Maternal Retinol Research Articles

Associations between Maternal Diet, Human Milk Macronutrients, and Breast-Fed Infant Growth during the First Month of Life in the SMILE Iwamizawa in Japan.

Maternal diet may affect human milk macronutrients, but it remains to be elucidated whether this is also influential in infant growth. This study aimed to examine (1) how maternal diet influences human milk macronutrients, and (2) to what extent the variation in milk macronutrients affects infant growth during the first month of life. In 71 Japanese lactating women, maternal dietary information was collected from the brief-type self-administered diet history questionnaire, and anthropometry of mother-infant dyads was collected from medical records. Macronutrients in milk were analyzed by a Human Milk Analyzer. Maternal retinol intake was associated with the carbohydrate content in human milk at 1-month postpartum (standardized β coefficient: 0.287; p = 0.038). Moreover, the energy content in human milk was associated with an increase in the weight standard deviation score based on the WHO growth standard at 1 month of age (standardized β coefficient: 0.399; p = 0.046). Nevertheless, the milk macronutrient was not associated with the risk of infant growth abnormalities. In conclusion, a part of the maternal diet impacts macronutrient contents in human milk, but milk macronutrients have a limited effect on infant growth only within the normal growth curve during the first month of life.

Factors that affect placental retinol transfer in preterm infants and mothers with retinol deficiency.

The retinol level and retinol delivery to the placenta may vary depending on various factors involving the mother and newborn. The present study evaluates the factors affecting retinol levels in newborns and the transplacental retinol passage in preterm newborns. In this prospective cohort study, the retinol and retinol binding protein (RBP) in the umbilical cord blood of 44 preterm infants with a gestation age of <30 weeks were studied. Serum retinol and RBP levels were determined using an enzyme-linked immunosorbent assay, and the rate of transplacental retinol passage was calculated. The demographic data of mothers and newborns, the use of vitamins by the mother, the application of antenatal corticosteroids, and any diseases diagnosed during pregnancy were recorded. An evaluation was made of the retinol, RBP, and other factors of the mother and newborn affecting transplacental retinol passage. A retinol deficiency was identified in 68.2% of the study population. Retinol and RBP levels in umbilical cord blood (273.7 ± 150.03 ng/mL, 7.88 ± 5.6 ng/mL, respectively) were significantly higher than the corresponding levels in the mother (206.4 ± 86.26 ng/ mL, 1.04 ± 0.97 ng/mL, respectively). Umbilical cord blood retinol deficiency was more common in the male participants, while the transplacental retinol passage rate was higher in females. The umbilical cord blood RBP was found to be lower in those administered antenatal corticosteroids than in those who did not receive antenatal corticosteroids, and median maternal RBP levels were lower in patients with anemia and pregnancy-induced hypertension than in those with no disease. Placental adaptation and contributing factors may vary in populations with severe retinol deficiency. The finding of significantly increased cord blood retinol levels when compared to maternal retinol levels in the present study suggests that some compensatory mechanisms, such as increased placental RBP levels, support the presentation of retinol to the fetus, even if the mother has a retinol deficiency.

Maternal Diet Influences Fetal Growth but Not Fetal Kidney Volume in an Australian Indigenous Pregnancy Cohort.

Suboptimal nutrition during pregnancy is recognised as a significant modifiable determinant in the development of chronic disease in offspring in later life. The current study aimed: (i) to assess the dietary intakes of pregnant Indigenous Australian women against national recommendations and (ii) to investigate the associations between maternal nutrition during pregnancy and the growth of the offspring, including kidney development in late gestation in the Gomeroi gaaynggal cohort (n = 103). Maternal dietary intake in the third trimester was assessed using the Australian Eating Survey Food Frequency Questionnaire. Estimated fetal weight (EFW) and kidney size were obtained by ultrasound. Birth weight was retrieved from hospital birth records. Of the five key nutrients for optimal reproductive health (folate, iron, calcium, zinc and fibre), the nutrients with the highest percentage of pregnant women achieving the nutrient reference values (NRVs) were zinc (75.7%) and folate (57.3%), whereas iron was the lowest. Only four people achieved all NRVs (folate, iron, calcium, zinc and fibre) important in pregnancy. Sodium and saturated fat intake exceeded recommended levels and diet quality was low, with a median score of 28 out of 73 points. After adjusting for smoking and pre-pregnancy body mass index, only maternal intake of retinol equivalents and the proportion of energy from nutrient-dense or energy-dense, nutrient-poor (EDNP) foods were associated with fetal growth. EFW decreased by 0.13 g and birth weight decreased by 0.24 g for every µg increase in maternal dietary retinol intake. Interestingly, EFW, but not actual birth weight, was positively associated with percentage energy from nutrient dense foods and negatively associated with percentage energy from EDNP foods. Dietary supplement usage was associated with increased birthweight, most significantly iron and folate supplementation. Current dietary intakes of pregnant Australian women from this cohort do not align with national guidelines. Furthermore, current findings show that maternal retinol intake and diet composition during pregnancy can influence fetal growth, but not fetal kidney growth in late gestation. Strategies that aim to support and optimise nutrient intakes of Indigenous pregnant women are urgently needed. Future studies with long-term follow-up of the children in the current cohort to assess renal damage and blood pressure are imperative.

Factors that affects placental retinol transfer in preterm infants and mothers with retinol deficiency

BACKGROUND The retinol level and retinol delivery to the placenta may vary depending on various factors involving the mother and baby. The present study evaluates the factors affecting retinol levels in babies and the transplacental retinol passage in preterm babies. MATERIALS AND METHODS In this prospective cohort study, the retinol and retinol binding protein (RBP) in the umbilical cord blood of 44 preterm infants with a gestation age of <30 weeks were studied. Serum retinol and RBP levels were determined using an enzyme-linked immunosorbent assay, and the rate of transplacental retinol passage was calculated. The demographic data of mothers and babies, the use of vitamins by the mother, the application of antenatal corticosteroids and any diseases diagnosed during pregnancy were recorded. An evaluation was made of the retinol, RBP and other factors of the mother and baby affecting transplacental retinol passage. RESULTS A retinol deficiency was identified in 68.2% of the study population. Retinol and RBP levels in umbilical cord blood (273.7±150.03 ng/ml, 7.88±5.6 ng/ml, respectively) were significantly higher than the corresponding levels in the mother (206.4±86.26 ng/ml, 1.04±0.97 ng/ml, respectively).Umbilical cord blood retinol deficiency was more common in the male participants, while the transplacental retinol passage rate was higher in females. The umbilical cord blood RBP was found to be lower in those administered antenatal corticosteroids than in those who did not receive antenatal corticosteroids, and median maternal RBP levels were lower in patients with anemia and pregnancy-induced hypertension than in those with no disease. CONCLUSION Placental adaptation and contributing factors may vary in populations with severe retinol deficiency. The finding of significantly increased cord retinol levels when compared to maternal retinol levels in the present study suggests that some compensatory mechanisms, such as increased placental RBP levels, support the presentation of retinol to the fetus, even if the mother has a retinol deficiency.

Effect of Maternal Retinol Status at Time of Term Delivery on Retinol Placental Concentration, Intrauterine Transfer Rate, and Newborn Retinol Status.

Retinol (vitamin A) is essential, so the objective of this Institutional Review Board approved study is to evaluate retinol placental concentration, intrauterine transfer, and neonatal status at time of term delivery between cases of maternal retinol adequacy, insufficiency, and deficiency in a United States population. Birth information and biological samples were collected for mother–infant dyads (n = 260). Maternal and umbilical cord blood retinol concentrations (n = 260) were analyzed by HPLC and categorized: deficient (≤0.7 umol/L), insufficient (>0.7–1.05 umol/L), adequate (>1.05 umol/L). Intrauterine transfer rate was calculated: (umbilical cord blood retinol concentration/maternal retinol concentration) × 100. Non-parametric statistics used include Spearman’s correlations, Mann–Whitney U, and Kruskal–Wallis tests. p-values <0.05 were statistically significant. Only 51.2% of mothers were retinol adequate, with 38.4% insufficient, 10.4% deficient. Only 1.5% of infants were retinol adequate. Placental concentrations (n = 73) differed between adequate vs. deficient mothers (median 0.13 vs. 0.10 μg/g; p = 0.003). Umbilical cord blood concentrations were similar between deficient, insufficient, and adequate mothers (0.61 vs. 0.55 vs. 0.57 μmol/L; p = 0.35). Intrauterine transfer increased with maternal deficiency (103.4%) and insufficiency (61.2%) compared to adequacy (43.1%), p < 0.0001. Results indicate that intrauterine transfer rate is augmented in cases of maternal retinol inadequacy, leading to similar concentrations in umbilical cord blood at term delivery.

Retinol status and associated factors in mother-newborn pairs.

Vitamin A deficiency is still considered to be a nutritional problem during pregnancy, lactation and early childhood. The present study aimed to assess the vitamin A status of women and their newborns in the Brazilian Northeast and to determine the association between retinol in the maternal serum, umbilical cord blood and colostrum. Vitamin A status in 65 pairs of women and newborns was assessed from samples of the mother's serum, umbilical cord serum and colostrum using high-performance liquid chromatography. The inadequacy of the vitamin A status of mothers and infants was identified if the retinol values were <0.7µmolL- 1 in maternal serum or umbilical cord blood or <1.05µmolL-1 in colostrum. The prevalence of inadequate maternal vitamin A status was 21.5% (95% CI: 11.5%-31.5%) and 13.8% [95% confidence interval (CI)=5.4%-22.2%] based on maternal serum and colostrum, respectively. Among newborns, 41.5% (95% CI=29.3%-53.5%) presented a low status of vitamin A based on cord serum. Multiple linear regression analysis identified that maternal serum retinol is a predictor of umbilical cord retinol (P=0.005). Retinol in maternal serum was lower in mothers who were less educated (P=0.04) and colostrum retinol was higher in older (P=0.04) and multiparous (P=0.002) mothers. Vitamin A deficiency is a common problem among mothers attended in public hospitals in Northeast Brazil and maternal retinol concentrations are associated with retinol status in newborns. Maternal age, parity and educational level were related to the maternal vitamin A status.

Status of Vitamin A and Related Compounds and Clinical Outcomes in Maternal-Infant Pairs in the Midwestern United States

Background: Vitamin A is an essential nutrient for pregnant women, and other vitamin A-related compounds, including lutein and lycopene, have been associated with maternal-infant outcomes. The objective of this study was to quantify the status of vitamin A and related compounds in maternal-infant pairs at the time of delivery, and to determine its impact on clinical outcomes. Methods: Maternal and cord blood samples were collected in 189 mother-infant pairs. Concentrations of lutein + zeaxanthin, β-cryptoxanthin, lycopene, carotenes, and retinol were measured using high-performance liquid chromatography. Descriptive statistics was calculated and Spearman coefficients were used to assess correlations between maternal and cord measurements. Kruskal-Wallis and independent samples t test were used to compare measures between retinol groups. Linear and logistic regression models were used to adjust for relevant confounders. p < 0.05 was considered statistically significant. Results: Ten percent of mothers had serum retinol concentrations ≤0.70 µmol/L; 80% of infants had serum retinol concentrations ≤0.70 µmol/L. Low maternal retinol concentrations were associated with maternal anemia (p = 0.04) and a trend toward low birth weight (p = 0.06). Maternal and infant concentrations of vitamin A compounds were highly correlated. After adjustment for confounders, maternal lutein was associated with a C-section (p = 0.03) and a diagnosis of respiratory distress syndrome in the infant (p = 0.02). Maternal lycopene was associated with growth parameters in the infant. Conclusions: As vitamin A-related compounds are modifiable by diet, future research determining the clinical impact of these compounds is warranted.

Nutritional, inflammatory, and ecological correlates of maternal retinol allocation to breast milk in agro-pastoral Ariaal communities of northern Kenya.

Vitamin A (VA) is an essential micronutrient required for a range of biological functions throughout life. VA deficiency (VAD) claims an estimated 1 million preschool children's lives annually. Human milk is enriched with VA (retinol) from the maternal blood, which originates from the hepatic reserve and dietary intake. Secreting retinol into milk will benefit the nursing infant through breast milk, but retaining retinol is also important for the maternal health. Previous studies found that the public health intervention of high-dose VA supplementation to lactating mothers did not significantly lower child mortality. The World Health Organization (WHO) recently acknowledged that our understanding about the principle of VA allocation within the maternal system and the secretion into milk is too incomplete to devise an effective intervention. We present a secondary analysis of data collected among lactating mothers in VAD endemic northern Kenya (n = 171), examining nutritional, inflammatory, and ecological factors that might associate with maternal retinol allocation. Regression models were applied using the outcome milk-retinol allocation index: milk retinol/(milk retinol + serum retinol). Ten percent of the sample was identified as VAD. The average milk retinol concentration was 0.1 μmo/L, grossly below what is considered minimally necessary for an infant (1 μmol/L). VAD mothers and mothers with inflammation did not seem to compromise their milk retinol even though their serum retinol was lower than non-VAD and noninflammation mothers. Breast milk fat concentration positively correlated with milk retinol but not with serum retinol. This exploratory study contributes toward an understanding of maternal retinol allocation.

Maternal serum retinol and β-carotene concentrations and neonatal bone mineralization: results from the Southampton Women’s Survey cohort

Background: Studies in older adults and animals have suggested contrasting relations between bone health and different vitamin A compounds. To our knowledge, the associations between maternal vitamin A status and offspring bone development have not previously been elucidated.Objective: We examined the associations between maternal serum retinol and β-carotene concentrations during late pregnancy and offspring bone mineralization assessed at birth with the use of dual-energy X-ray absorptiometry.Design: In the Southampton Women’s Survey mother-offspring birth cohort, maternal health, lifestyle, and diet were assessed prepregnancy and at 11 and 34 wk of gestation. In late pregnancy, maternal serum retinol and β-carotene concentrations were measured. Offspring total body bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were measured within 2 wk after birth.Results: In total, 520 and 446 mother-offspring pairs had measurements of maternal serum retinol and β-carotene, respectively. Higher maternal serum retinol in late pregnancy was associated with lower offspring total body BMC (β = −0.10 SD/SD; 95% CI: −0.19, −0.02; P = 0.020) and BA (β = −0.12 SD/SD; 95% CI: −0.20, −0.03; P = 0.009) but not BMD. Conversely, higher maternal serum β-carotene concentrations in late pregnancy were associated with greater total body BMC (β = 0.12 SD/SD; 95% CI: 0.02, 0.21; P = 0.016) and BA (β = 0.12 SD/SD; 95% CI: 0.03, 0.22; P = 0.010) but not BMD.Conclusions: Maternal serum retinol and β-carotene concentrations had differing associations with offspring bone size and growth at birth: retinol was negatively associated with these measurements, whereas β-carotene was positively associated. These findings highlight the need for further investigation of the effects of maternal retinol and carotenoid status on offspring bone development.

Decidual β-carotene-15,15'-oxygenase-1 and 2 (BCMO1,2) expression is increased in nitrofen model of congenital diaphragmatic hernia.

Retinoids are essential for fetal and lung development. Beta-carotene(BC) is the main dietary retinoid source and beta-carotene-15,15'-oxygenase-1 and 2 (Bcmo1,2) is the primary enzyme generating retinoid from BC in adult mammalian tissues. Placenta has a major role in the retinol homeostasis in fetal life: Since there is no fetal retinol synthesis, maternal retinol has to cross the placenta. It has been recently shown that BC can be converted to retinol by Bcmo1,2 in placenta for retinol transfer and moreover, BC can cross the placenta intact. The placental Bcmo1,2 expression is tightly controlled by placental retinol level. In severe retinol deficiency it has been shown that placental Bcmo1,2 expression are increased for generating retinol from dietary maternal BC even when the main retinol transfer is blocked. In recent years, low pulmonary retinol levels and disrupted retinoid signaling pathway have been implicated in the pathogenesis of pulmonary hypoplasia and congenital diaphragmatic hernia (CDH) in the nitrofen model of CDH. Recently, it has been demonstrated that the main retinol transfer in the placenta is blocked in the nitrofen model of CDH causing increased placental and decreased serum retinol level. The aim of our study was to determine maternal and fetal β-carotene levels and to investigate the hypothesis that placental expression of BCMO1 and BCMO2 is altered in nitrofen-exposed rat fetuses with CDH. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Maternal and fetal serum, placenta, liver and left lungs were harvested on D21 and divided into two groups: control (n = 8) and nitrofen with CDH (n = 8). Immunochistochemistry was performed to evaluate trophoblasts by cytokeratin expression and placental Bcmo1,2 expression. Expression levels of Bcmo1,2 genes in fetal lungs and liver were determined using RT-PCR and immunohistochemistry. BC level was measured using HPLC. Markedly increased decidual Bcmo1,2 immunoreactivity was observed in CDH group compared to controls. There was no difference neither in the trophoblastic Bcmo1,2 immunoreactivity nor in the pulmonary and liver Bcmo1,2 expression compared to controls. There was no significant difference in maternal serum BC levels between control and CDH mothers (2.14 ± 0.55 vs 2.56 ± 1.6 μM/g, p = 0.8). BC was not detectable neither in the fetal serum nor liver or lungs. Our data show that nitrofen increases maternal but not fetal Bcmo1,2 expression in the placenta in nitrofen-induced CDH group. The markedly increased decidual Bcmo1,2 expression suggests that nitrofen may trigger local, decidual retinol synthesis in the nitrofen model of CDH.

Nitrofen increases total retinol levels in placenta during lung morphogenesis in the nitrofen model of congenital diaphragmatic hernia.

It has been shown that pulmonary retinol level is decreased during lung morphogenesis in the nitrofen-induced PH in congenital diaphragmatic hernia (CDH). Placenta has a major role in the retinol homeostasis in fetal life. Since there is no fetal retinol synthesis, maternal retinol has to cross the placenta. Placenta is the main fetal retinol store where retinol is stored in retinyl-ester formation. Trophoblasts have to produce its own retinol-binding protein (RBP) for retinol transport from placenta to fetus. Recently, we demonstrated that trophoblastic RBP expression is decreased in the nitrofen model of CDH. The aim of this study was to investigate the retinol transfer from mother to the placenta in nitrofen model of CDH. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetal placenta harvested on D21 and divided into two groups: control (n=11) and nitrofen with CDH (n=11). Retinoid levels in placenta were measured using HPLC. Immunohistochemistry was performed to evaluate trophoblastic expression of main RSP genes. Total retinol levels in the placenta were significantly increased in CDH placenta compared to control placenta. The retinyl-ester levels were significantly increased in CDH placenta compared to control placenta. Markedly, decreased immunoreactivity of retinoid signaling pathway was observed in trophoblast cells in CDH compared to control placenta. Increased placental retinol levels show that retinol is transferred from mother to placenta and stored in the placenta in nitrofen model of CDH during lung morphogenesis. Nitrofen may disturb the mobilization of retinol from placenta to fetal circulation causing PH in CDH.

Increased uptake of dietary retinoids at the maternal-fetal barrier in the nitrofen model of congenital diaphragmatic hernia

Background/PurposeThe retinol signaling pathway is disrupted in congenital diaphragmatic hernia (CDH). Since there is no fetal retinol synthesis, maternal retinol has to cross the placenta. Nitrofen interferes with the retinol-binding protein (RBP) transfer pathway in CDH. However, in RBP knockout mice, retinol has been shown to be present. In this model, increased uptake of maternal dietary retinyl ester (RE) bounded in low-dense-lipoprotein (LDL) through low-density-lipoprotein-receptor 1 (LRP1) and increased activity of RE hydrolysis by lipoprotein-lipase (LPL) have been found. The aim of this study was to investigate the RE transfer pathway in the nitrofen CDH model. MethodsPregnant rats were treated with nitrofen or vehicle on gestational day (D9) and sacrificed on D21. Immunohistochemistry was performed to evaluate LRP1 and LPL protein expression. Serum LDL levels were measured by ELISA. Pulmonary and serum retinoid levels were measured using HPLC. ResultsMarkedly increased trophoblastic and pulmonary LRP1 and LPL immunoreactivity were observed in CDH compared to controls. Significantly increased serum LDL and RE levels were observed in CDH compared to controls. ConclusionsThe increased uptake of dietary retinoids at the maternal-fetal barrier in the nitrofen CDH model suggests that the RE transfer pathway may be the main source of retinol in this model.

Oxidative stress markers and micronutrients in maternal and cord blood in relation to neonatal outcome

Oxidative stress and micronutrient deficiencies have been related to lower birth weight (BW), small for gestational age (SGA) offspring and preterm delivery. The relation between neonatal outcome (BW, head circumference, SGA, preterm delivery) with markers of oxidative stress and micronutrients in maternal and cord blood was to be examined. Oxidative stress markers (protein carbonyls (PrCarb), 3-nitrotyrosine (3NT), malondialdehyde (MDA)), total protein concentration and lipid-soluble micronutrients (carotenoids, retinol, tocopherols) were measured in 200 newborns (11% preterms, 13% SGA) and 151 mothers. Associations between target parameters in cord plasma and maternal serum with BW, head circumference and risk of being SGA or preterm were explored. Maternal protein concentration, PrCarb, MDA and all lipid-soluble micronutrients were significantly higher compared with newborns, except for 3NT, which was significantly elevated in newborns. Newborn parameters correlated positively with those of mothers. Preterms had lower proteins and retinol but higher PrCarb than terms. Maternal PrCarb and retinol were inversely associated with BW and head circumference. Mothers with PrCarb, MDA and retinol in the highest quintile had a 3.3-fold (0.9; 12.1), 2.1-fold (0.7; 6.4) and 3.3-fold (1.2; 9.4) risk, respectively, for delivering an SGA newborn, whereas the lowest quintile of retinol in cord blood was associated with an increased risk for preterm delivery. Oxidative stress (elevated PrCarb) was associated with lower BW/head circumference and SGA. Inadequate hemodilution may explain the inverse relation of maternal retinol with BW and head circumference, and the association between highest maternal retinol and risk for SGA.

Association of retinol binding protein 4 with risk of gestational diabetes

AimWe investigated association of maternal retinol binding protein 4 (RBP4) with risk of gestational diabetes (GDM). MethodsGDM cases (N=173) and controls (N=187) were selected from among participants of a cohort study of risk factors of pregnancy complications. Early pregnancy (16 weeks on average) serum RBP4 concentration was measured using an ELISA-based immunoassay. Logistic regression was used to estimate unadjusted and adjusted odds ratios (ORs/aORs) and 95% confidence intervals (95%CI). ResultsMean serum RBP4 was significantly higher among GDM cases compared with controls (47.1 vs. 41.1μg/ml, respectively; p-value <0.05). Participants in the highest quartile for serum RBP4 had a 1.89-fold higher risk of GDM compared with participants in the lowest quartile (95%CI: 1.05–3.43). However, this relationship did not reach statistical significance after adjustment for confounders (aOR: 1.54; 95%CI: 0.82–2.90). Women who were ≥35 years old and who had high RBP4 (≥38.3μg/ml, the median) had a 2.31-fold higher risk of GDM compared with women who were <35 years old and had low RBP4 (<38.3μg/ml) (aOR: 2.31; 95%CI: 1.26–4.23; p-value for interaction=0.021). ConclusionOverall, there is modest evidence of a positive association of early pregnancy elevated RBP4 concentration with increased GDM risk, particularly among women with advanced age.

The Effects of Two Maternal Vitamin A Supplementation Regimens on Serum Retinol in Postpartum Mothers: A Randomised Controlled Trial in Brazil

Objective. To test whether the serum retinol level in mothers supplemented with 400,000 IU of vitamin A is higher than in those supplemented with 200,000 IU and to estimate duration of the protective effect of vitamin A supplementation in the serum retinol level. Methods. Double-blind, randomised controlled trial performed in two hospitals in the state of Pernambuco in northeast Brazil. Three hundred twelve mothers were recruited immediately postpartum. All women received a capsule containing 200,000 IU of vitamin A, and 10 days after delivery, they were randomly assigned to one of two treatment groups. One group received a second capsule containing vitamin A and the other group received a placebo. Each group was invited back after 2, 4, and 6 months for serum retinol analyses. Results. No difference was found between the two groups in serum maternal retinol concentration at 2 months (2.13 versus 2.03 μmol/L), 4 months (2.20 versus 2.24 μmol/L) or 6 months (2.29 versus 2.31 μmol/L). Because there was no further effect and because this population has a level of vitamin A deficiency considered mild, our results do not support a proposal to increase the dosing schedule for vitamin A in postpartum women as recommended by the IVACG.

Low maternal retinol as a risk factor for schizophrenia in adult offspring

BackgroundPrenatal micronutrient deficiency has been linked to later development of schizophrenia among offspring; however, no study has specifically investigated the association between vitamin A and this disorder. Vitamin A is an essential nutrient which is required by the early embryo and fetus for gene expression and regulation, cell differentiation, proliferation and migration. Previous work suggests that vitamin A deficiency in the second trimester may be particularly relevant to the etiopathogenesis of neurobehavioral phenotypes some of which are observed in schizophrenia. MethodsWe examined whether low maternal vitamin A levels in the second trimester are associated with the risk of schizophrenia and other schizophrenia spectrum disorders (SSD) in the Prenatal Determinants of Schizophrenia study; third trimester vitamin A levels were also examined in relation to SSD. The cases were derived from a population-based birth cohort; all cohort members belonged to a prepaid health plan. Archived maternal serum samples were assayed for vitamin A in cases (N=55) and up to 2 controls per case (N=106) matched on length of membership in the health plan, date of birth (±28days), sex, and gestational timing and availability of archived maternal sera. ResultsFor the second trimester, low maternal vitamin A, defined as values in the lowest tertile of the distribution among controls, was associated with a greater than threefold increased risk of SSD, adjusting for maternal education and age (OR=3.04, 95% CI=1.06, 8.79, p=.039). No association between third trimester maternal vitamin A and SSD was observed. ConclusionsAlthough further investigations are warranted, this is the first birth cohort study to our knowledge to report an association between low maternal vitamin A levels and SSD among offspring.

Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment

Retinoic acid (RA), an active vitamin A metabolite, is a key signaling molecule in vertebrate embryos. Morphogenetic RA gradients are thought to be set up by tissue-specific actions of retinaldehyde dehydrogenases (RALDHs) and catabolizing enzymes. According to the species, two enzymatic pathways (β-carotene cleavage and retinol oxidation) generate retinaldehyde, the substrate of RALDHs. Placental species depend on maternal retinol transferred to the embryo. The retinol-to-retinaldehyde conversion was thought to be achieved by several redundant enzymes; however, a random mutagenesis screen identified retinol dehydrogenase 10 [Rdh10(Trex) allele; Sandell LL, et al. (2007) Genes Dev 21:1113-1124] as responsible for a homozygous lethal phenotype with features of RA deficiency. We report here the production and characterization of unique murine Rdh10 loss-of-function alleles generated by gene targeting. We show that although Rdh10(-/-) mutants die at an earlier stage than Rdh10(Trex) mutants, their molecular patterning defects do not reflect a complete state of RA deficiency. Furthermore, we were able to correct most developmental abnormalities by administering retinaldehyde to pregnant mothers, thereby obtaining viable Rdh10(-/-) mutants. This demonstrates the rescue of an embryonic lethal phenotype by simple maternal administration of the missing retinoid compound. These results underscore the importance of maternal retinoids in preventing congenital birth defects, and lead to a revised model of the importance of RDH10 and RALDHs in controlling embryonic RA distribution.

Changes in Plasma Retinol of American Kestrels (Falco sparverius) in Response to Dietary or in Ovo Exposure to Environmentally Relevant Concentrations of a Penta-Brominated Diphenyl Ether Mixture, De-71

Polybrominated diphenyl ethers (PBDE) are ubiquitous, lipophilic, and bioaccumulative brominated flame retardants. Plasma retinol concentrations of captive adult American kestrels were assessed at the beginning of the breeding season following 3 wk of daily dietary exposure to vehicle (control), low (0.3 ng/g wet weight [ww]), or high (1.6 ng/g ww) concentrations of DE-71 and in their 25-d-old nestlings following embryonic exposure by maternal deposition to environmentally relevant low (291 ± 48 ng/g ww) or high (1111 ± 160 ng/g ww) sum (Σ) PBDE concentrations. Unexpectedly, low in ovo concentrations of total-α-hexabromocyclododecane (HBCD) were detected. Plasma retinol concentrations of adult males exposed to higher DE-71 concentrations were negatively correlated with in ovo ΣPBDE, BDE-100, and HBCD levels. Maternal (13%) and nestling (11%) retinol levels were lower in the low-exposure group compared to respective controls, and biologically significant since their retinol levels were correlated with hatching success and growth, respectively. Maternal retinol levels were also correlated with BDE-153. The underlying mechanisms may involve (1) PBDE exposure, hydroxylated (OH-) metabolites, and subsequent changes in retinol mobilization; (2) decreased maternal food consumption; and (3) reduced maternal retinol yolk deposits. The apparent lack of retinol changes in the high-exposure kestrel may reflect compensation occurring, either by increased mobilization and transportation of retinol, and/or higher food consumption in these birds. When highly mobile as evidenced during reproduction or development, retinol concentrations of adult and nestling kestrels are sensitive to environmentally relevant PBDE and HBCD levels.

Retinol Status of Newborn Infants Is Associated With Congenital Diaphragmatic Hernia

Genetic analyses in humans suggest a role for retinoid-related genes in the pathogenesis of congenital diaphragmatic hernia (CDH). The goal of this study was to investigate the vitamin A status of mothers and their newborns in association with CDH. We conducted a hospital-based, case-control study with 22 case and 34 control mothers and their newborns. In maternal and cord blood samples, retinol and retinol-binding protein (RBP) levels were measured with high-performance liquid chromatography and an enzyme-linked immunosorbent assay, respectively. Univariate and multivariate logistic regression analyses were performed to determine crude and adjusted risk estimates. Case newborns had significantly lower levels of retinol (0.60 vs 0.76 μmol/L; P=.003) and RBP (5.42 vs 7.11 mg/L; P=.02) than did control newborns. The multivariate logistic regression analysis showed lower levels of retinol and RBP in association with CDH risk; the odds ratio for retinol levels of <15th percentile (<0.61 μmol/L) was 11.11 (95% confidence interval: 2.54-48.66; P=.001), and that for RBP levels of <15th percentile (<4.54 mg/L) was 4.00 (95% confidence interval: 1.00-15.99; P=.05). Retinol and RBP levels were not different between case and control mothers. CDH is strongly associated with low retinol and RBP levels in newborns, independent of maternal retinol status. This is an important finding supporting the idea that human CDH is linked with abnormal retinoid homeostasis.

Dynamic expression of the retinoic acid‐synthesizing enzyme retinol dehydrogenase 10 (rdh10) in the developing mouse brain and sensory organs

Organs develop through many tissue interactions during embryogenesis, involving numerous signaling cascades and gene products. One of these signaling molecules is retinoic acid (RA), an active vitamin A derivative, which in mammalian embryos is synthesized from maternal retinol by two oxidative reactions involving alcohol/retinol dehydrogenases (ADH/RDHs) and retinaldehyde dehydrogenases (RALDHs), respectively. The activity of RALDHs is known to be crucial for RA synthesis; however, recently a retinol dehydrogenase (RDH10) has been shown to represent a new limiting factor in this synthesis. We investigated the spatiotemporal distribution of Rdh10 gene transcripts by in situ hybridization and quantitative polymerase chain reaction (PCR) during development of the brain and sensory organs. Although Rdh10 relative mRNA levels decline throughout brain development, we show a strong and lasting expression in the meninges and choroid plexuses. Rdh10 expression is also specifically seen in the striatum, a known site of retinoid signaling. In the eye, regional expression is observed both in the prospective pigmented epithelium and neural retina. In the inner ear Rdh10 expression is specific to the endolymphatic system and later the stria vascularis, both organs being involved in endolymph homeostasis. Furthermore, in the peripheral olfactory system and the vibrissae follicles, expression is present from early stages in regions where sensory receptors appear and mesenchymal/epithelial interactions take place. The distribution of Rdh10 transcripts during brain and sensory organ development is consistent with a role of this enzyme in generating region-specific pools of retinaldehyde that will be used by the various RALDHs to refine the patterns of RA synthesis.