We finished the analysis of samples collected from the human study performed in 2000, designed to validate the measurement of fractional zinc absorption using 65Zn as well as 67and 70Zn. Results show that 65Zn and 70Zn have the same disappearance rates after I.V. administration, that fractional zinc absorption varies both between subjects and and within subject when it is repeated 12 days apart regardless of method. The second measurement was lower than the first: from 45% to 23 % for the stable isotope ratio, and from 54 % to 25 % for the 65Zn method. Results are no different between methods. The 65Zn method must be validated when zinc is ingested together with food because the previous study was done with a zinc solution in the fasting state. The whole body retention of 65Zn in this normal population was a constant at 5 % 6 days after the ingestion of the dose. The 65Zn method appears promising for application in population studies in the developing world. We also
continued our active collaboration with Drs. P.B. Walter and B.N. Ames in the study of iron-induced oxidative stress and oxidative damage following our human and animal experimental models of daily and intermittent iron supplementation. We have demonstrated that iron-deficient rats have malfunctional liver mitochondria, and DNA breakage; that a similar effect is observed among rats receiving daily iron supplements, and that these effects are ameliorated by administering the supplements every third day. We have also determined that liver copper is elevated in iron deficiency possibly explaining oxidative damage. This does not occur in kidneys. Zinc levels parallel those of iron in both tissues. In collaboration with Dr. H. Gonzalez at the Pediatric Hospital of the Province of Buenos Aires in Argentina, we have explored further the effectiveness of purified hemoglobin iron as a source of heme iron under taxing conditions (short bowel syndrome). Results show that 1.25 mg of heme iron
ingested with food is comparable to the ingestion of 15 mg of ferrous fumarate in replenishng deficient iron status in these patients. We have continued our collaboration with Dr. E. Casanueva at the Instituto Nacional de Perinatologia in Mexico City on the relative effectiveness and safety of weekly and daily iron supplementation to pregnant women. The administration of 60 mg of iron daily to non-anemic women results in elevated hemoglobin levels that have been associated with birth weights below the average for the population. This undesirable effect is rare in women receiving weekly supplementation. The infants of the mothers in this study are being followed to determine their developmental characteristics. Lastly, in collaboration with Drs. J.M. Ceriani, R. Schwrcz and M.dC. Morasso we researched the literature from the obstetric, perinatological and nutritional perspectives and wrote a document on the "opportune timing of umbilical cord ligation", published by UNICEF, Argentina
for use in Latin America. This document is having an important effect in providing proof of the nutritional benefits (mainly iron) and safety of the recommended procedures. It is already in its second printing.
Impacts
We have continued to prove that iron deficiency, which is highly prevalent the all over the world, has serious consequences; that daily iron supplementation as currently recommended is not innocuous, and that the intermittent administration of iron supplements is safer and as effective as daily supplement administration. We have also continued to provide alternative measures to control, iron deficiency: we have demonstrated the effectiveness of minute amounts of hemoglobin iron as a meal supplement in children with short bowel syndrome. This may open a new avenue for overcoming iron deficiency; and we have supported the delayed ligation of the umbilical cord. We are also opening the possibility of studying fractional zinc absorption in developing world populations, where zinc deficiency is suspected on the basis of zinc intake and bioavailability.
Publications
- Viteri, F.E. and Warren, R. 2002. Why and how to use radioisotopes in human nutrition research. Int. Atomic Energy Agency/International Congress of Nutrition. In press.
- Viteri, F.E. and Gonzalez, H. 2002. Adverse Outcomes of Poor Micronutrient Status in Childhood and Adolescence. Nutr. Rev. In Press.
- Viteri, F.E. and Warren, R.W. 2002. Considerations on the use of radioisotopes in human nutrition research. Food and Nutr. Rev. In press.
- Walter, P.B., Knutson, M.D., Paler-Martinez, A., Lee, S., Xu, Y., Viteri, F.E. and Ames, B.N. 2002. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats. Proc. Nat. Acad. Sci., In press.
- Morasso, MdC., Ceriani-Cernadas, J.M., Jajam, R.O., Lomuto, C., Schwarcz, R.y, Viteri, F.E. 2001. Ligadura oportuna del cordon umbilical. Una estrategia para prevenir la anemia en la infancia. Gobierno de la Proivincia del Chaco, Ministerio de Salud de la Nacion y UNICEF, Argentian. 32 pages.
- Morasso, MdC., Molero, J., Vinocur, P., Acosta, L., Paccussi, N., Rasselli, S., Falivene, G. y, Viteri, F.E. 2002. Deficiencia de hierro y "anemia" en mujeres embarazadas en Chaco, Argentina. Arch. Latinoam. Nutr., In press.
- Morasso, MdC., Molero, J., Vinocur, P., Acosta, L., Paccussi, N., Rasselli, S., Falivene, G. y Viteri, F.E. 2002. Deficiencias de hierro y de vitamina A y prevalencia de anemia en ninos y ninas de 6 a 24 meses de edad en Chaco, Argentina. Arch. Latinoam. Nutr., In press.
- Viteri, F.E. 2002. Por que y como usar radiosiotopos para la investigacion en nutricion human. Cuadernos de Nutricion, Mexico. In press.
- Mendoza, C., Viteri, F.E., Lonnerdal, B., Raboy, V., Young, K.A. and Brown, K.H. 2001. Absorption of iron from unmodified maize and genetically altered, low-phyate maize fortified with ferrous sulfate or sodium iron EDTA. Am. J. Clin. Nutr. 73:80-85.
- Gonzalez, H., Mendoza, C. and Viteri, F.E. 2001. Absorption of unlabeled reduced iron of small particle size from a commercial source. A method to predict absorption of unlabeled iron compounds in humans. Arch. Latinoam. Nutr., 51(3):217-224.
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Progress 01/01/00 to 12/31/00
Outputs
During the year 2000 my laboratory completed a study on the absorption of commercial reduced iron using human volunteers and a new method developed in our laboratory. Reduced iron is the most commonly used form of iron in food fortification in this country and world-wide, and yet there is essentially no information on its availability. We found that given alone, its absorption is about 20% that of the best absorbed iron salt (ferrous sulfate). We are to study its absorption when added to a standard meal without the natural iron inhibitors in foods and when these are added. We also conducted a study to validate and compare the reproducibility (accuracy) of a new method we have developed to allow countries and research centers in developing countries to conduct research on zinc absorption using minimal and safe doses of radioactive zinc. At present, the methods available for studying zinc absorption require very expensive, scarce, and hard to maintain equipment. Also,
studies requiring stable isotopes are extremely expensive making them unaffordable to centers with scarce resources. Because of these limitations, studies of zinc absorption can not be conducted by local scientists in regions where zinc deficiency appears to be wide spread. Equipment where radioactive zinc can be measured are available in most countries in the world. We have studied nine human volunteers in whom three methods of zinc absorption were used simultaneously: whole-body radioactive zinc counting in a spacial chamber, double stable isotope enrichment in urine with measurements in a mass spectrometer and our method. We are finishing the study but results so far indicate that the method we have developed is accurate and reproducible. We are finishing the stable isotope determinations. The last two methods use measurements of zinc absorption by determining radioactive or stable zinc tracers in urine after an intravenous dose of a stable or radioactive zinc tracer dose as well
as after ingesting a dose of another stable or radioactive zinc isotope. We have also completed studies in humans and experimental animals designed to define the most efficient and safe dose of iron supplements to prevent and control iron deficiency. We have, in collaboration with Drs.Patric Walter and Bruce N. Ames of the Department of Cell and Molecular Biology completed studies that indicate serious mitochondrial damage when iron deficiency exists as well as when iron excess is administered as a supplement. This damage translates into defective mitochondrial and cell function as well as in potentially serious DNA damage. These studies expand our previous findings that both iron deficiency and even mild-moderate excess produce damage attributed to free radical generation. We are currently seeking possible mechanisms by which free radicals are generated in iron deficiency.
Impacts
By developing and validating new methods to study mineral absorption and metabolism we are providing tools to scientists and centers in less developed countries for enabling them to study their prevalent nutritional problems and seek appropriate solutions. Our findings on reduced iron absorption are vital for designing and predicting the effect of nutritional programs using this compound and for industry in its use as a food fortificant. Our studies on iron deficiency and mild excess are providing information that will allow us to determine desirable limits of iron intake both to effectively prevent and control iron deficiency keeping the upper levels of intake within safe limits. It is important to be reminded that iron deficiency affects nearly 2.5 billion people the world-over, especially young children and women of childbearing age, and that it has serious health, functional and developmental consequences.
Publications
- No publications reported this period
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