Department of Food Science and Rutgers Center for Lipid Research; Rutgers University, New Brunswick, NJ 08901, USA
Received Date: July 27, 2012; Accepted Date: July 30, 2012; Published Date: August 01, 2012
Citation: Kim YK, Quadro L (2012) Who Needs ß-Carotene? A focus on Embryonic Development. J Nutr Food Sci 2:e113. doi: 10.4172/2155-9600.1000e113
Copyright: © 2012 Kim YK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Vitamin A is an essential nutrient that is required to support many crucial biological functions, including reproduction and embryonic development . Mammals acquire retinoids (vitamin A and its derivatives) from the diet, either as preformed vitamin A (retinol, retinyl ester and small amount of retinoic acid) from meat and dairy products, or as provitamin A carotenoids (β-carotene, α-carotene and β-cryptoxanthin) from fruits and vegetables [1,2]. β-carotene is the most abundant and well characterized provitamin A carotenoid in human diet. In the Western countries, it contributes to about 30% of the vitamin A intake, and for certain populations it represents the most abundant source of vitamin A [3,4].
According to the World Health Organization, Vitamin A Deficiency (VAD) is the leading cause of preventable blindness in children and increases their risk of disease, stunted growth, and death from severe infections [5,6]. About 250 million pre-school children are estimated to be vitamin A-deficient worldwide. In addition, almost 20 million pregnant women are estimated to be vitamin A-deficient, thus severely hindering the growth, development, and health of the baby [5,6]. Supplementation of infants and children as well as maternal supplementation before, during, and after pregnancy with vitamin A or β−carotene has been shown to improve development and infant growth and to reduce the incidence of premature birth, external birth defects, and infant infectious morbidity and mortality .
Surprisingly, vitamin A deficiency is a problem that afflicts not only the developing world, but also industrialized countries. Intake of preformed vitamin A is inadequate in a substantial part of the general population, with various groups being particularly at risk. These include people on a poor or highly restrictive dietary regimen like young individuals, pregnant and lactating women [3,4]. Notably, 3% of all children born in the United States have a major malformation at birth, and 70% of these are of unknown etiology . It is a general consensus that both pre-formed vitamin A and β−carotene are required to meet the dietary needs of such vitamin .
In order to function as vitamin A, β-carotene can be converted into retinoids (vitamin A and its derivatives) by two possible mechanisms: 1. Symmetric cleavage of β-carotene at the 15, 15’ -carbon double bond mediated by β,β-carotene-15,15’-oxygenase (CMOI or BCMOI) to give rise to two molecules of retinaldehyde . 2. Asymmetric cleavage of β-carotene by β,β-carotene-9’,10’-oxygenase (CMOII or BCDOII) to generate a β-ionone ring and apocarotenals, which in turn can produce one molecule of retinaldehyde upon chain shortening . Retinaldehyde can be oxidized into retinoic acid, the biologically active form of vitamin A and the ligand of specific nuclear receptors (RARs and RXRs) that regulate the transcription of hundreds of genes, many of which are crucial to proper embryonic development . Retinaldehyde can also be reduced to retinol and then esterified by Lecithin:Retinol Acyltransferase (LRAT) into retinyl ester, the tissue retinoid storage form .
The developing embryo relies on different forms of retinoids circulating into the maternal bloodstream to fulfill its retinoids needs for proper embryogenesis . In humans, up to about 40% of the dietary β-carotene circulates in its intact form in the bloodstream [2,12]. Therefore, the question arises as to whether intact β-carotene can be used to generate retinoids locally in the developing tissues, where the cleavage enzymes are expressed . Recent study from our laboratory has revealed the fundamental mechanisms of β-carotene action during development. We have unequivocally demonstrated the ability of the developing embryo to take up, metabolize and utilize intact β-carotene from the maternal circulation. Loss of CMOI function studies in an established model of mouse VAD, such as mice lacking Retinol-Binding Protein (RBP), the sole specific carrier for retinol in the bloodstream [14-16], revealed that lack of CMOI in the developing tissues further exacerbates the severity of the embryonic malformations . This severe embryonic phenotype was accompanied by reduced levels of retinoids and was due to the lack of CMOI in the developing tissues . Using this model, we also demonstrated in vivo that intact β-carotene circulating in the maternal bloodstream crosses the placenta, and that embryonic CMOI generates retinoids from β-carotene in the developing tissues . Indeed, CMOI+/-RBP-/- embryos from double knockout dams deprived of vitamin A throughout gestation and supplemented with β-carotene, showed a reduced frequency of developmental defects and increased embryonic retinoid levels, compared to un-supplemented animals .
Our study provides the first in vivo evidence that intact β-carotene circulating in the maternal bloodstream is an alternative local source of retinoids for the developing mammalian tissues. Giving that intact β−carotene is present in the human circulation [2,12] and that it is generally considered “safer” than preformed vitamin A, as both its intestinal uptake and cleavage are regulated by retinoic acid to prevent toxicity [17,18], our data support and provide the molecular basis for the current recommendation of supplementing pregnant women with β-carotene, not only in the developing countries but also in the western world .
Grants R01HD057493 and R01HD057493-02S1 from the U.S. National Institute of Health (NIH) supported our work on β-carotene metabolism in the developing tissues.