The role of vitamin A and its pro-vitamin carotenoids in fetal and neonatal programming: gaps in knowledge and metabolic pathways.

Vitamin A (VA) and its pro-vitamin carotenoids are naturally occurring lipophilic compounds involved in several cellular processes and metabolic pathways. Despite their broad spectrum of activities in the general population, dietary deficiencies of these compounds can potentially affect pregnancy outcomes. Since maternal nutritional status and diet composition during pregnancy and lactation can have long-lasting effects in offspring until adulthood, this study presents an overview of VA and the role of pro-VA carotenoids during pregnancy and lactation - the nutrition, metabolism, and biological effects in the offspring. The review aimed to discuss the pro-VA carotenoids and VA-associated pathways and summarize the results with reference to gestational disorders, and VA and pro-VA carotenoids as preventive agents. Also, considering that obesity, overweight, and metabolic diseases are major public health concerns worldwide, fetal and neonatal development is discussed, highlighting the physiological role of these molecules in obesity prevention. This review comprehensively summarizes the current data and shows the potential impact of these compounds on nutritional status in pregnancy and lactation.

Early-Life Nutrition and Gut Immune Development.

Gut immune function conditions the development of local and systemic diseases that result from defects in immune regulation, such as inflammatory bowel disease, allergy and obesity. As epidemiological studies support the developmental origin of health and disease, deciphering the critical factors modulating gut immune development should allow the advance of primary prevention strategies specifically adapted to the early-life immune system. Here, we will review gut mucosal immunity development and cover in more detail the recent understanding of the impact of early nutrition on this process. We will emphasize how nutrition can shape microbiota composition and metabolic function and thereby the production of metabolites with immune-modulatory properties. We will also focus on the role of dietary compounds recently demonstrated to be essential in immune development and function, such as dietary antigens, vitamin A, and aryl hydrocarbon receptor ligands. Finally, we will discuss that early-life physiologic food for mammals contains factors capable of compensating for neonatal immune deficiencies, but also factors that are decisive for immune maturation towards a maternal milk-independent and efficient immune system.

Effects of micronutrients on placental function: evidence from clinical studies to animal models.

Micronutrient deficiencies are common in pregnant women due to low dietary intake and increased requirements for fetal development. Low maternal micronutrient status is associated with a range of pregnancy pathologies involving placental dysfunction, including fetal growth restriction (FGR), small-for-gestational age (SGA), pre-eclampsia and preterm birth. However, clinical trials commonly fail to convincingly demonstrate beneficial effects of supplementation of individual micronutrients, attributed to heterogeneity and insufficient power, potential interactions and lack of mechanistic knowledge of effects on the placenta. We aimed to provide current evidence of relationships between selected micronutrients (vitamin D, vitamin A, iron, folate, vitamin B12) and adverse pregnancy outcomes, combined with understanding of actions on the placenta. Following a systematic literature search, we reviewed data from clinical, in vitro and in vivo studies of micronutrient deficiency and supplementation. Key findings are potential effects of micronutrient deficiencies on placental development and function, leading to impaired fetal growth. Studies in human trophoblast cells and rodent models provide insights into underpinning mechanisms. Interestingly, there is emerging evidence that deficiencies in all micronutrients examined induce a pro-inflammatory state in the placenta, drawing parallels with the inflammation detected in FGR, pre-eclampsia, stillbirth and preterm birth. Beneficial effects of supplementation are apparent in vitro and in animal models and for combined micronutrients in clinical studies. However, greater understanding of the roles of these micronutrients, and insight into their involvement in placental dysfunction, combined with more robust clinical studies, is needed to fully ascertain the potential benefits of supplementation in pregnancy.

Reflections About Inflammatory Bowel Disease and Vitamins A and D.

Ulcerative colitis and Crohn's disease are two major forms of the inflammatory bowel diseases (IBDs). Vitamin A (VA) and vitamin D (VD) may be associated with reduction in inflammation in these disorders. The aim of this review was to show the current evidence that may associate VA and VD with IBDs. Data linking VA, VD, and IBDs were studied. Both VA and VD may be related to the immune system in different manners. The active form of VA, retinoic acid, may be related to the growth factor-ß and release of interleukin-10 (IL-10), thus involved with the resolution of the inflammation. Its deficiency is associated with the increase of disease activity. The active form of VD is 1,25(OH)2D3 that produces biological effects via the nuclear hormone receptor named VD receptor (VDR), which may interfere with the immune cells and macrophages leading to the suppression of the inflammatory process by decreasing the release of TNF-α, IL-1, IL-6, and IL-8, IL-12, and IL-23. VDR may also activate nucleotide-binding oligomerization domain 2 expression and stimulate the production of the defensin and cathelicidin that are important to the homeostasis of the mucosal immune barrier. The use of VA and VD could be helpful in the treatment and prevention of IBDs but more studies are necessary to establish the precise role of these compounds in the prevention or remission of these inflammatory processes.

The oxytocin-CD38-vitamin A axis in pregnant women involves both hypothalamic and placental regulation.

OBJECTIVE: Oxytocin, a hypothalamic hormone secreted upon release of ectoenzyme CD38, plays a vital role in interpersonal bonding behaviors. Reduced plasma oxytocin characterizes autistic individuals. CD38 levels, which were found to be low in LBCs derived from autistic patients, is upregulated upon the addition of a vitamin A derivative. During pregnancy, oxytocin is also secreted by placenta. Recent controversial studies have suggested an increased risk for autism when oxytocin is used during induction and augmentation of labor. We aimed to examine the tripartite relationship between oxytocin, CD38 and vitamin A in pregnant women and their newborns. METHODS: Thirty-one healthy expectant mothers were enlisted for this study. Levels of oxytocin, CD38 and ATRA were measured in both maternal peripheral and newborn cord blood, and the tripartite relationship between these parameters examined. Estrogen and progesterone levels of the mothers were also recorded. Several clinical measures were also noted. RESULTS: Mean maternal oxytocin and vitamin A levels were approximately 8- and 4-fold higher, respectively, than neonatal levels. CD38 expression, however, was 9 times higher in neonates than in the maternal group. Positive correlation was found between maternal and cord blood for both oxytocin and CD38. CONCLUSIONS: This establishment of normative values for oxytocin, CD38 and vitamin A in healthy pregnant women and newborns may serve as a reference in the investigation of developing pathologies of disorders such as autism.

Topical retinoids in skin ageing: a focused update with reference to sun-induced epidermal vitamin A deficiency.

Vitamin A is an important constituent of the epidermis, where it plays a crucial role in epidermal turnover. A deficiency of epidermal vitamin A may be the consequence of nutritional vitamin A deficiency, exposure to sunlight or any UV source, oxidative stress or chronological ageing. As a consequence, any treatment aiming at increasing epidermal vitamin A would exert a protective effect against these deleterious conditions. Retinoids may counteract some deleterious actions of UV radiation by physical and biological mechanisms. Topical natural retinoic acid precursors such as retinaldehyde or retinol are less irritant than acidic retinoids and may prevent epidermal vitamin A deficiency due to nutritional deficiency, exposure to sunlight or any condition leading to free radical production. Retinoids may be combined with other compounds with complementary actions against ageing, nutritional deficiency and cancer, such as antioxidants, to potentiate their beneficial effects in the skin.

The potential of orange-fleshed sweet potato to prevent vitamin A deficiency in Africa.

PURPOSE: Vitamin A deficiency is among major health problems worldwide that leads to blindness, retarded growth and death, particularly in developing countries. In these countries, vitamin A deficiency largely affects pre-school children, pregnant and lactating mothers, and the rural poor. For instance, the predicted prevalence of vitamin A deficiency for 36 sub-Saharan African countries is 19.1%. METHODS: Different strategies, including vitamin A supplementation, food fortification and dietary diversification, have been used to combat this problem. However, these strategies are not sustainable due to their high costs. RESULTS: Orange-fleshed sweet potato (Ipomoea batatas L. Lam) is a low priced crop, which is part of staple foods in most of sub-Saharan Africa that can be a year-round source of vitamin A. Most of the orange-fleshed sweet potato varieties contain 3000-16000 µg 100 g(-1) of ß-carotene and this contributes to 250 to 1300 µg 100 g(-1) Retinol Activity Equivalents (RAE). Therefore, by using orange-fleshed sweet potato, it is possible to improve vitamin A status, increase the bio-availability of different micro-nutrients such as Fe, Zn, Ca and Mg, reduce vitamin A deficiency and hence reduce child mortality rates by 23 to 30%. CONCLUSION: The article highlights the significance of vitamin A for human nutrition, the effect of vitamin A deficiency, the different prevention methods and the potential of orange- fleshed sweet potato as a food crop to prevent vitamin A deficiency.

Vitamin A in prevention of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) remains one of the most serious challenges in the care of the very preterm infants, affecting approximately one-quarter of infants born < 1500g birth weight and 30% < 1000g. Oxygen toxicity may contribute to its pathogenesis. Vitamin A concentrations are lower in BPD infants which may result in a reduction of the antioxidant protection. It has been found to up regulate genes necessary for fetal lung growth and increase surfactant production in animal models and is also involved in the modulation of immunological and inflammatory responses by regulation of cytokine production. Retinoic acid plays a key role in lung development improving alveolar septation. Evidence exists that vitamin A supplementation for very low birth weight (VLBW) infants, beyond that routinely given in multivitamin preparations, is associated with a reduction in death or BPD. So, parenteral administration of vitamin A to the newborn is one of the current recommended preventive therapies for BPD (number needed to treat 12; 95% CI: 6-94; The information on long-term neurodevelopmental status suggests no evidence of either benefit or harm. Estimates for cerebral palsy range from a number needed to treat of 11 to a number needed to harm of 33. Nowadays, it seems that administration of antenatal vitamin A to the mother in late pregnancy associated with neonatal supplementation can better prevent the development of BPD in areas of endemic vitamin A deficiency. The benefits, in terms of vitamin A status, safety and acceptability of delivering vitamin A in an intravenous emulsion compared with repeat intramuscular injections, the association of vitamin A prenatal and postnatal, as well as the effectiveness and safety of administered high dose vitamin A in ELBW infants await evaluation and should be assessed in further trials.

Mammalian carotenoid-oxygenases: key players for carotenoid function and homeostasis.

Humans depend on a dietary intake of lipids to maintain optimal health. Among various classes of dietary lipids, the physiological importance of carotenoids is still controversially discussed. On one hand, it is well established that carotenoids, such as ß,ß-carotene, are a major source for vitamin A that plays critical roles for vision and many aspects of cell physiology. On the other hand, large clinical trials have failed to show clear health benefits of carotenoids supplementation and even suggest adverse health effects in individuals at risk of disease. In recent years, key molecular players for carotenoid metabolism have been identified, including an evolutionarily well conserved family of carotenoid-oxygenases. Studies in knockout mouse models for these enzymes revealed that carotenoid metabolism is a highly regulated process and that this regulation already takes place at the level of intestinal absorption. These studies also provided evidence that ß,ß-carotene conversion can influence retinoid-dependent processes in the mouse embryo and in adult tissues. Moreover, these analyses provide an explanation for adverse health effects of carotenoids by showing that a pathological accumulation of these compounds can induce oxidative stress in mitochondria and cell signaling pathways related to disease. Advancing knowledge about carotenoid metabolism will contribute to a better understanding of the biochemical and physiological roles of these important micronutrients in health and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.

Vitamin A supplementation for the prevention of morbidity and mortality in infants six months of age or less.

BACKGROUND: Vitamin A deficiency is a significant public health problem in low and middle income countries. Vitamin A supplementation (VAS) provided to lactating postpartum mothers or to infants less than six months of age are two possible strategies to improve the nutrition of infants at high risk of vitamin A deficiency and thus potentially reduce their mortality and morbidity. OBJECTIVES: To evaluate the effect of:1. VAS in postpartum breast feeding mothers in low and middle income countries, irrespective of antenatal VAS status, on mortality, morbidity and adverse effects in their infants up until the age of one year.2. VAS initiated in the first half of infancy (< 6 months of age) in low and middle income countries, irrespective of maternal antenatal or postnatal VAS status, on mortality, morbidity and adverse effects up until the age of one year. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), EMBASE, MEDLINE, clinical trials websites, conference proceedings, donor agencies, 'experts' and researchers (up to October 15, 2010). SELECTION CRITERIA: Randomized or quasi-randomised, individually or cluster randomised, placebo controlled trials involving synthetic VAS provided to the postpartum mothers or their infants up to the age of six months were eligible. DATA COLLECTION AND ANALYSIS: Two review authors assessed the studies for their risk of bias and collected data on outcomes. MAIN RESULTS: Of the 18 included studies, eight provided information on maternal VAS and 15 on infant VAS.For maternal VAS, there was no evidence of a reduced risk of mortality of their babies during infancy (96,203 participants, seven studies, high quality evidence; random-effects model RR 1.00, 95% CI 0.94 to 1.06, P = 0.9; test of heterogeneity I(2) = 0%, P = 0.9) or in the neonatal period (moderate quality evidence); nor of morbidities (very low quality evidence).  For infant VAS, there was no evidence of a reduced risk of mortality during infancy (59,402 participants, nine studies, moderate quality evidence; random-effects model RR 0.97, 0.83 to 1.12, P = 0.65; test of heterogeneity I(2) = 49%, P = 0.05) or in the neonatal period, nor morbidities (low quality evidence), but an increased risk of bulging fontanelle (32,978 participants, 10 studies, low quality evidence; random-effects model RR 1.55, 1.05 to 2.28, P = 0.03; test of heterogeneity I(2) = 68%, P = 0.0009). AUTHORS' CONCLUSIONS: There is no convincing evidence that either maternal postpartum or infant vitamin A supplementation results in a reduction in infant mortality or morbidity in low and middle income countries.

Significance of vitamin A to brain function, behavior and learning.

Retinoid acid, the bioactive metabolite of vitamin A, is a potent signaling molecule in the brains of growing and adult animals, regulates numerous gene products, and modulates neurogenesis, neuronal survival and synaptic plasticity. Vitamin A deficiency (VAD) is a global health problem, yet our knowledge of its effects on behavior and learning is still emerging. Here we review studies that have implicated retinoids in learning and memory deficits of post-embryonic and adult rodent and songbird models. Dietary vitamin A supplementation improves learning and memory in VAD rodents and can ameliorate cognitive declines associated with normal aging. Songbird studies examine the effects of retinoid signaling on vocal/auditory learning and are uniquely suited to study the behavioral effects of VAD because the neural circuitry of the song system is discrete and well understood. Similar to human speech acquisition, avian vocal learning proceeds in well-defined stages of template acquisition, rendition and maturation. Local blockade of retinoic acid production in the brain or excess dietary retinoic acid results in the failure of song maturation, yet does not affect prior song acquisition. Together these results yield significant insights into the role of vitamin A in maintaining neuronal plasticity and cognitive function in adulthood.

Augmentation of antibody responses by retinoic acid and costimulatory molecules.

Antibody production is crucial for a successful vaccine response. Beyond the ability of vitamin A (VA) and its active metabolite, all-trans-retinoic acid (RA) to restore growth in VA-deficient animals, supplementation with VA and/or treatment with RA can augment antibody responses in both VA-deficient and VA-adequate animals. RA alone, and in combination with stimuli that are ligands for the Toll-like receptor family, can augment the adaptive immune response leading to a heightened primary antibody response, and a stronger recall response upon restimulation. Mechanisms may include regulation of cell populations, type 1/type 2 cytokines, and B cell-related transcription factors, leading to accelerated B cell maturation.

What do -omics mean for the science and policy of the nutritional sciences?

The development of systems biology is revolutionizing the way we are studying and learning about human health. It is a way of thinking and a systematic attempt to integrate information from several fields of study (physical, biological, chemical, engineering, etc) to develop a more kinetic and real-time understanding of complex biological processes. It uses mathematical modeling tools to chart dynamic interactions between the components of a biological system, eg, genes, transcripts, proteins, metabolites, and cells, to simulate and analyze networks and pathways and the spatial and temporal relations that exist in biological systems. The term -omics represents the rigorous study of various collections of molecules, biological processes, or physiologic functions and structures as systems, represented most prominently by genomics. In the field of nutrition, had a systems approach been applied to evaluating the effect of vitamin A status on mortality rates in young children in developing countries, it might not have taken 20 y to go from the initial epidemiologic observations to global vitamin A supplementation programs. Better understanding of the functional biology of retinoids on different tissues that mediate host resistance to infection, and their synergistic interactions in biological, metabolic, and functional terms, could have provided a plausible mechanism for the observed effect on mortality. There are 3 policy take-home messages: 1) When controversies exist, invest in the science needed to sort them out. 2) Increase the amounts of money available for health research and interventions relevant to developing countries. 3) Ensure that policymakers understand the issues and why they are important and understand the science and its relevance.

Alcohol, vitamin A, and cancer.

Chronic and excessive alcohol intake is associated with an increased risk of a variety of cancers (e.g., oral cavity, larynx, esophagus, liver, lung, colorectal, and breast). Retinoids (vitamin A and its derivatives) are known to exert profound effects on cellular growth, cellular differentiation, and apoptosis, thereby controlling carcinogenesis. Lower hepatic vitamin A levels have been well documented in alcoholics. Substantial research has been done, investigating the mechanisms by which excessive alcohol interferes with retinoid metabolism. More specifically, (1) alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases; (2) alcohol-induced cytochrome P450 enzymes (CYP), particularly CYP2E1, enhance catabolism of vitamin A and retinoic acid; and (3) alcohol alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. As a consequence, long-term and excessive alcohol intake results in impaired status of retinoic acid, the most active derivative of vitamin A and a ligand for both retinoic acid receptors and retinoid X receptors. Moreover, this alcohol-impaired retinoic acid homeostasis interferes with (1) retinoic acid signaling (e.g., down-regulates retinoid target gene expression) and (2) retinoic acid "cross-talk" with the mitogen-activated protein kinase [(MAPK), including Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 kinase] signaling pathway. In addition, restoration of retinoic acid homeostasis by retinoic acid supplementation restored the normal status of both retinoid and MAPK signaling, thereby maintaining normal cell proliferation and apoptosis in alcohol-fed animals. These observations would have implications for the prevention of alcohol-promoted liver (and peripheral tissue) carcinogenesis. However, a better understanding of the alcohol-retinoid interaction and the molecular mechanisms involved is needed before retinoids can be pursued in the prevention of alcohol-related carcinogenesis in human beings, particularly regarding the detrimental effects of polar metabolites of vitamin A.

The roles of vitamin A for cytoplasmic maturation of bovine oocytes.

Vitamin A is one of the micronutrients which have been implicated in cattle reproduction. In cattle, ingested vitamin A, mainly as beta-carotene (BC) from forages and retinol ester from formula feed, is metabolized and transported to the oocytes and cumulus-granulosa cells in ovarian follicles through binding to various interacting molecules. The active form of vitamin A, retinoic acid (RA), functions as a regulator of gene expression in these targets. Early research showed the positive effects of vitamin A supplementation on bovine fertility in artificial insemination, and several studies on effects of vitamin A metabolites used in other artificial reproductive techniques (ART), including superovulation, ovum pick up, and in vitro maturation culture have provided evidence for the specific roles of vitamin A in oocyte cytoplasmic maturation (acquisition of developmental competence of oocytes during their meiotic maturation period for the embryonic development after fertilization). BC may enhance cytoplasmic maturation by its antioxidant properties which cannot be replaced by RA. Furthermore, RA may promote cytoplasmic maturation of bovine oocytes via its modulatory effects on the gene expression of gonadotrophin receptors, midkine, cyclooxygenase-2, and nitric oxide synthase in cumulus-granulosa cells.

Vitamin A exerts its activity at the transcriptional level in the small intestine.

THE AIM OF THIS STUDY: was to examine the effects of vitamin-A deficiency on the small intestinal morphology and on brush-border enzyme function and expression. METHODS: Weanling male rats were fed a vitamin-A deficient (VAD), sufficient (VAS), or supplemented (VASUP) diet, or were pair-fed (PF) with the VAD rats. Average food intakes were not different among the groups. RESULTS: From days 35 to 42, the body weight of VAD rats began to plateau, whereas the other groups, including the PF rats, continued to gain weight. At days 48 to 51, the final mean body weight of VAD rats was significantly lower than that of PF, VAS and VASUP rats (P < 0.05). Serum and liver retinol levels were lower in VAD rats (by 85 % and 99%, respectively) and higher in the VASUP group (by 126 % and 160%, respectively) compared to the VAS group (P < 0.01). Histological examination of the jejunum revealed that in VAD rats the villi were shorter and thicker and there was an elevation in crypt depth relative to the other treatment groups. Infiltration of inflammatory cells was also observed in the jejunum of most of the VAD rats, but not in rats from other groups. Biochemical assays revealed that in VAD rats, alkaline phosphatase (ALP) and sucrase-isomaltase (SI) activities are significantly decreased in the jejunum, compared to PF, VAS and VASUP groups (P < 0.01). ALP activity was decreased in the duodenum of VAD rats as well. By comparison, amino-peptidase (AP) activity per mg protein in the jejunum and ileum of VAD rats was significantly increased compared to VAS and VASUP rats (P < 0.01), but was not different from PF rats. In all of the small intestinal sections, mRNA expression of all three brush-border enzymes relative to beta-actin were significantly lower in VAD rats than in the other treatment groups. SI was similarly expressed in all of the small intestinal organs, whereas AP and ALP expression varied. CONCLUSIONS: Our results suggest that vitamin-A deficiency modifies the maturation and differentiation processes of the small intestinal mucosa at the transcriptional and post-transcriptional levels respectively. This in turn may be one explanation for the alteration or elimination of nutrient digestion and absorption during VAD.

Vitamin and mineral status: effects on physical performance.

Public health recommendations encourage the selection of a balanced diet and increasing physical activity to foster health and well-being. Whereas the adverse effects of restricted intakes of protein, fat, and carbohydrate on physical performance are well known, there is limited information about the impact of low intakes of vitamins and minerals on the exercise capacity and performance of humans. Physically active people generally consume amounts of vitamins and minerals consistent with the recommendations for the general public. However, when intakes are less than recommendations, some noticeable functional impairments occur. Acute or short-term marginal deficiencies, identified by blood biochemical measures of vitamin B status, had no impacts on performance measures. Severe deprivation of folate and vitamin B12 result in anemia and reduce endurance work performance. Evidence of vitamin A and E deficiencies in athletic individuals is lacking apparently because body storage is appreciable. In contrast to vitamins, marginal mineral deficiencies impair performance. Iron deficiency, with or without anemia, impairs muscle function and limits work capacity. Magnesium deprivation increases oxygen requirements to complete submaximal exercise and reduces endurance performance. Use of vitamin and mineral supplements does not improve measures of performance in people consuming adequate diets. Young girls and individuals participating in activities with weight classifications or aesthetic components are prone to nutrient deficiencies because they restrict food intake and specific micronutrient-rich foods. This information will be useful to professionals who counsel physically active people and scientific groups who make dietary recommendations to improve health and optimize genetic potential.

Vitamin A and infancy. Biochemical, functional, and clinical aspects.

Vitamin A is a very intriguing natural compound. The molecule not only has a complex array of physiological functions, but also represents the precursor of promising and powerful new pharmacological agents. Although several aspects of human retinol metabolism, including absorption and tissue delivery, have been clarified, the type and amounts of vitamin A derivatives that are intracellularly produced remain quite elusive. In addition, their precise function and targets still need to be identified. Retinoic acids, undoubtedly, play a major role in explaining activities of retinol, but, recently, a large number of physiological functions have been attributed to different retinoids and to vitamin A itself. One of the primary roles this vitamin plays is in embryogenesis. Almost all steps in organogenesis are controlled by retinoic acids, thus suggesting that retinol is necessary for proper development of embryonic tissues. These considerations point to the dramatic importance of a sufficient intake of vitamin A and explain the consequences if intake of retinol is deficient. However, hypervitaminosis A also has a number of remarkable negative consequences, which, in same cases, could be fatal. Thus, the use of large doses of retinol in the treatment of some human diseases and the use of megavitamin therapy for certain chronic disorders as well as the growing tendency toward vitamin faddism should alert physicians to the possibility of vitamin overdose.