Prenatal manganese and cord blood mitochondrial DNA copy number: Effect modification by maternal anemic status.
ABSTRACT: INTRODUCTION:Manganese (Mn) is an essential nutrient but also a toxicant at high exposures, when it can induce oxidative stress (OS). Mn uptake is inversely correlated with iron status, therefore anemic individuals may be more susceptible to Mn overload induced-OS, which can manifest as changes in mitochondrial DNA copy number (mtDNA CN). Our objectives were to: 1) determine stage-specific associations of prenatal Mn exposure with cord blood MtDNA CN; and 2) investigate effect modification by maternal anemia, ferritin, and mean corpuscular volume (MCV). MATERIALS AND METHODS:We measured whole blood Mn, hemoglobin, serum ferritin, and MCV in the 2nd and 3rd trimester, in maternal blood at birth, and in cord blood from a prospective birth cohort in Mexico City, Mexico (n?=?485). We then extracted DNA from cord blood leukocytes to determine mtDNA CN. We used robust regression to measure associations between Mn and mtDNA CN at each trimester and at birth. Anemia (hemoglobin ?11?g/dL), iron deficiency (ferritin ?15?ng/mL) and MCV (stratified at median), were examined as effect modifiers. RESULTS:Mn levels increased throughout pregnancy, and Mn was inversely correlated with ferritin. We observed a positive association between Mn in the 3rd trimester and Mn in cord blood and mtDNA CN (??=?0.04-0.05; 95% CI?=?0.01, 0.08). Anemia significantly modified the association between mtDNA CN and Mn in the 2nd trimester. We found a positive association between 2nd trimester Mn and mtDNA CN in mothers with normal hemoglobin, and a negative association in those with low hemoglobin. (?high?=?0.06; 95% CI?=?0.01, 0.11; p?=?0.01 and ?low?=?-0.06; 95% CI?=?0.03, -0.13; p?=?0.06). No associations were detected between anemia, iron deficiency and MCV and mtDNA CN. CONCLUSIONS:Maternal blood Mn in the 3rd trimester and in cord blood was positively associated with mtDNA CN, suggesting that higher late pregnancy prenatal Mn exposures can impact newborn mitochondria by promoting OS. Furthermore, 2nd trimester Mn was positively associated with mtDNA in non-anemic mother-child pairs but inversely associated in anemic individuals, indicating potential interactions between Mn and chronic anemia.
Project description:BACKGROUND:We evaluated: (1) associations of prenatal manganese (Mn) levels with child neurodevelopment at 4-6 years; (2) effect modification by maternal anemia and iron deficiency; and (3) sex-specific effects. METHODS:We measured blood Mn, hemoglobin, and serum ferritin in mothers at the second trimester, third trimester, and at birth, and in cord blood from a prospective birth cohort in Mexico City (n?=?571). McCarthy Scales of Children's Abilities were measured at 4-6 years. Using linear regression, we estimated associations between prenatal Mn and neurodevelopment, examined anemia and iron deficiency as effect modifiers, and analyzed associations by child sex. RESULTS:No direct associations were observed between Mn, anemia, or iron deficiency and McCarthy Scales. Second trimester iron deficiency and third trimester anemia modified the effect of Mn on child neurodevelopment. For instance, second trimester Mn was positively associated child memory scores in mother's with normal ferritin (1.85 (0.02, 3.45)), but negatively associated in mother's with low ferritin (-2.41 (-5.28, 0.47), interaction P value?=?0.01), a pattern observed across scales. No effect modification at birth or in cord blood was observed. CONCLUSIONS:Anemia/iron deficiency during pregnancy may modify Mn impacts on child neurodevelopment, particularly in boys.
Project description:INTRODUCTION:Lead (Pb) crosses the placenta and can cause oxidative stress, reduced fetal growth and neurological problems. The principal source of oxidative stress in human cells is mitochondria. Therefore, disruption of normal mitochondrial function during pregnancy may represent a primary mechanism behind the adverse effects of lead. We sought to assess the association of Pb exposure during pregnancy with mitochondrial DNA (mtDNA) content, a sensitive marker of mitochondrial function, in cord blood. MATERIALS AND METHODS:This study comprised mother-infant pairs from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a prospective birth-cohort that enrolled 1050 pregnant women from Mexico City who were receiving prenatal care between December 2007 and July 2011. Quantitative PCR was used to calculate relative MtDNA content (mitochondrial-to-nuclear DNA ratio (mtDNA/nDNA)) in cord blood. Lead concentrations in both maternal blood (2nd and 3rd trimester and at delivery day) and in cord blood were measured by ICP-MS. Multivariable regression models adjusting for multiple confounders were fitted with 410 mother-infant pairs for whom complete data for mtDNA content, lead levels, and covariates were available. RESULTS:Maternal blood Pb measured in the second (mean 3.79??g/dL, SD 2.63; ??=?0.059, 95% CI 0.008, 0.111) and third trimester (mean 3.90??g/dL; SD 2.84; ??=?0.054, 95% CI 0.002, 0.107) during pregnancy and PB in cord blood (mean 3.50??g/dL, SD 2.59; ??=?0.050, 95% CI 0.004; 0.096) were associated with increased cord blood mtDNA content (mean 1.46, SD 0.44). In two-way interaction analyses, cord blood Pb marginally interacted with gestational age leading to an increase in mtDNA content for pre-term births (Benjamini-Hochberg False Discovery Rate correction; BH-FDR?=?0.08). CONCLUSION:This study shows that lead exposure in pregnancy alters mtDNA content in cord blood; therefore, alteration of mtDNA content might be a mechanism underlying the toxicity of lead.
Project description:Studies addressing health effects of manganese (Mn) excess or deficiency during prenatal development are hampered by a lack of biomarkers that can reconstruct fetal exposure. We propose a method using the neonatal line, a histological feature in deciduous teeth, to identify regions of mantle dentine formed at different prenatal periods. Micromeasurements of Mn in these regions may be used to reconstruct exposure at specific times in fetal development. To test our hypothesis, we recruited pregnant women before 20 weeks gestation from a cohort of farmworkers exposed to Mn-containing pesticides. We collected house floor dust samples and mother's blood during the second trimester; umbilical cord blood at birth; and shed deciduous incisors when the child was ?7 years of age. Mn levels in mantle dentine formed during the second trimester (as (55)Mn:(43)Ca area under curve) were significantly associated with floor dust Mn loading (r(spearman) = 0.40; p = 0.0005; n = 72). Furthermore, (55)Mn:(43)Ca in sampling points immediately adjacent the neonatal line were significantly associated to Mn concentrations in cord blood (r(spearman) = 0.70; p = 0.003; n = 16). Our results support that Mn levels in mantle dentine are useful in discerning perinatal Mn exposure, offering a potentially important biomarker for the study of health effects due to environmental Mn exposure.
Project description:We aimed at finding out reliable parameter in the differentiation of iron deficiency anemia (IDA) and beta-thalassemia trait (β-TT) in the adult population subjected to Saudi Arabian Premarital Screening Program.A total of 620 adults (age range 21-36 years) reported during February 2012 to November 2012. Tests for serum iron and ferritin were carried out in individuals showing low hemoglobin (Hb). All the selected subjects' samples were subjected to blood morphology, comparison of MCV, RBC count. Red Cell Distribution Width (RDW) was noted from the Coulter Report whereas Red Cell Distribution Width Index (RDWI) value was calculated for all the samples.A total of one hundred &thirty-five individuals with hypochromic microcytic anemia having normal hemoglobin F and hemoglobin A2 < 3.2% were inducted in the study. Ninety-three were diagnosed having IDA, whereas thirty-two were having βTT. Ten individuals revealed other causes of anemia. The RBC count was higher, and MCV was much lower in βTT as compared to IDA. Both groups were subjected to RDW and RDWI, however, RDWI which showed better sensitivity and specificity for βTT.RDWI is a reliable and useful index for differentiation among IDA and βTT, as compared to RDW.
Project description:Paracetamol is the first choice for antipyretic or analgesic treatment throughout pregnancy. Products with Paracetamol are readily available over the counter and therefore easily accessible for self-medication. Epidemiological data on Paracetamol intake pattern during pregnancy and its potential immunological effects are sparse. We aimed to analyze a possible association between Paracetamol medication and numbers of hematopoietic stem cells (HSC) in cord blood.The objective was addressed in the PRINCE (PRENATAL DETERMINANTS OF CHILDREN'S HEALTH) study, a population-based prospective pregnancy cohort study initiated in 2011 at the University Medical Center in Hamburg, Germany. 518 healthy pregnant women with singleton pregnancies were recruited during the first trimester. Three examinations were scheduled at the end of the 1st (gestational week 12-14), the 2nd (gestational week 22-24) and the 3rd trimester (gestational week 34-36). For 146 of these women, cord blood flow cytometry data were available. Paracetamol intake was assessed for each trimester of pregnancy.Among the 518 enrolled women, 40% took Paracetamol as main analgesic treatment during pregnancy. The intake frequency and dosage of Paracetamol varied between the women and was overall low with a tendency towards higher frequencies and higher dosages in the third trimester. Paracetamol intake, particularly during the third trimester, resulted in decreased relative numbers of HSCs in cord blood, independent of maternal age, first-trimester BMI, parity, gestational age and birth weight (-0.286 (95% CI -0.592, 0.021), p=0.068).Prenatal Paracetamol intake, especially during the third trimester, may be causally involved in decreasing HSCs in cord blood.
Project description:The aim of the study was to evaluate the effect of early parenteral iron supplementation combined erythropoietin for prevention of anemia in preterm infants.In total, 96 preterm infants were randomly assigned to 3 groups: a control group receiving standard parenteral nutrition (group 1: n = 31), an iron-supplemented group (group 2: IS, n = 33), and an iron-supplemented combined erythropoietin group (group 3: IS+EPO, n = 32). The primary objective was to assess hemoglobin (Hb) levels. The secondary objectives included assessment of red blood cell counts (RBC), mean cell volume (MCV), serum iron, ferritin, percentages of reticulocyte (RET), total iron binding capacity (TIBC) and oxidative stress, which was assessed by measuring plasma levels of malondialdehyde and superoxide dismutase at baseline and at 2 weeks. The blood routine indices including Hb, RBC, MCV, and percentages of RET were measured at corrected age of 1 and 3 months.At 2 weeks of life, the percentages of reticulocyte in group 2 and group 3 were significantly higher than those in group 1 (2.1±0.4, 2.5±0.3, and 1.7±0.3, respectively, P < 0.001, P<0.001), whereas TIBC were significantly lower than those in group 1 (36.7±4.6, 36.0±4.7, and 41.6 ± 5.2 respectively, P = 0.011, P = 0.006). There were no significant differences in RBC counts, the levels of hemoglobin, ferritin, malondialdehyde, and superoxide dismutase among the 3 groups at 2weeks of life. RBC, Hb, MCV, body weight, body length, and head circumference at a corrected age of 1 month did not differ among 3 groups. At corrected age of 3months, more infants in the control group had abnormal Hb and MCV levels (Hb levels: 114.3 ± 21.3, 123.7 ± 31.6, and 125.1 ± 21.2, P = 0.021, P = 0.034, respectively; MCV: 74.1 ± 3.5, 78.3 ± 4.7 and 79.1 ± 5.2, P = 0.017, P = 0.012, respectively), whereas cases of oral iron, cases of breastfeeding, RBC, body weight, body length, and head circumference were not different among 3 groups.Early parenteral iron supplementation combined erythropoietin in preterm infants improved the percentages of reticulocyte, decreased total iron binding capacity, and improved the Hb and MCV levels at 3 months of age. Early parenteral iron supplementations with EPO were beneficial for the preterm infants.
Project description:Because arsenic (As) and manganese (Mn) are able to pass the placenta, infants among exposed populations may be exposed to considerable levels in utero. The main objective of this paper is to evaluate infant toenails, hair, and cord blood as biomarkers of prenatal exposure to As and Mn and determine the relationship between maternal and infant As and Mn concentrations in these biomarkers. Of the 1196 pregnant women in Bangladesh who were monitored throughout pregnancy until 1 month post-partum and completed all study visits, we included 711 mother-infant pairs who had at least one maternal and one infant biomarker of exposure available for analysis. Toenail and hair samples were collected from the women during the first trimester and 1 month post-partum and from the infants at the age of 1 month. Cord blood was collected at the time of delivery. Maternal toenail concentrations were correlated with infant toenail concentrations for As and Mn (n=258, r=0.52, 95% CI: 0.43-0.60, P<0.0001 and r=0.39, 95% CI: 0.28-0.49, P<0.0001), respectively. Similarly, maternal hair concentrations were correlated with infant hair As (n=685, r=0.61, 95% CI: 0.56-0.65, P<0.0001) and infant hair Mn (n=686, r=0.21, 95% CI: 0.14-0.28, P<0.0001). Cord blood As was correlated with infant toenail and hair As, although cord blood Mn was only correlated with infant toenail. Toenails and cord blood appear to be valid biomarkers of maternal-fetal transfer of As and Mn, whereas hair may not be a suitable biomarker for in utero exposure to Mn.
Project description:INTRODUCTION:Changes in mitochondrial DNA (mtDNA) can serve as a marker of cumulative oxidative stress (OS) due to the mitochondria's unique genome and relative lack of repair systems. In utero particulate matter ?2.5?m (PM2.5) exposure can enhance oxidative stress. Our objective was to identify sensitive windows to predict mtDNA damage experienced in the prenatal period due to PM2.5 exposure using mtDNA content measured in cord blood. MATERIAL AND METHODS:Women affiliated with the Mexican social security system were recruited during pregnancy in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study. Mothers with cord blood collected at delivery and complete covariate data were included (n=456). Mothers' prenatal daily exposure to PM2.5 was estimated using a satellite-based spatio-temporally resolved prediction model and place of residence during pregnancy. DNA was extracted from umbilical cord leukocytes. Quantitative real-time polymerase chain reaction (qPCR) was used to determine mtDNA content. A distributive lag regression model (DLM) incorporating weekly averages of daily PM2.5 predictions was constructed to plot the association between exposure and OS over the length of pregnancy. RESULTS:In models that included child's sex, mother's age at delivery, prenatal environmental tobacco smoke exposure, birth year, maternal education, and assay batch, we found significant associations between higher PM2.5 exposure during late pregnancy (35-40weeks) and lower mtDNA content in cord blood. CONCLUSIONS:Increased PM2.5 during a specific prenatal window in the third trimester was associated with decreased mtDNA content suggesting heightened sensitivity to PM-induced OS during this life stage.
Project description:BACKGROUND: Studies emphasize the importance of particulate matter (PM) in the formation of reactive oxygen species and inflammation. We hypothesized that these processes can influence mitochondrial function of the placenta and fetus. OBJECTIVE: We investigated the influence of PM?? exposure during pregnancy on the mitochondrial DNA content (mtDNA content) of the placenta and umbilical cord blood. METHODS: DNA was extracted from placental tissue (n = 174) and umbilical cord leukocytes (n = 176). Relative mtDNA copy numbers (i.e., mtDNA content) were determined by real-time polymerase chain reaction. Multiple regression models were used to link mtDNA content and in utero exposure to PM?? over various time windows during pregnancy. RESULTS: In multivariate-adjusted analysis, a 10-µg/m³ increase in PM?? exposure during the last month of pregnancy was associated with a 16.1% decrease [95% confidence interval (CI): -25.2, -6.0%, p = 0.003] in placental mtDNA content. The corresponding effect size for average PM?? exposure during the third trimester was 17.4% (95% CI: -31.8, -0.1%, p = 0.05). Furthermore, we found that each doubling in residential distance to major roads was associated with an increase in placental mtDNA content of 4.0% (95% CI: 0.4, 7.8%, p = 0.03). No association was found between cord blood mtDNA content and PM?? exposure. CONCLUSIONS: Prenatal PM?? exposure was associated with placental mitochondrial alterations, which may both reflect and intensify oxidative stress production. The potential health consequences of decreased placental mtDNA content in early life must be further elucidated.
Project description:Background:Influence of TMPRSS6 A736V and HFE (C282Y and H63D) polymorphisms on serum hepcidin-25 levels and iron status parameters in end-stage renal disease (ESRD) patients stratified according to gender has not been previously investigated. In addition, we aimed to evaluate the diagnostic accuracy of the parameters to separate iron-deficiency anemia (IDA) from anemia of chronic disease. Materials and Methods:Iron status parameters and genetic analysis were performed in 126 ESRD patients and in 31 IDA patients as the control group. Results:ESRD patients had significantly higher ferritin and hepcidin-25 (<0.001) relative to IDA patients. Cut-off values with the best diagnostic accuracy were found for hepcidin ?9.32?ng/mL, ferritin ?48.2??g/L, transferrin saturation ?16.8%, and MCV ?81?fL. Interaction between gender and HFE haplotypes for the hepcidin-25 and ferritin levels in ESRD patients (p = 0.005, partial eta squared = 0.09; p = 0.027, partial eta squared = 0.06, respectively) was found. Serum transferrin was influenced by the combined effect of gender and TMPRSS6 A736V polymorphism in ESRD patients (p = 0.002, partial eta squared = 0.07). Conclusion:Our findings could contribute to the further investigation of mechanisms involved in the pathophysiology and important gender-related involvement of the TMPRSS6 and HFE polymorphisms on anemia in ESRD patients.