TY - JOUR
AU - Pisani, Luciana, P
AB - Abstract 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. fetal programming, maternal nutrition, obesity, pro-vitamin A carotenoids, vitamin A INTRODUCTION Based on accumulated knowledge on fetal programming, maternal nutritional status and diet composition during pregnancy and lactation determine both short- and long-term health effects on offspring until adulthood.1 Pregnancy is a critical period with high metabolic pressure, with increased inflammatory and oxidative stress.2 Environmental factors such as maternal lifestyle, endocrine disorders, malnutrition, toxins, infectious agents, depression, stress, and anxiety are just some of the factors influencing pregnancy and lactation, which impact on fetal development.3,4 Epidemiological studies have shown that maternal obesity during pregnancy increases the risk of metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease developing in the offspring by 2- to 8-fold.5 For example, a lack of specific vitamins, minerals, and macronutrients may alter the epigenetic pattern related to metabolism, appetite, and growth in the offspring.6 Therefore, from a nutritional perspective, an adequate intrauterine environment for providing the essential nutrients is mandatory for an uneventful pregnancy.7 Gestational obesity is a global concern, resulting in adverse outcomes for both women and fetuses.8 Obese women may have associated insulin resistance, which results in greater availability of lipids to the fetus, and consequently, weight gain.9 Furthermore, maternal obesity increases the risk of spontaneous abortion, hypertension, preeclampsia, and hypoxia,10 which are the primary causes of fetal mortality worldwide.11 Additionally, some bioactive compounds, macronutrients, and micronutrients present in foods may attenuate the unfavorable physiological conditions inherent in gestation.12 Optimal nutrition is the essential basis of a healthy life and has a considerable impact on pregnant women, developing newborns, and fetuses. For example, the ingestion of adequate doses of vitamin A and its pro-vitamin A (pro-VA) carotenoids is correlated with a lower risk of pregnancy pathologies induced by oxidative stress, such as prevention of preeclampsia, preterm birth, and intrauterine growth restriction.13 Additionally, some recent studies have demonstrated anti-obesity effects of carotenoids during pregnancy and lactation.13–15 According to the Dietary Reference Intakes, adequate vitamin A intake for pregnant and lactating women is 770 µg/d and 1300 µg/d, respectively. For carotenoids, owing to the lack of data on adverse effects in pregnant and lactating women, no tolerable upper intake limit has been determined. Nevertheless, despite the well-known dietary significance of these compounds, their underlying mechanisms in fetal development are still poorly elucidated. MATERIALS AND METHODS Web of Science, National Center for Biotechnology Information, and Scopus were searched for relevant articles in May 2020. The search terms used for article selection were TOPIC = [(carotenoids or carotene or “β-carotene” or “α-carotene” or “β-cryptoxanthin” or “α-cryptoxanthin” or “vitamin A”) and (pregnancy or gestation or lactation or “fetal development” or “metabolic development” or “adipose tissue” or obesity)]. A total of 1248 articles were retrieved, and no restrictions were imposed on the publication year and publication type. For the present narrative review, only articles published in English and reports published by the World Health Organization and United Nations Children’s Fund were included. This study focuses on 3 main topical themes regarding fetal programming and carotenoids: (1) biochemistry of the carotenoids and fetal programming, (2) prevention (which explores carotenoids and vitamin A as potential agents to decrease the incidence of gestational diseases and future problems in the fetus/child), and (3) obesity (carotenoids and vitamin A and their impacts on obesity, since a link between maternal obesity and risk of early-onset obesity in offspring has been demonstrated in many epidemiological studies,16,17 including studies on children and adolescents).18 RESULTS Carotenoids and the biochemistry of fetal development Mechanisms of action of carotenoids and vitamin A Carotenoids are natural lipophilic pigments of conjugated polyenic chain that are present in all photosynthetic organisms and function as photoprotective and antioxidant agents.19 Furthermore, they have considerable economic value in the global market (according to the BCC Research website, the global market for carotenoids should reach $2.0 billion by 2022). For many decades, these pigments have been produced by large-scale chemical synthesis, through photocatalytic reactions using conventional petroleum-derived organic solvents.20 The use of these synthetic carotenoid derivatives by humans resulted in severe side effects, such as allergies, respiratory conditions, decreased vitamin A delivery to tissues, alterations in hepatic lipid metabolism, and cardiovascular problems.21,22 Consequently, strategies – such as the use of less toxic and more sustainable alternative solvents for natural compound extraction – are required urgently in order to increase the production of natural carotenoids.23–26 The antioxidant and anti-inflammatory activity of carotenoids, besides being vital for improving macular and cardiovascular health, is quite well established.27,28 More recently, the biological relevance of carotenoids was highlighted in obesity management.14,15 Despite the lipophilic structure of carotenoids, they can be metabolized through multiple pathways that contribute to their effects on adiposity, as reported earlier.29 These mechanisms include the following: (1) interacting with various transcription factors of the nuclear receptor superfamily (peroxisome proliferator-activated receptors [PPARs], canonical retinoic acid receptors [RARs], and retinoid X receptors [RXRs]); (2) interfering in the activation of other transcription factors (activator of uncoupling protein-1 and CCAAT-enhancer-binding proteins); (3) acting on the signaling pathways of nuclear factor κB and nuclear factor erythroid 2–related factor; and (4) extragenomic actions such as a scavenging of oxygen reactive species (ROS), retinoylation of proteins, and activation of protein kinase cascades. Moreover, some carotenoids are pro-VA, namely all-trans-β-carotene, all-trans-α-carotene, all-trans-γ-carotene, all-trans-β-cryptoxanthin, and all-trans-α-cryptoxanthin.30 A pro-VA carotenoid is characterized by the presence of a beta-ionone ring at the terminal position of the polyenic chain. As shown in Figure 1, vitamin A is produced by the symmetrical cleavage of β-carotene (βC) mediated by the enzyme β-carotene 15,15′-monooxygenase (BCO1). Owing to the hydrophobic nature of these pigments, carotenoids are incorporated into mixed micelles of bile salts and dietary lipids for absorption in the intestine and subsequent metabolism.31,32 In the liver (mainly), the initial βC conversion to vitamin A step is mediated by the BCO1 enzyme, yielding 2 molecules of retinal (RH – aldehyde form), required for maintenance of visual cycle and macular health.33 In the enterocyte, the enzyme retinol dehydrogenase converts RH into retinol (ROH – vitamin A molecule), which is converted further into retinyl ester (RE) mediated by the lecithin:retinol acyltransferase enzyme. The RE is the storage form of vitamin A, present mainly in the liver but also in adipose tissues.34 Adipose tissue also plays an essential role in retinoid homeostasis, since it takes up ROH from the blood, stores it in RE form, and converts it to active retinoic acid (RA)35 – a process also mediated by the retinal dehydrogenase enzyme for the conversion of RH into RA. Similarly, the retinyl ester hydrolase enzyme acts on RE to convert RE to ROH, and subsequent alcohol dehydrogenase activity converts ROH to RH. The ROH form is toxic to humans, and when ROH is transported into the tissues, an intracellular specific transport protein is activated (cellular retinol-binding protein) and binds one hydrophobic molecule of ROH and carries it through the aqueous media.36 These identified mechanisms are due to BCO1 enzyme activity, which acts only on pro-VA carotenoids. However, mammals express a second βC cleavage enzyme, β-carotene-9′-10′-oxygenase (BCO2). The BCO2 enzyme cleaves the βC asymmetrically, to yield apocarotenals and apocarotenones as products, which are converted to RH by further enzymatic activity of BCO1.29 Figure 1 Open in new tabDownload slide Schematic representation of the carotenoid metabolic pathway for conversion to vitamin A. The all-trans-β-carotene is a precursor of active retinoid forms. After the ingestion of carotenoid-containing foods, the pigments are micellarized and transferred into the blood. In the liver (primary storage tissue), the carotenoids are metabolized by two enzymes: β-carotene 15,15′-monooxygenase (BCO1) and β-carotene-9′-10′-oxygenase (BCO2). Thus, carotenoids can be symmetrically cleaved by BCO1, generating retinal (RH) and further derivatives retinol (ROH), retinyl ester (RE), and retinoic acid (RA), or BCO2 causes an asymmetrical cleavage, leading to the production of apocarotenals and apocarotenones. Abbreviations: ADH, alcohol dehydrogenase; LRAT, retinol acyltransferase; RALDH, retinaldehyde dehydrogenase; RAR, retinoic acid receptor; RDH, retinol dehydrogenase; REH, retinyl ester hydrolase; RXR, retinoid X receptor Figure 1 Open in new tabDownload slide Schematic representation of the carotenoid metabolic pathway for conversion to vitamin A. The all-trans-β-carotene is a precursor of active retinoid forms. After the ingestion of carotenoid-containing foods, the pigments are micellarized and transferred into the blood. In the liver (primary storage tissue), the carotenoids are metabolized by two enzymes: β-carotene 15,15′-monooxygenase (BCO1) and β-carotene-9′-10′-oxygenase (BCO2). Thus, carotenoids can be symmetrically cleaved by BCO1, generating retinal (RH) and further derivatives retinol (ROH), retinyl ester (RE), and retinoic acid (RA), or BCO2 causes an asymmetrical cleavage, leading to the production of apocarotenals and apocarotenones. Abbreviations: ADH, alcohol dehydrogenase; LRAT, retinol acyltransferase; RALDH, retinaldehyde dehydrogenase; RAR, retinoic acid receptor; RDH, retinol dehydrogenase; REH, retinyl ester hydrolase; RXR, retinoid X receptor RA gene expression has been studied extensively for many years.37 Some studies38,39 have shown that the active-RA form regulates more than 500 genes directly or indirectly, by binding to common transcription factors or associating with receptors of other proteins. Mainly, 2 receptor families are affected by RAs (RARs and RXRs), working as ligand-dependent transcriptional regulators by binding to specific DNA sequences, namely the retinoic acid response element or retinoic acid X response element, which are present in the promoter regions of RA genes such as RAR-RXR, or RXR-RXR, dimers.40 Furthermore, products derived from asymmetric βC-cleavage, mediated by BCO2, interact with RARs, RXRs, and PPARs to antagonize their action on cellular target genes.29 Moreover, when not metabolized, carotenoids in their intact form can physically interact with the same receptors, resulting in adipocyte differentiation.41,42 Fetal programming Tissue plasticity and development are affected primarily by intrauterine exposure during pregnancy, lactation, and newborn stages. Therefore, women’s health status and maternal diet composition during pregnancy have metabolic importance for their offspring’s health, even before conception, and could permanently program their offspring.43,44 Some periods during pregnancy are more critical and should be treated with the utmost care, since failure to restore maternal physiology may result in pregnancy complications, including gestational diabetes or obesity, abnormal birth weight, and preeclampsia.9,45 During the first trimester of pregnancy (up to 14 wk), vital body parts are formed, namely the spine, head, arms, and legs, along with complete development of the heart and stomach. In late pregnancy, the maturation of the hypothalamus-pituitary axis occurs, making it more susceptible to endocrine alterations.46 In addition, the establishment of glycemic metabolism also occurs in later gestation. Hence, it is a critical period for insulin sensitivity and glucose tolerance in the offspring.47 Several explanations are offered for the maternal nutritional influences on offspring development, and murine generational studies have indicated that effects on body composition, body weight, and glucose metabolism appear to be propagated to subsequent generations.48 These facts demonstrate that metabolic development studies are urgently needed, in light of the fact that several development mechanisms are still not fully understood. Nevertheless, 3 main mechanisms often underlie the relationship between maternal nutrition and fetal programming: endocrine signals, epigenetics, and oxidative stress. Besides, postbirth, breastfeeding needs to be considered as a continuation of the communication between the mother and her child, which also demonstrates an important role in the characterization of the future offspring phenotype.49,50 Thus, the topics described below will individually explore the involvement of the main mechanisms in fetal programming and in the lactation period. Endocrine mechanism Several hormones regulate the growth and healthy development of the fetus and prepare the mother for delivery. Human gestation is approximately 40 weeks on average, but each woman undergoes different metabolic, nutritional, social, and physiological modifications during this period.51 These modifications involve endocrine and metabolic changes that result from physiological alterations between mother and fetus.52 The placental hormones are crucial during gestation for regulating distinct pregnancy stages, maternal metabolic adaptation, and breastfeeding preparation.53 The critical hormones during pregnancy are progesterone, human chorionic gonadotropin, estrogen, human placental lactogen, human chorionic somatomammotropin, placental growth hormone, leptin, and adiponectin. These hormones act as nutritional and maturational cues for fetal development and fetal well-being, and after birth.54 Therefore, an irregularity in the concentration of these hormones can trigger severe endocrine imbalance and consequences for fetal development. Obese/overweight pregnant women are predisposed to clinical complications, which manifest as metabolic disturbances.55 Maternal obesity during pregnancy or lactation, or both, leads to several endocrine changes in the offspring,56 modifying both central (eg, hypothalamic response to leptin and regulation of appetite) and peripheral (eg, pancreatic β-cell dysfunction and low-grade chronic inflammation) regulatory pathways. Also, maternal obesity and overnutrition (the main factors triggering negative fetal-programming events) were associated with adverse effects on the growth and adiposity of offspring, thereby increasing the risk for developing obesity, diabetes, cardiovascular diseases, and fatty liver disorders in later life.57 In addition, nutritional status and metabolism, especially in obese women with high body mass index, were associated significantly with enhanced offspring adiposity at age 5–6 years.58 The hormonal imbalance, caused by a lack of micronutrients, leaves pregnant women vulnerable to pregnancy problems and fetus complications.59 During pregnancy, carotenoids play an important role in promoting communication between the cells (gap junctions), enhancing the immune response and preventing gestational complications.13,60 It has already been demonstrated that metabolic alterations inherent to a lack of vitamin A, and its pro-VA carotenoids, could display some modifications regarding the immunity of pregnant women and fetuses.61,62 Moreover, vitamin A deficiency (VAD) predisposes the pregnant woman to spontaneous abortion, as well as brain, macular, renal, and vascular birth defects.63 Epigenetic mechanism Fetal and neonatal periods show considerable epigenetic plasticity. During epigenetic programming, gene expression is modified without any alteration of the original DNA sequence. The key epigenetic markers include DNA methylation, modification of histone proteins (addition of an acyl, methyl, or phosphate groups), and expression of microRNAs.64 Several authors support the concept that gene transcription is silenced by DNA methylation and potentially activated by acetylation of histone proteins.65,66 In contrast, the microRNAs – a class of short noncoding RNA molecules – repress messenger RNA translation and induce its destabilization by incomplete pairing to nucleotide sequences in the 3′-untranslated regions of target messenger RNAs.67 The epigenome could be re-established at specific developmental stages and is maintained throughout life, suggesting an individual molecular fingerprinting role in supporting fetal programming.68 Transgenerational effects can also be modulated epigenetically via 3 different routes (prenatal life, behavioral transfer, and germline pathways), which corroborate the impact of the epigenome on triggering fetal programming.69 In addition, dietary supplementation can dramatically alter a heritable phenotype. For example, in the study by Godfrey et al,70 the epigenetic alterations in RXR-α correlated with increased adiposity in the children of mothers with insufficient carbohydrate intake. In contrast, Feng et al71 showed that embryo hearts from pregnant women exposed to a diet without vitamin A (0 IU vitamin A per gram of diet), before and during pregnancy, exhibited a high incidence of cardiac defects. In the same embryos, the authors observed increased methylation of GATA binding protein 4 (a critical transcriptional activator involved in cardiac development and function), accompanied by decreased gene and protein expression of GATA binding protein 4 in the offspring heart tissue at embryonic day 13.5. This study also suggested that maternal dietary administration of vitamin A (10 IU vitamin A per gram of diet) during pregnancy – after 10 weeks without vitamin A – can partially ameliorate the expression of GATA binding protein 4 and the phenotype of embryo hearts.71 Additionally, a recent experimental study by Arreguín et al72 revealed that oral supplementation of vitamin A (as retinyl palmitate or as βC) in young rats during the suckling period showed changes in the methylation status of genes involved in the differentiation and development of white adipose tissue (eg, peroxisome proliferator-activated receptor-gamma 2 and retinol-binding protein 4). Epigenetic differences were also identified in lactating animals supplemented with retinyl palmitate or βC (different forms of vitamin A). Altogether, these findings suggest the crucial role of pro-VA carotenoids and vitamin A in the epigenetic programming of offspring, possibly influencing the phenotype, and on the development of disease in later life. Oxidative stress mechanism Oxidative stress is inherent in pregnancy owing to increased oxygen consumption and energy utilization for maintaining fetal and maternal homeostasis.73 Lower ROS levels promote defense against infectious agents and the induction of mitogenic response.74 However, higher ROS levels lead to oxidative stress, which damages the cell structures, including phospholipid membranes, proteins, and DNA.75 At the end of the first trimester of the human pregnancy, there is a 3-fold increase in oxygen concentration induced by placental maturation (particularly in the syncytiotrophoblast), which consequently leads to an exponential increase in ROS.76 This condition, when aggravated, can lead to hypoxia, preeclampsia, fetal malformation, fetal growth restriction, and even premature birth.77 Further, at this time, there is a concurrent production of hypoxia-inducible factors as well as the expression of antioxidant enzymes, namely heme oxygenase 1 and 2, zinc-copper superoxide dismutase, catalase, and glutathione peroxidase.78 These genes are expressed primarily in the mitochondria, the main cellular organelle for controlling placental oxidative stress.79 For example, some authors have suggested that placental adaptations that determine the severity of gestational diseases (arising from oxidative stress) and allow pregnancies to progress to term involve antioxidant responses mediated by dynamic mitochondrial-related processes.80 Some studies have confirmed the role of oxidative stress in fetal programming. Therefore, antioxidative therapy offers promise in reducing oxidative stress during pregnancy, in addition to reducing infection and inflammation induced by oxidative stress and damage to the placenta, thus conferring a healthy life to the offspring.81 This was also concluded in a recent meta-analysis,82 where the role of the carotenoids and vitamin A act as promising antioxidant agents, preventing metabolic syndrome. Lactation period After birth, the primary link between the mother and newborn is through breast milk. Based on World Health Organization recommendations, breastfeeding is recommended exclusively during the first trimester, to provide the newborn with beneficial effects, such as immunity, allergy prevention, strengthening of the lungs, and cognitive development.83 In addition, human milk protects offspring against antibody-secreting infections and stimulates the offspring’s immune system with many long-term positive effects.84 Since infants are born with incipient reserves of fat-soluble vitamins and other micro- and macronutrients, the first breastfeeding of colostrum is a critical phase.85 Colostrum provides energy, protein, and antibodies, in addition to lipophilic micronutrients such as vitamins A and E.86 After the initial support by colostrum milk (<72 h postpartum), transitional milk (up to 15 d) starts to support the newborn, and milk production then increases considerably to support the nutritional and developmental needs of the rapidly growing infant.87 After 16 days, the mature milk supports the infant, and in this stage, the milk composition exhibits fewer variabilities than in early lactation, but a switch from protein production to fatty acid synthesis occurs.88 For carotenoids, the colostrum is the gold standard for infant breastfeeding. The bright yellow color of the human colostrum reflects the rich carotenoid content, compared with transitional and mature milk.89–91 In addition, the fat content of breast milk could be a useful vehicle for improving carotenoid bioaccessibility and bioavailability.92 The nutrient composition of breast milk is influenced by the dietary habits of the breastfeeding mother, especially the consumption of fruits and vegetables, which have a substantial impact on the carotenoid content of breast milk.93 Owing to the carotenoid content and antioxidant activity of breast milk, breastfeeding could decrease the risk of retinopathy and prematurity, as well as the risk of premature death after hospital discharge.94 These data support many scientific reports in a variety of global populations, showing that children who are not breastfed (or receive insufficient breastfeeding) have a higher chance of developing chronic diseases such as obesity and type 2 diabetes mellitus.95–97 However, when breastfeeding is absent (unknown reasons), artificial infant milk formulation is substituted. According to the United Nations Children’s Fund’s website, artificial infant formula is not an ideal substitute for breast milk, since the original composition of breast milk is a complex biological nutritional fluid containing not just nutrients, but antibodies, enzymes, long-chain fatty acids, and hormones, many of which cannot be replaced in an infant formula. As proved in a recent study, Hanson et al98found that decreased antioxidant levels (including carotenoids) were present in donor milk compared with maternal milk, but that these levels were still higher than in artificial infant formula. One recent report99 on healthy pregnant women from Poland showed that the carotenoid profile and their concentrations in breast milk were unchanged during the first trimester of lactation. This study identified lycopene (the consumption of lycopene-rich food in Poland is high) as the major carotenoid present in breast milk, justifying the contrasting results in other reports where βC was shown to be the predominant carotenoid in mature breast milk samples from Brazil,100 Germany,90 and Cuba.101 The mother’s nutritional status before and during pregnancy influences the vitamin A reserves in the newborn, and, as a consequence, in the breast milk. In late gestation and early lactation, the serum levels of circulating retinoids decrease, since increased uptake of retinoids by the mammary gland is necessary for the production of colostrum (by the flow of low-density lipoproteins into the secretory cells).102,103 At birth, the newborn has low vitamin A reserves owing to maternal homeostatic control, which regulates the placental transfer of VA to the fetus and prevents the transfer of high concentrations of VA.104 Therefore, the offspring of VAD pregnant women may have decreased VA reserves, and breast milk constitutes the primary source.105,106 Thus, pro-VA carotenoids in breast milk could be a potential source of VA for the nursing infant.107 Therefore, dietary intake of carotenoids and vitamin A during gestation and lactation promotes the accumulation of adequate levels in breast milk, crucial for infant development.108 Prevention: gestational complications associated with vitamin A deficiency and pro-vitamin A carotenoids – effects on fetal and neonatal development Pregnancy-related, childbirth and postpartum complications lead to considerable mortality in women. The global maternal mortality between 2000 and 2017 was 38%, with nearly 94% of all maternal deaths occurring in low- and lower-middle-income countries.109 Although maternal nutritional status significantly affects pregnancy outcome, at least 20%–30% of pregnant women worldwide have some form of vitamin and other micronutrient deficiencies.12 VAD affects 15% of pregnant women in low-income countries, which is identified by low serum retinol content (<0.70 µmol/L); although not considered a direct cause of maternal death, vitamin A plays a significant role in fetal reproductive system development, synthesis of steroid hormones, embryo development, and maintenance of the immune system.59 VAD is also correlated with anemia and risk of death from severe infections.110,111 Therefore, adequate carotenoid and vitamin A levels during pregnancy and postpartum periods are extremely critical to avoid pregnancy-related problems, such as anemia, preeclampsia, gestational diabetes, abortion, and preterm delivery.112 Several epidemiological studies have demonstrated an association between high carotenoid intake and lower incidence of chronic diseases.113 As a consequence of the low aqueous solubility of carotenoids, dietary carotenoids are transported into the embryo by lipoproteins, namely low-density lipoproteins, high-density lipoproteins, and very-low-density lipoproteins, which serve as an in-situ source of retinoids once taken up by the developing tissues.114 The primary communication between the fetus and mother is mediated by the placenta, which has a high lipoprotein content, suggesting that carotenoids and vitamin A are transferred to the fetus by this mechanism. In mice, the transfer of intact βC to the embryo is attenuated by high vitamin A concentrations in the placental tissue; maternal vitamin A intake and βC availability exhibit a dose-response relationship to protect the embryo from high doses of carotenoids and retinoid derivatives.115 However, the exact transfer mechanisms of these molecules have not yet been elucidated.13 Anemia is a common clinical occurrence during pregnancy116 owing to increased blood production by pregnant women to support the growth of the fetus; in the absence of adequate dietary iron and other micronutrients, the maternal organism will not produce sufficient red blood cells to support the embryo.117 Several studies have suggested that VAD causes anemia by modulating iron metabolism – a finding that is supported by observations from both experimental and human studies.118 In addition, in Wistar rats, studies have shown that severe VAD might impair oocyte implantation, resulting in gestational problems.119 Since there is a direct correlation between carotenoids and vitamin A, βC supplementation during pregnancy is routinely reported. In addition, supplementation of 6 mg of βC in lactating women from Zimbabwe (n = 207) improved the vitamin A status and increased hemoglobin content (Hb%) to 12 g/L.120 In Egypt, a study involving 200 newborns delivered from VAD mothers showed significantly lower mean Hb% values compared with newborns delivered from mothers without VAD. In Indonesia, one study, conducted with 251 pregnant women, showed that vitamin A supplementation alone increased hemoglobin concentrations.121 Further, in pregnant women from India (conducted with 81 subjects), vitamin A supplementation combined with iron and folate reduced anemia up to 10% during gestation and postpartum periods.122 Small weekly gestational weight gain is sometimes associated with anemia and VAD, in addition to high blood pressure, which can lead to preeclampsia. Some studies have shown increased lipid peroxidation and decreased antioxidant capacity during pregnancy, which is often associated with an inflammatory state, thus strongly suggesting that oxidative stress could be a potential etiological factor for preeclampsia.123It follows, then, that some studies have found an association between carotenoid supplementation and significant improvements in preeclampsia. Palan et al124 observed that in human preeclampsia (n = 22), the placental tissue and maternal serum samples had lower carotenoid content than the control group. In addition, a study involving 359 pregnant women in Zimbabwe found a 50% decreased preeclampsia risk in women with high βC blood levels.125 Regarding vitamin A, one meta-analysis126 of 58 studies observed an association between preeclampsia and lipid-soluble micronutrients and concluded that small amounts of vitamin A in the sera of pregnant women are associated with preeclampsia risk. However, the authors recommend that these data be carefully evaluated as they have been the subject of considerable controversy. Some studies have suggested a correlation between maternal VAD and increased risk of insulin resistance and diabetes mellitus development in adult rats.127 Moreover, regarding gestational diabetes mellitus (GDM), some studies have suggested a positive association between carotenoids and serum retinol levels in pregnant women. During midpregnancy, in addition to the inherent pregnancy-related increase in oxidative stress, there is a progressive increase in insulin resistance, which may lead to GDM status. Thus, in pregnancy, GDM is defined as glucose intolerance resulting in the onset or diagnosis of hyperglycemia.128 The GDM pathology stems from a placental lactogen deficiency, leading to β-cell adaptations and an overload of insulin produced from the pancreas,129 leading to potential cardiac and renal dysfunction, metabolic syndrome, overweight/obesity, insulin resistance, higher blood pressure, and type 2 diabetes mellitus in the offspring.130 A recent cross-sectional study131 involving 1978 pregnant women in China concluded that intake of lycopene and other pro-VA carotenoids is associated with a lower risk of GDM, particularly among primigravid women. In addition, in one rodent study,132 a vitamin A-deficient diet impaired the structure of fetal pancreatic islets in the offspring by inducing cellular stress-mediated apoptosis and decreased levels of plasma insulin, glucagon, and C-peptide. These studies showed a strong association between GDM and serum retinoid levels during pregnancy since a marginal biochemical state or VAD was established.133 Thus, despite limited knowledge on the effect of carotenoids and vitamin A on glucose metabolism, considerable evidence on the role of these molecules in triggering fetal programming was shown in some studies. The role of vitamin A in the structural development of the fetus, as well as maternal health, is well established.12 However, it is important to note that high vitamin A doses have a teratogenic effect on offspring (7.5–40 mg/kg/d), leading to miscarriage and death.134 Consequently, vitamin A supplementation to prevent night blindness is recommended for pregnant women only in places where VAD is a severe public health concern.135 In contrast, VAD leads to low birth weight, which is also a significant public health problem worldwide, affecting immediate and long-term childhood.136 Obesity: carotenoids and derivatives – impact on obesity Obesity is a disease of multifactorial etiology characterized by chronic low-grade inflammation.137 Currently, obesity or overweight is a major global public health issue and increases the risk of contracting diseases.138 Obese or overweight pregnant women are predisposed to developing many diseases of gestational origin, with adverse cardiometabolic and neurodevelopmental outcomes.16 Additionally, the oxidative stress and pronounced inflammation status inherent to pregnancy may lead to the occurrence of metabolic alterations. Among the inflammation markers where carotenoids and vitamin A are involved, those markers related to changes in nuclear factor κB, PPAR-γ, mitogen-activated protein kinase, nuclear factor erythroid 2–related factor, retinol-binding protein, superoxide dismutase, glutathione peroxidase, and catalase expression were highlighted in a study by Rubin et al.62 In addition, recent reviews have shown beneficial effects of carotenoids and their derivatives on metabolic pathways during obesity therapy.14,15 Kawada et al87 reported that vitamin A and its precursors inhibit the activation and differentiation of adipocytes through RAR upregulation and PPAR-γ suppression. Likewise, the asymmetric cleavage of βC yielding apo-14′-carotenal product inhibits adipogenesis by transcriptional repression of RXR, PPAR-α, and PPAR-γ. More recently, the effect of physiological amounts of dietary carotenoids, specifically βC in an animal model (wild-type and BCO1-/- mice), showed downregulation of adipogenic genes (mostly PPAR-γ-responsive), supporting results from studies on the in vitro preadipocyte NIH 3T3-L1 cell line.139 In addition, it has been shown that βC, after conversion into VA, reduces obesity and does not affect in vivo BCO1 gene expression.139 However, these data do not agree with a recent meta-analysis, showing that, unlike retinol, total and individual carotenoids are inversely related to metabolic syndrome.82 Studies have demonstrated the presence of VA and low serum carotenoid levels in obese individuals.140 Both in vitro and in vivo studies have shown the role of VA metabolites in regulating adipose tissue metabolism and obesity.141 For example, it is well established that RA induces expression of the uncoupling protein-1 gene, activating the thermogenic program in brown adipocyte tissue142 and the browning of white adipose tissue.143,144 Additionally, RA administration increases lipolysis of white adipose tissue (via PPAR-γ), decreases leptin expression, and improves oxidative metabolism.143,145,146 Some carotenoids have been found to regulate gene expression of transcription factors involved in detoxification, via nuclear factor κB and mitogen-activated protein kinase.146,147 Other reports suggest that pro-VA carotenoids help control energy homeostasis by modulating the production of leptin and inflammatory cytokines.40 Interestingly, some carotenoids – specifically, βC, α-carotene, and lutein (trans-forms) – have been shown to dose-dependently promote in vitro expression of uncoupling protein-1 in confluent primary cultures of mice brown adipocytes.15 Therefore, the preventive effect of VA, and its pro-VA carotenoids (including derivatives), applies to all the stages that trigger fetal programming. Even before conception – depending on the mother’s lifestyle – many biological, biochemical, and psychological stressors can potentially affect the maternal conditions, which will be reflected in the intrauterine environment. After childbirth, the lactation period is the main form of physiological communication between the mother and child, which also translates into modulations in the offspring phenotype. Thus, VA and its pro-VA carotenoids are promising candidates for the prevention of nutrition-related disorders in pregnancy and fetal programming which could lead to several consequences until adulthood (Figure 2). Figure 2 Open in new tabDownload slide Schematic representation of the influence of some stressor factors on gestational and lactation periods, demonstrating an important role in the future phenotypic characterization of offspring Figure 2 Open in new tabDownload slide Schematic representation of the influence of some stressor factors on gestational and lactation periods, demonstrating an important role in the future phenotypic characterization of offspring CONCLUSION This review discusses the importance of VA and pro-VA carotenoid levels during pregnancy, lactation, or both, since maintaining adequate levels is particularly critical in terms of the lifestyle and physiological needs of the mother. Despite the significant role of carotenoids and VA in the nutritional status of pregnant and lactating women, a considerable percentage of women globally do not consume a sufficient amount of these nutrients. Maternal nutrition status is one of the most important factors triggering fetal programming, and vitamin A and its pro-VA carotenoids (mainly βC) are important molecules that assist conception, implantation, placentation, and regular fetal growth. In summary, these nutrients display an important role not only in the prevention of several gestational complications but also in a biochemical stage (promoting successful communication between mother and fetus), and by epigenetic alterations. Besides, some studies have demonstrated the true significance of VA and its derivatives as therapeutic agents against obesity, which denotes the importance of discussing dosages in line with the socioeconomic conditions of the expectant women (mainly in low-income countries). Therefore, this work acts not only as a narrative but also as a prerogative to consider further experimental studies in the current area. Funding. This work was supported by “Fundação de Amparo à Pesquisa do Estado de São Paulo- FAPESP” through the projects (2016/14133-0, and 2016/18910-1) and fellowships (2016/23242–8, and 2019/09359–8). Declaration of interest. The authors have no relevant interests to declare. Acknowledgments Author contributions. L.M. de S.M., L.V.M., and L.P.P. conducted the literature search, conceptualized and executed the review, and drafted the first manuscript. V.V. de R. and L.P.P. guided the development of the work. All the authors approved the final version of the manuscript and take responsibility for all aspects of the reliability, freedom from bias, and interpretation of the data presented. References 1 Koletzko B , Brands B , Grote V , et al. Long-term health impact of early nutrition: the power of programming . Ann Nutr Metab. 2017 ; 70 : 161 – 169 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Sultana Z , Maiti K , Aitken J , et al. 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TI - The role of vitamin A and its pro-vitamin carotenoids in fetal and neonatal programming: gaps in knowledge and metabolic pathways
JF - Nutrition Reviews
DO - 10.1093/nutrit/nuaa075
DA - 2021-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/the-role-of-vitamin-a-and-its-pro-vitamin-carotenoids-in-fetal-and-WFlyd7yFEl
SP - 76
EP - 87
VL - 79
IS - 1
DP - DeepDyve
ER -