Vitamin B12 Status in Pregnant Adolescents and Their Infants.

Vitamin B12 deficiency has been associated with increased risk of adverse pregnancy outcomes. Few prospective studies have investigated the burden or determinants of vitamin B12 deficiency early in life, particularly among pregnant adolescents and their children. The objectives of this study were to determine the prevalence of vitamin B12 deficiency and to examine associations between maternal and neonatal vitamin B12 status in a cohort study of healthy pregnant adolescents. Serum vitamin B12 and folate concentrations were measured in adolescents at mid-gestation (n = 124; 26.4 ± 3.5 weeks) and delivery (n = 131; 40.0 ± 1.3 weeks), and in neonates at birth using cord blood. Linear regression was used to examine associations between maternal and neonatal vitamin B12 status. Although the prevalence of vitamin B12 deficiency (<148.0 pmol/L; 1.6%) in adolescents was low during pregnancy, 22.6% of adolescents were vitamin B12 insufficient (<221.0 pmol/L; 22.6%) at mid-gestation. Maternal vitamin B12 concentrations significantly decreased from mid-gestation to delivery (p < 0.0001), and 53.4% had insufficient vitamin B12 status at delivery. Maternal vitamin B12 concentrations (p < 0.001) and vitamin B12 deficiency (p = 0.002) at delivery were significantly associated with infant vitamin B12 concentrations in multivariate analyses, adjusting for gestational age, maternal age, parity, smoking status, relationship status, prenatal supplement use, pre-pregnancy body mass index, race, and intake of vitamin B12 and folate. Maternal vitamin B12 concentrations significantly decreased during pregnancy and predicted neonatal vitamin B12 status in a cohort of healthy pregnant adolescents.

CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis.

: New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of AMP-activated protein kinase (Ampk) ß1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer. SIGNIFICANCE: These findings show that CAMKK2 and its downstream target AMPK have opposing effects on prostate cancer development and raise the possibility of a new combined therapeutic approach that inhibits CAMKK2 and activates AMPK.

Elemental content of the placenta: A comparison between two high-risk obstetrical populations, adult women carrying multiples and adolescents carrying singletons.

BACKGROUND: The placenta is responsible for the exchange of nutrients and for preventing harmful compounds from entering the fetal circulation. With increasing industrialization, exposures to commercial and toxic metals become a concern for both pregnant women and those planning a pregnancy. The understanding of transport mechanisms and pharmacokinetics for most inorganic elements is incomplete and limited to normal term deliveries. OBJECTIVES: To obtain novel data on 46 inorganic elements in placentae from two high-risk obstetric populations, women carrying multiples and adolescents carrying singletons, evaluating differences, if present, and identifying predictors of placental content. METHODS: Placental tissue was collected from adolescents carrying singletons and adults carrying multiples. Elemental content was analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). Multivariate regression and factor analyses were used. RESULTS: With the exception of Au and Pt, almost all placentae contained quantifiable concentrations of each element analyzed. All placentae contained the essential elements Ca, Fe, Mg, Se and Zn, which clustered together onto the same factor. Most elements were higher in placentae from women carrying multiples. Differences in placental content disappeared after adjusting for maternal age. Rare earth elements (REEs) clustered together and remained higher in the multiples even after adjusting for maternal age. CONCLUSION: Human placentae contain a wide range of elements, including REEs. Ranges differed considerably between cohorts. Elements with similar chemical properties, like REEs or nutritionally essential elements, clustered together. Maternal age, and therefore longer environmental exposure, was significantly associated with elevated element concentrations in the placenta. Placental concentrations of several metals that are known to be nutritionally essential (e.g., Fe, Ca, Mg, and Zn) did not differ significantly between cohorts, suggesting tight regulation, whereas concentrations of environmental contaminants differed significantly between groups, even after adjusting for maternal age.

Iron deficiency and anemia are prevalent in women with multiple gestations.

BACKGROUND: Little attention has been placed on the unique iron demands that may exist in women with multiple gestations. This merits attention because iron deficiency (ID) during pregnancy is associated with adverse pregnancy outcomes that are known to be more prevalent in multiple births. OBJECTIVE: We characterized longitudinal changes in iron status across pregnancy in a cohort of healthy women with multiple gestations and identified determinants of maternal ID and anemia. DESIGN: A group of 83 women carrying twins, triplets, or quadruplets (aged 20-46 y) was recruited from 2011 to 2014. Blood samples obtained during pregnancy (∼24 wk; n = 73) and at delivery (∼35 wk; n = 61) were used to assess hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, serum iron, erythropoietin, serum folate, vitamin B-12, C-reactive protein, and interleukin-6. RESULTS: The prevalence of tissue ID (sTfR >8.5 mg/L) increased significantly from pregnancy to delivery (9.6% compared with 23%, P = 0.03). Women with depleted iron stores (SF <12 µg/L, n = 20) during pregnancy had a 2-fold greater risk of anemia at delivery, and 25% (n = 5) developed iron deficiency anemia (IDA). Overall, 44.6% of women studied (n = 37/83) were anemic at delivery, and 18% of women (n = 11/61) had IDA. Erythropoietin during pregnancy was significantly negatively associated with hemoglobin at delivery. Women with erythropoietin >75th percentile during pregnancy exhibited a 3-fold greater risk of anemia, suggesting that erythropoietin is a sensitive predictor of anemia at delivery. Inflammation was present at delivery, which limited the utility of ferritin or hepcidin as iron-status indicators at delivery. CONCLUSIONS: ID and anemia are highly prevalent in women with multiple gestations. Additional screening and iron supplementation may be warranted in this high-risk population given the known associations between ID anemia and adverse maternal and neonatal outcomes. This trial was registered at clinicaltrials.gov as NCT01582802.

Vitamin B12 and placental expression of transcobalamin in pregnant adolescents.

BACKGROUND: Transcobalamin is a key placental protein involved in transport of vitamin B12 to the fetus. However, few data currently exist on the ability of the placenta to modify vitamin B12 transporter expression, particularly in high-risk populations such as pregnant adolescents. OBJECTIVE: This study was conducted to determine the impact of maternal and neonatal serum vitamin B12 concentrations on placental transcobalamin (TC) expression in a cohort of healthy pregnant adolescents in the United States. DESIGN: Serum vitamin B12 concentrations were measured in maternal blood samples at mid-gestation (26.4 ± 2.8 weeks) and delivery (39.8 ± 1.4 weeks) and infant cord blood samples at birth. Placentas were collected at delivery and TC mRNA expression (ΔΔCt) and TC protein abundance (TC:α-actin) were evaluated. Linear and binomial regression models were used to examine the associations of maternal serum (mid-gestation, delivery) and cord blood vitamin B12 concentrations with placental TC mRNA expression and protein abundance (n = 63). RESULTS: Maternal serum vitamin B12 concentrations at mid-gestation or delivery were not significantly associated with placental TC mRNA expression or TC protein abundance (p > 0.05). Higher placental TC protein abundance was associated with increased cord blood vitamin B12 concentrations (p = 0.003). CONCLUSIONS: Higher placental TC protein abundance was associated with higher cord blood vitamin B12 concentrations, suggesting a potential role in vitamin B12 transport to the fetus.

Maternal iron status during pregnancy compared with neonatal iron status better predicts placental iron transporter expression in humans.

The placenta richly expresses nonheme and heme Fe transport proteins. To address the impact of maternal and neonatal Fe status and hepcidin on the regulation of these proteins, mRNA expression and protein abundance of nonheme and heme Fe transport proteins were evaluated in placental tissue from 154 adolescents. Regression analyses found maternal Fe status was significantly associated with multiple placental nonheme and heme transporters, whereas neonatal Fe status was related to only 3 heme transporters. Across statistical analyses, maternal Fe status was consistently associated with the placental nonheme Fe importer transferrin receptor 1 (TfR1). Protein abundance of TfR1 was related to midgestation maternal serum ferritin (SF) (ß = -0.32; P = 0.005) and serum TfR (ß = 0.25; P = 0.024). Protein abundance of the heme importer, proton-coupled folate transporter, was related to neonatal SF (ß = 0.30; P = 0.016) and serum TfR (ß = -0.46; P < 0.0001). Neonatal SF was also related to mRNA expression of the heme exporter feline leukemia virus subgroup C receptor 1 (ß = -0.30; P = 0.004). In summary, maternal Fe insufficiency during pregnancy predicts increased expression of the placental nonheme Fe transporter TfR1. Associations between placental heme Fe transporters and neonatal Fe status require further study.-Best, C. M., Pressman, E. K., Cao, C., Cooper, E., Guillet, R., Yost, O. L., Galati, J., Kent, T. R., O'Brien, K. O. Maternal iron status during pregnancy compared with neonatal iron status better predicts placental iron transporter expression in humans.

Vitamin D status is inversely associated with anemia and serum erythropoietin during pregnancy.

BACKGROUND: Vitamin D and iron deficiencies frequently co-exist. It is now appreciated that mechanistic interactions between iron and vitamin D metabolism may underlie these associations. OBJECTIVE: We examined interrelations between iron and vitamin D status and their regulatory hormones in pregnant adolescents, who are a group at risk of both suboptimal vitamin D and suboptimal iron status. DESIGN: The trial was a prospective longitudinal study of 158 pregnant adolescents (aged ≤18 y). Maternal circulating biomarkers of vitamin D and iron were determined at midgestation (∼25 wk) and delivery (∼40 wk). Linear regression was used to assess associations between vitamin D and iron status indicators. Bivariate and multivariate logistic regressions were used to generate the OR of anemia as a function of vitamin D status. A mediation analysis was performed to examine direct and indirect relations between vitamin D status, hemoglobin, and erythropoietin in maternal serum. RESULTS: Maternal 25-hydroxyvitamin D [25(OH)D] was positively associated with maternal hemoglobin at both midgestation and at delivery (P < 0.01 for both). After adjustment for age at enrollment and race, the odds of anemia at delivery was 8 times greater in adolescents with delivery 25(OH)D concentrations <50 nmol/L than in those with 25(OH)D concentrations ≥50 nmol/L (P <0.001). Maternal 25(OH)D was inversely associated with erythropoietin at both midgestation (P <0.05) and delivery (P <0.001). The significant relation observed between 25(OH)D and hemoglobin could be explained by a direct relation between 25(OH)D and hemoglobin and an indirect relation that was mediated by erythropoietin. CONCLUSIONS: In this group of pregnant adolescents, suboptimal vitamin D status was associated with increased risk of iron insufficiency and vice versa. These findings emphasize the need for screening for multiple nutrient deficiencies during pregnancy and greater attention to overlapping metabolic pathways when selecting prenatal supplementation regimens.

Vitamin D Status Affects Serum Metabolomic Profiles in Pregnant Adolescents.

Vitamin D is linked to a number of adverse pregnancy outcomes through largely unknown mechanisms. This study was conducted to examine the role of vitamin D status in metabolomic profiles in a group of 30 pregnant, African American adolescents (17.1 ± 1.1 years) at midgestation (26.8 ± 2.8 weeks), in 15 adolescents with 25-hydroxy vitamin D (25(OH)D) ≥20 ng/mL, and in 15 teens with 25(OH)D <20 ng/mL. Serum metabolomic profiles were examined using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. A novel hierarchical mixture model was used to evaluate differences in metabolite profiles between low and high groups. A total of 326 compounds were identified and included in subsequent statistical analyses. Eleven metabolites had significantly different means between the 2 vitamin D groups, after correcting for multiple hypothesis testing: pyridoxate, bilirubin, xylose, and cholate were higher, and leukotrienes, 1,2-propanediol, azelate, undecanedioate, sebacate, inflammation associated complement component 3 peptide (HWESASXX), and piperine were lower in serum from adolescents with 25(OH)D ≥20 ng/mL. Lower maternal vitamin D status at midgestation impacted serum metabolic profiles in pregnant adolescents.