Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

Prenatal arsenic exposure is associated with increased risk of disease in adulthood. This has led to considerable interest in arsenic’s ability to disrupt fetal programming. Many studies report that arsenic exposure alters DNA methylation in whole blood but these studies did not adjust for cell mixture. In this study, we examined the relationship between arsenic in maternal drinking water collected ≤ 16 weeks gestational age and DNA methylation in cord blood (n = 44) adjusting for leukocyte-tagged differentially methylated regions. DNA methylation was quantified using the Infinium HumanMethylation 450 BeadChip array. Recursively partitioned mixture modeling examined the relationship between arsenic and methylation at 473,844 CpG sites. Median arsenic concentration in water was 12 µg/L (range < 1- 510 µg/L). Log₁₀ arsenic was associated with altered DNA methylation across the epigenome (P = 0.002); however, adjusting for leukocyte distributions attenuated this association (P = 0.013). We also observed that arsenic had a strong effect on the distribution of leukocytes in cord blood. In adjusted models, every log₁₀ increase in maternal drinking water arsenic exposure was estimated to increase CD8+ T cells by 7.4% (P = 0.0004) and decrease in CD4+ T cells by 9.2% (P = 0.0002). These results show that prenatal exposure to arsenic had an exposure-dependent effect on specific T cell subpopulations in cord blood and altered DNA methylation in cord blood. Future research is needed to determine if these small changes in DNA methylation alter gene expression or are associated with adverse health effects.     

Zinc-α2-Glycoprotein Is Unrelated to Gestational Diabetes: Anthropometric and Metabolic Determinants in Pregnant Women and Their Offspring

Context

Zinc-α2-Glycoprotein (ZAG) is an adipokine with lipolytic action and is positively associated with adiponectin in adipose tissue. We hypothesize that ZAG may be related with hydrocarbonate metabolism disturbances observed in gestational diabetes mellitus (GDM).

Objective

The aim of this study was to analyze serum ZAG concentration and its relationship with carbohydrate metabolism in pregnant women and its influence on fetal growth.

Design

207 pregnant women (130 with normal glucose tolerance (NGT) and 77 with GDM) recruited in the early third trimester and their offspring were studied. Cord blood was obtained at delivery and neonatal anthropometry was assessed in the first 48 hours. ZAG was determined in maternal serum and cord blood.

Results

ZAG concentration was lower in cord blood than in maternal serum, but similar concentration was observed in NGT and GDM pregnant women. Also similar levels were found between offspring of NGT and GDM women. In the bivariate analysis, maternal ZAG (mZAG) was positively correlated with adiponectin and HDL cholesterol, and negatively correlated with insulin and triglyceride concentrations, and HOMA index. On the other hand, cord blood ZAG (cbZAG) was positively correlated with fat-free mass, birth weight and gestational age at delivery. After adjusting for confounding variables, gestational age at delivery and HDL cholesterol emerged as the sole determinants of cord blood ZAG and maternal ZAG concentrations, respectively.

Conclusion

mZAG was not associated with glucose metabolism during pregnancy. ZAG concentration was lower in cord blood compared with maternal serum. cbZAG was independently correlated with gestational age at delivery, suggesting a role during the accelerated fetal growth during latter pregnancy.     

Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

Prenatal arsenic exposure is associated with increased risk of disease in adulthood. This has led to considerable interest in arsenic’s ability to disrupt fetal programming. Many studies report that arsenic exposure alters DNA methylation in whole blood but these studies did not adjust for cell mixture. In this study, we examined the relationship between arsenic in maternal drinking water collected ≤ 16 weeks gestational age and DNA methylation in cord blood (n = 44) adjusting for leukocyte-tagged differentially methylated regions. DNA methylation was quantified using the Infinium HumanMethylation 450 BeadChip array. Recursively partitioned mixture modeling examined the relationship between arsenic and methylation at 473,844 CpG sites. Median arsenic concentration in water was 12 µg/L (range < 1- 510 µg/L). Log₁₀ arsenic was associated with altered DNA methylation across the epigenome (P = 0.002); however, adjusting for leukocyte distributions attenuated this association (P = 0.013). We also observed that arsenic had a strong effect on the distribution of leukocytes in cord blood. In adjusted models, every log₁₀ increase in maternal drinking water arsenic exposure was estimated to increase CD8+ T cells by 7.4% (P = 0.0004) and decrease in CD4+ T cells by 9.2% (P = 0.0002). These results show that prenatal exposure to arsenic had an exposure-dependent effect on specific T cell subpopulations in cord blood and altered DNA methylation in cord blood. Future research is needed to determine if these small changes in DNA methylation alter gene expression or are associated with adverse health effects.     

Maternal urinary cadmium concentrations in early pregnancy in relation to prenatal and postpartum size of offspring

BackgroundThe impacts of environmental cadmium (Cd) exposure on birth size parameters including weight, length and head circumference (HC) have been reported in multiple studies. However, little remains known of the impacts of maternal Cd exposure during pregnancy on size during in utero development and during early childhood. The aim of this study was to comprehensively investigate impacts of maternal Cd exposure during pregnancy on the size of offspring in utero (from 24 weeks pregnancy) until six months of age.MethodsPregnant mothers were recruited as part of an ongoing prospective birth cohort study based in Guangdong, China. Maternal urine samples were collected in the first and third trimesters of pregnancy, in which Cd concentrations were measured by inductively couple plasma mass spectrometry (ICPMS). In utero size indicators at 24 and 32 week of gestation, including biparietal diameter (BPD), abdominal circumference (AC), femur length (FL) and HC were derived from ultrasound examinations. Anthropometric measures of weight, height and HC at birth and one, three and six months of age were also collected. Associations of size measures at the various time points with maternal urinary Cd concentrations were assessed using linear regression models.ResultsThe median urinary Cd concentration was 1.00 and 0.98 μg/g creatinine in the first and third trimesters respectively. In univariate analysis, increased maternal Cd levels in the first trimester were associated with decreased HC (-0.17 cm/ug/g urinary Cd) at birth, and the association was particularly pronounced among males (-0.30 cm/ug/g urinary Cd). First trimester Cd exposure was also found to be significantly associated with decreased infant weight at three and six months of age among girls (−101 g/ug/g and −97 g/ug/g urinary Cd, respectively). Associations of similar magnitude were observed after adjustment for various maternal factors. No significant associations were observed with infant size measures or with measures of Cd in the third trimester.ConclusionsOur detailed study suggests that the first trimester is particularly critical window of susceptibility to sex-specific effects of Cd on size parameters at birth, with some effects persisting to six months of age. These compelling sex-dependent effects on HC and body weight warrant future studies examining longer-term health effects of pregnancy-related Cd exposures.     

Maternal and cord blood ghrelin in the pregnancies of smoking mothers: possible markers of nutrient availability for the fetus

AIMS: To investigate the role of ghrelin in maternal and fetal metabolism, we determined its value in maternal smoking, a specific cause of reduced placenta function and fetal growth. METHODS: In 85 normal term pregnancies, 42 in smoking and 43 in non-smoking mothers, we measured ghrelin in the maternal blood at the onset of labor and in the cord blood of their 85 singletons immediately after birth. We determined the relationships between ghrelin and placental GH (PGH), pituitary GH (pitGH), and IGF-I. RESULTS: The newborns of smoking mothers weighed 0.24 kg less (p < 0.05) than those of non-smoking mothers. Cord blood ghrelin was 71% higher and PGH and cord blood IGF-I were 34% and 32% lower, respectively, in the pregnancies of smoking compared with non-smoking mothers (p < 0.05). Cord blood ghrelin was unrelated to pitGH and cord blood IGF-I. Maternal ghrelin was unchanged in smoking mothers, increased with maternal fasting duration (r = 0.26, p < 0.05), showed no correlation with PGH and negative correlation with cord blood IGF-I (r = -0.42, p < 0.01). CONCLUSION: The decrease in placental function and fetal growth in smoking mothers is associated with an increase in cord blood ghrelin, and no change in maternal ghrelin. Maternal ghrelin concentration increases with fasting, and is negatively correlated with cord blood IGF-I: it may signal a reduction in the level of nutrients available for placental transfer. No correlation supports a role for ghrelin in PGH or pitGH secretion.     

The role of arsenic in obesity and diabetes

As many individuals worlwide are exposed to arsenic, it is necessary to unravel the role of arsenic in the risk of obesity and diabetes. Therefore, the present study reviewed the effects of arsenic exposure on the risk and potential etiologic mechanisms of obesity and diabetes. It has been suggested that inflammation, oxidative stress, and apoptosis contribute to the pathogenesis of arsenic-induced diabetes and obesity. Though arsenic is known to cause diabetes through different mechanisms, the role of adipose tissue in diabetes is still unclear. This review exhibited the effects of arsenic on the metabolism and signaling pathways within adipose tissue (such as sirtuin 3 [SIRT3]- forkhead box O3 [FOXO3a], mitogen-activated protein kinase [MAPK], phosphoinositide-dependant kinase-1 [PDK-1], unfolded protein response, and C/EBP homologous protein [CHOP10]). Different types of adipokines involved in arsenic-induced diabetes are yet to be elucidated. Arsenic exerts negative effects on the white adipose tissue by decreasing adipogenesis and enhancing lipolysis. Some epidemiological studies have shown that arsenic can promote obesity. Nevertheless, few studies have indicated that arsenic may induce lipodystrophy. Arsenic multifactorial effects include accelerating birth and postnatal weight gains, elevated body fat content, glucose intolerance, insulin resistance, and increased serum lipid profile. Arsenic also elevated cord blood and placental, as well as postnatal serum leptin levels. The data from human studies indicate an association between inorganic arsenic exposure and the risk of diabetes and obesity. However, the currently available evidence is insufficient to conclude that low-moderate dose arsenic is associated with diabetes or obesity development. Therefore, more investigations are needed to determine biological mechanisms linking arsenic exposure to obesity and diabetes.     

Cord blood ASP is predicted by maternal lipids and correlates with fetal birth weight

Background: The acylation stimulating protein (ASP) is a potent lipogenic adipokine that correlates with postprandial triglyceride (TG) clearance and is linked to the pathophysiology of obesity and related disorders. Objective: To investigate ASP levels in cord blood and its relation to maternal and cord blood lipid parameters and fetal birth weight. Methods and Procedures: Thirty nondiabetic pregnant women, their newborns, and thirty‐three nonpregnant controls were included in this study. Fasting maternal and cord blood ASP, TGs, nonesterified fatty acids (NEFAs), cholesterol, glucose levels, in addition to maternal BMI and fetal birth weight were measured. Results: No significant difference was found between cord blood ASP (16.3 ± 0.96 nmol/l) and ASP levels in the adult controls (15.7 ± 1.0 nmol/l). Cord blood ASP, however, was lower than maternal plasma ASP levels (25.4 ± 1.6 nmol/l, P < 0.001). Yet, lipid levels in cord blood, particularly TGs were markedly decreased compared to control and maternal TG levels (threefold and 7.4‐fold, P < 0.001 respectively). Maternal TGs significantly correlated with fetal birth weight (r = 0.54, P = 0.002). Multiple regression analysis showed that maternal TGs (β = 0.57, P = 0.01) and NEFAs (β = 0.43, P = 0.024) predicted 45% variation in cord blood ASP levels, independent of all measured maternal and cord blood parameters. Cord blood ASP showed a positive correlation with fetal birth weight (r = 0.524, P = 0.037) in neonates above average fetal birth weight of the studied population. Discussion: This is the first study investigating ASP in cord blood. We suggest that maternal hypertriglyceridemia is associated with increased fetal ASP production, thus enhancing fetal fat storage independent of maternal glucose variations in nondiabetic women.     

Associations of Maternal Retinal Vasculature with Subsequent Fetal Growth and Birth Size

Objective

We aimed to study the maternal retinal microvasculature at mid-trimester and its relationship with subsequent fetal growth and birth size.

Methods

We recruited 732 pregnant women aged 18-46 years in the first trimester with singleton pregnancies. All had retinal photography and fetal scan performed at 26-28 weeks gestation, and subsequent fetal scan at 32-34 weeks gestation. Infant anthropometric measurements were done at birth. Retinal microvasculature was measured using computer software from the retinal photographs.

Results

In multiple linear regression models, each 10 μm narrowing in maternal retinal arteriolar caliber was associated with decreases of 1.36 mm in fetal head circumference at 32-34 weeks gestation, as well as decreases of 1.50 mm and 2.30 mm in infant head circumference and birth length at delivery, respectively. Each standard deviation decrease in maternal retinal arteriolar fractal dimension was associated with decreases of 1.55 mm in fetal head circumference at 32-34 weeks gestation, as well as decreases of 1.08 mm and 46.42 g in infant head circumference and birth weight at delivery, respectively.

Conclusions

Narrower retinal arteriolar caliber and a sparser retinal vascular network in mothers, reflecting a suboptimal uteroplacental microvasculature during mid-pregnancy, were associated with poorer fetal growth and birth size.     

Effects of Gestational Cadmium Exposure on Pregnancy Outcome and Development in the Offspring at Age 4.5 Years

The objective of the present study was to evaluate the potential effect of maternal cadmium exposure on pregnancy outcome and development in the offspring at age 4.5 years. Between November 2002 and December 2003, 109 normal pregnant women were enrolled in our cohort from Da-Ye Country, Hubei Province in Central China. The placental, whole blood, and cord blood levels of cadmium were determined by inductively coupled plasma mass spectrometer (ICP-MS). The 106 children at 4.5 years of age given birth by the aforementioned women were followed up and the following rate was 97.25%. Detailed questionnaire surveys, anthropometric measurements were performed, and IQ development was evaluated by Wechsler Preschool and Primary Scale of Intelligence Revised Edition (WPPSI-R). Multiple linear regression analysis indicated that cord blood cadmium level was significantly negatively correlated with fetus development. Low birth weight (less than 2,500 g) occurred significantly more frequently in infants with higher cord blood cadmium than in those exposed to lower levels of cord blood cadmium. Significantly negative correlation was found between cord blood cadmium exposure and WPPSI-R IQ full score after controlling for confounding variables. It was concluded that cord blood cadmium concentration was a factor that influenced fetus growth and later IQ development.     

Association of organophosphate pesticide exposure and paraoxonase with birth outcome in Mexican-American women

BackgroundEpidemiologic studies suggest that maternal organophosphorus (OP) pesticide exposure is associated with poorer fetal growth, but findings are inconsistent. We explored whether paraoxonase (PON1), a key enzyme involved in detoxification of OPs, could be an effect modifier in this association.MethodsThe study population included 470 pregnant women enrolled in the CHAMACOS Study, a longitudinal cohort study of mothers and children living in an agricultural region of California. We analyzed urine samples collected from mothers twice during pregnancy for dialkyl phosphate (DAP) metabolites of OP pesticides. We analyzed maternal and fetal (cord) blood samples for PON1 genotype (PON1₁₉₂ and PON1₋₁₀₈) and enzyme activity (paraoxonase and arylesterase). Infant birth weight, head circumference, and gestational age were obtained from medical records.ResultsInfants'' PON1 genotype and activity were associated with birth outcome, but mothers'' were not. Infants with the susceptible PON1_−108TT genotype had shorter gestational age (β = −0.5 weeks, 95% Confidence Interval (CI): −0.9, 0.0) and smaller head circumference (β = −0.4 cm, 95% CI: −0.7, 0.0) than those with the PON1_−108CC genotype. Infants'' arylesterase and paraoxonase activity were positively associated with gestational age. There was some evidence of effect modification with DAPs: maternal DAP concentrations were associated with shorter gestational age only among infants of the susceptible PON1_−108TT genotype (p-value_interaction = 0.09). However, maternal DAP concentrations were associated with larger birth weight (p-value_interaction = 0.06) and head circumference (p-value_interaction<0.01) in infants with non-susceptible genotypes.ConclusionsInfants whose PON1 genotype and enzyme activity levels suggested that they might be more susceptible to the effects of OP pesticide exposure had decreased fetal growth and length of gestation. PON1 may be another factor contributing to preterm or low birth weight birth.     

Associations between post translational histone modifications,myelomeningocele risk,environmental arsenic exposure,and folate deficiency among participants in a case control study in Bangladesh

Arsenic exposure may contribute to disease risk in humans through alterations in the epigenome. Previous studies reported that arsenic exposure is associated with changes in plasma histone concentrations. Posttranslational histone modifications have been found to differ between the brain tissue of human embryos with neural tube defects and that of controls. Our objectives were to investigate the relationships between plasma histone 3 levels, history of having an infant with myelomeningocele, biomarkers of arsenic exposure, and maternal folate deficiency. These studies took place in Bangladesh, a country with high environmental arsenic exposure through contaminated drinking water. We performed ELISA assays to investigate plasma concentration of total histone 3 (H3) and the histone modification H3K27me3. The plasma samples were collected from 85 adult women as part of a case-control study of arsenic and myelomeningocele risk in Bangladesh. We found significant associations between plasma %H3K27me3 levels and risk of myelomeningocele (P<0.05). Mothers with higher %H3K27me3 in their plasma had lower risk of having an infant with myelomeningocele (odds ratio: 0.91, 95% confidence interval: 0.84, 0.98). We also found that arsenic exposure, as estimated by arsenic concentration in toenails, was associated with lower total H3 concentrations in plasma, but only among women with folate deficiency (β = ?9.99, standard error = 3.91, P=0.02). Our results suggest that %H3K27me3 in maternal plasma differs between mothers of infants with myelomeningocele and mothers of infants without myelomeningocele, and may be a marker for myelomeningocele risk. Women with folate deficiency may be more susceptible to the epigenetic effects of environmental arsenic exposure.     

Relationship between Measures of Exposure to PCBs/Dioxins and Behavioral Effects in Recent Developmental Studies

This paper does not reflect official EPA policy. Epidemiological studies on the neurodevelopmental effects of exposure to PCBs initiated in the last decade have had the opportunity to take advantage of modern methodologies for the analysis of congeners of PCBs, dioxins, and related orga-nochlorine compounds. Each of these studies is a longitudinal prospective study, in which women were recruited during pregnancy and the children are being followed for at least several years after birth. The study from which the largest body of data has been published to date is being performed in the Netherlands, in which exposure to PCBs and related compounds is through the general food supply. Mother-infant pairs were recruited in two cities. Half of the infants were bottle-fed and half breast-fed in each city. Four PCB congeners (118, 138, 153, 180) were assessed in maternal and cord plasma, breast milk, and plasma of the child at 3.5 years. TEQ in breast milk was calculated based on PCDDs/PCDFs and dioxin-like PCBs. Various measures of in utero exposure were associated with suboptimal neurological status during infancy, whereas maternal plasma PCB concentration was associated with cognitive deficits (Kaufman scores) at 3.5 years of age. The child's concurrent plasma PCB levels and maternal PCB plasma levels independently predicted performance on various aspects of a vigilance task, and maternal and cord plasma levels predicted impairment of complex play behavior. Poor scores on behavioral ratings were associated with concurrent blood PCB concentrations in the child. A study in Oswego in Lake Ontario fish eaters includes mothers who never ate Great Lakes fish and mothers who consumed greater than 40 PCB-equivalent pounds of Lake Ontario fish over their lifetime. Sixty-eight PCB congeners were measured in cord blood. Suboptimal neurological status during infancy was associated with maternal fish consumption and highly chlorinated cord PCB levels, whereas deficits in short-term memory at 6 months and 1 year of age were associated with total chlorinated cord PCB levels. In a study in Germany of 171 mother-infant pairs, PCB congeners 138, 153, and 180 were measured in cord plasma and milk 2 weeks after birth; both measures are considered markers of in utero exposure. Suboptimal neurological status during infancy, decrements in Bayley scores at 30 months and Kaufman scores at 42 months were associated with PCBs in milk but not cord plasma. These studies, combined with data from previous studies, reveal a consistent relationship between PCB exposure and suboptimal neurological status during infancy, and cognitive deficits associated with in utero exposure. Data from the Dutch study revealed effects on other behavioral domains associated with concurrent (postnatal) exposure. Although it is not possible to identify specific congeners or groups of congeners that may be responsible for the neurotoxic effects observed in these studies, the TEQ approach was not particularly predictive for neurotoxic outcomes.     

Androgen concentrations in umbilical cord blood and their association with maternal, fetal and obstetric factors

The aim of this study was to measure umbilical blood androgen concentrations in a birth cohort using a highly specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay and assesses the effects of sex, labor, and gestational age on fetal androgen levels at birth. We performed a prospective cohort study of androgen concentrations in mixed arterial and venous umbilical cord serum from 803 unselected singleton pregnancies from a general obstetric population in Western Australia. Total testosterone (TT), Δ4-androstenedione, and dehydroepiandrosterone were extracted from archived cord serum samples and measured using LC-MS/MS. SHBG was measured by ELISA; free testosterone (FT) and bioavailable testosterone (BioT) values were also calculated. Median values for all three androgens were generally lower than previously published values. Levels of TT, FT, BioT, and SHBG were significantly higher in male verses female neonates (P<0.0001), while dehydroepiandrosterone levels were higher in females (P<0.0001). Labor was associated with a significant (～15-26%) decrease in median cord blood TT and FT levels (both sexes combined), but a modest (～16-31%) increase in SHBG, Δ4-androstenedione, and dehydroepiandrosterone concentrations. TT and FT were significantly negatively correlated with gestational age at delivery, while SHBG, Δ4-androstenedione, and dehydroepiandrosterone were positively correlated. Antenatal glucocorticoid administration also had a significant effect in the multiple regression models. This is the first study to report umbilical cord androgen levels in a large unselected population of neonates using LC-MS/MS. Our findings suggest that previous studies have over-estimated cord androgen levels, and that fetal, maternal, and obstetric factors influence cord androgen levels differentially. Caution should be exercised when interpreting previously-published data that have not taken all of these factors into account.     

Effects of Prenatal Multiple Micronutrient Supplementation on Fetal Growth Factors: A Cluster-Randomized,Controlled Trial in Rural Bangladesh

Prenatal multiple micronutrient (MM) supplementation improves birth weight through increased fetal growth and gestational age, but whether maternal or fetal growth factors are involved is unclear. Our objective was to examine the effect of prenatal MM supplementation on intrauterine growth factors and the associations between growth factors and birth outcomes in a rural setting in Bangladesh. In a double-blind, cluster-randomized, controlled trial of MM vs. iron and folic acid (IFA) supplementation, we measured placental growth hormone (PGH) at 10 weeks and PGH and human placental lactogen (hPL) at 32 weeks gestation in maternal plasma (n = 396) and insulin, insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) in cord plasma (n = 325). Birth size and gestational age were also assessed. Early pregnancy mean (SD) BMI was 19.5 (2.4) kg/m² and birth weight was 2.68 (0.41) kg. There was no effect of MM on concentrations of maternal hPL or PGH, or cord insulin, IGF-1, or IGFBP-1. However, among pregnancies of female offspring, hPL concentration was higher by 1.1 mg/L in the third trimester (95% CI: 0.2, 2.0 mg/L; p = 0.09 for interaction); and among women with height <145 cm, insulin was higher by 59% (95% CI: 3, 115%; p = 0.05 for interaction) in the MM vs. IFA group. Maternal hPL and cord blood insulin and IGF-1 were positively, and IGFBP-1 was negatively, associated with birth weight z score and other measures of birth size (all p<0.05). IGF-1 was inversely associated with gestational age (p<0.05), but other growth factors were not associated with gestational age or preterm birth. Prenatal MM supplementation had no overall impact on intrauterine growth factors. MM supplementation altered some growth factors differentially by maternal early pregnancy nutritional status and sex of the offspring, but this should be examined in other studies.

Trial Registration

ClinicalTrials.gov NCT00860470     

Differential DNA methylation in umbilical cord blood of infants exposed to mercury and arsenic in utero

Mercury and arsenic are known developmental toxicants. Prenatal exposures are associated with adverse childhood health outcomes that could be in part mediated by epigenetic alterations that may also contribute to altered immune profiles. In this study, we examined the association between prenatal mercury exposure on both DNA methylation and white blood cell composition of cord blood, and evaluated the interaction with prenatal arsenic exposure. A total of 138 mother-infant pairs with postpartum maternal toenail mercury, prenatal urinary arsenic concentrations, and newborn cord blood were assessed using the Illumina Infinium Methylation450 array. White blood cell composition was inferred from DNA methylation measurements. A doubling in toenail mercury concentration was associated with a 2.5% decrease (95% CI: 5.0%, 1.0%) in the estimated monocyte proportion. An increase of 3.5% (95% CI: 1.0, 7.0) in B-cell proportion was observed for females only. Among the top 100 CpGs associated with toenail mercury levels (ranked on P-value), there was a significant enrichment of loci located in North shore regions of CpG islands (P = 0.049), and the majority of these loci were hypermethylated (85%). Among the top 100 CpGs for the interaction between arsenic and mercury, there was a greater than expected proportion of loci located in CpG islands (P = 0.045) and in South shore regions (P = 0.009) and all of these loci were hypermethylated. This work supports the hypothesis that mercury may be contributing to epigenetic variability and immune cell proportion changes, and suggests that in utero exposure to mercury and arsenic, even at low levels, may interact to impact the epigenome.     

Maternal diet and dioxin-like activity, bulky DNA adducts and micronuclei in mother-newborns

Maternal diet can contribute to carcinogenic exposures and also modify effects of environmental exposures on maternal and fetal genetic stability. In this study, associations between maternal diet and the levels of dioxin-like plasma activity, bulky DNA adducts in white blood cells and micronuclei (MN) in lymphocytes from mother to newborns were examined. From 98 pregnant women living in the greater area of Copenhagen, Denmark in 2006-2007, maternal peripheral blood and umbilical cord blood were collected, together with information on health, environmental exposure and lifestyle. Maternal diet was estimated on the basis of maternal food frequency questionnaire (FFQ) completed by the end of pregnancy. Biomarkers were detected in paired blood samples through the dioxin-responsive chemical-activated luciferase expression (CALUX)(?) bioassay, (32)P-postlabelling technique and cytokinesis-block MN assay. Maternal preference for meats with dark surface were significantly associated with higher bulky DNA adducts in both maternal (β 95%CI; 0.46 (0.08, 0.84)) and cord blood (β 95%CI; 0.46 (0.05, 0.86)) before and after adjustment for potential confounders. No other significant associations between the 18 dietary variables and the biomarkers measured in maternal and fetal samples were identified. The present study suggests that maternal intake of meats with dark surface contributes to the bulky DNA adduct levels in maternal and umbilical cord blood. Relationship between food preparation and bulky DNA adducts appear to be captured by a FFQ while potential associations for other biomarkers might be more complex or need larger sample size.     

Correlation between birth weight, leptin, zinc and copper levels in maternal and cord blood

Leptin and zinc are involved in the regulation of appetite. Copper is a trace element regulating the functions of several cuproenzymes that are essential for life. To evaluate the relationship between zinc and copper status and the leptin system in humans, we examined whether leptin concentrations in the mother and the newborn correlate with the weight of mother, placenta and newborn. A total of 88 pregnant women at 38-42 weeks' gestation were studied. All infants were categorized as small for gestational age (SGA) (n = 16), average for gestational age (AGA) (n = 59) or large for gestational age (LGA) (n = 13). Leptin, zinc, and copper levels were measured in maternal and cord serum at birth. Maternal BMI and placental weight of the LGA groups were significantly higher than those of the SGA and AGA groups. Cord and maternal leptin levels of the SGA groups were significantly lower than those of the AGA and LGA groups. Maternal serum leptin levels were positively correlated with BMI and maternal zinc levels in all groups. Cord serum leptin levels of all groups were positively correlated with birth weight and placental weight. Birth weight was negatively correlated with maternal and cord copper level of all groups. Umbilical leptin concentrations of SGA newborns correlated with leptin concentrations of their mothers. In all pregnancies, birth weight increases in association with increase in cord leptin level. Our results suggest that maternal zinc but not copper level has an effect on maternal serum leptin levels. The increase in copper level in both maternal and cord blood may contribute to restriction in fetal growth.     

Maternal and fetal leptin,adiponectin levels and associations with fetal insulin sensitivity

Objective:

It remains uncertain whether leptin and adiponectin levels are correlated in maternal vs. fetal circulations. Little is known about whether leptin and adiponectin affect insulin sensitivity during fetal life.

Design and Methods:

In a prospective singleton pregnancy cohort (n = 248), we investigated leptin and adiponectin concentrations in maternal (at 24‐28 and 32‐35 weeks of gestation) and fetal circulations, and their associations with fetal insulin sensitivity (glucose/insulin ratio, proinsulin level).

Results:

Comparing concentrations in cord vs. maternal blood, leptin levels were 50% lower, but adiponectin levels more than doubled. Adjusting for gestational age at blood sampling, consistent and similar positive correlations (correlation coefficients: 0.31‐0.34, all P < 0.0001) were observed in leptin or adiponectin levels in maternal (at 24‐28 or 32‐25 weeks of gestation) vs. fetal circulations. For each SD increase in maternal plasma concentration at 24‐28 weeks, cord plasma concentration increased by 12.7 (95% confidence interval 6.8‐18.5) ng/ml for leptin, and 2.9 (1.8‐4.0) µg/ml for adiponectin, respectively (adjusted P < 0.0001). Fetal insulin sensitivity was negatively associated with cord blood leptin (each SD increase was associated with a 5.4 (2.1‐8.7) mg/dl/µU/ml reduction in cord plasma glucose/insulin ratio, and a 5.6 (3.9, 7.4) pmol/l increase in proinsulin level, all adjusted P < 0.01) but not adiponectin (P > 0.4) levels). Similar associations were observed in nondiabetic full‐term pregnancies (n = 211).

Conclusions:

The results consistently suggest a maternal impact on fetal leptin and adiponectin levels, which may be an early life pathway in maternal‐fetal transmission of the propensity to obesity and insulin resistance.