DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium.

Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (ß = 2.28 × 10-4, p-value = 5.87 × 10-5) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (ß = 0.004, p-value = 4.97 × 10-5), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (ß = 0.002, p-value = 4.81 × 10-7) in GRK1 and cg02212000 (ß = -0.001, p-value = 8.13 × 10-7) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.

Foetal exposure to heavy metals and risk of atopic diseases in early childhood.

BACKGROUND: Accumulating evidence suggests that in utero exposures can influence the development of the immune system and thus contribute to disease development. Studies investigating the association between prenatal exposures to heavy metals and atopic diseases, however, are scarce. METHODS: Children from the EDEN birth cohort were prospectively followed up using parental questionnaires with validated questions on asthma, allergic rhinitis, eczema, and food allergy symptoms. The questionnaires were administered every 4 months during the children's first year, and then every year until the age of 5, with a final survey at the age of 8. Serum concentrations of lead (Pb), cadmium (Cd), and manganese (Mn) were assessed in maternal blood samples collected during mid-pregnancy and in cord blood of 651 mother-children pairs. Hazard ratios (HR) for the incidence of each atopic disease in relation to the exposure to metals were calculated using Cox proportional hazard models. RESULTS: Levels of Cd in cord blood were associated with greater risk of asthma (hazard ratio [95% confidence interval] for upper vs lower quartile: 1.81 [1.00-3.29]), eczema (1.60 [1.09-2.35]), and food allergy (3.17 [1.36-7.38]), while Mn levels in maternal serum were associated with eczema (1.55 [1.05-2.28]). These associations were similar in males and females and were confirmed using log concentrations of metals as exposures. CONCLUSIONS: Our results support the hypothesis that fetal exposure to heavy metals may affect the development of asthma, eczema, and food allergy in childhood and suggest that timing of exposure in utero may have a role in these associations.

Exposure to heavy metals during pregnancy related to gestational diabetes mellitus in diabetes-free mothers.

Evidence is cumulating on the adverse health effects of environmental exposures on health of the fetus and the childbearing mothers. Among mother's conditions, gestational diabetes mellitus has been considered rarely in spite of its importance for both mother and child. We determined the role of maternal exposure to lead (Pb), cadmium (Cd) and manganese (Mn) to gestational diabetes mellitus (GDM) on diagnosed GDM and impaired glucose tolerance (IGT) in diabetes-free mothers from the French EDEN mother-child cohort. 623 pregnant women without pre-existing diabetes were included in the study. GDM and IGT were diagnosed by a gynecologist during consultations after blood analysis. Pb, Cd and Mn were measured in second-trimester blood samples. Associations between ln-transformed concentrations of metals and GDM and IGT respectively were examined using multiple logistic regression analysis adjusted for potential confounders. The prevalences of GDM and IGT were 7.1% and 10.1% respectively. After adjustment for confounders, Cd was statistically related to having had a diagnosis of GDM or IGT (Adjusted Odds-Ratio (AOR): 1.61, 1.05-2.48), and Pb to GDM at borderline significance (AOR: 1.65, 0.82-3.34). Our findings add to the growing evidence supporting the role of maternal exposure to heavy toxic metals that persist longtime in the environment as a risk factor for GDM.

Prenatal mercury contamination: relationship with maternal seafood consumption during pregnancy and fetal growth in the 'EDEN mother-child' cohort.

Maternal seafood intake is of great health interest since it constitutes an important source of n-3 fatty acids, but provides also an important pathway for fetal exposure to Hg. The objective of the present study was to determine associations between Hg contamination and both maternal seafood consumption and fetal growth in French pregnant women. Pregnant women included in the 'EDEN mother-child' cohort study answered FFQ on their usual diet in the year before and during the last 3 months of pregnancy, from which frequencies of seafood intake were evaluated. Total hair-Hg level was determined for the first 691 included women. Associations between Hg level, seafood intake and several neonatal measurements were studied using linear regressions adjusted for confounding variables. The median Hg level for mothers was 0.52 µg/g. Maternal seafood intake was associated with Hg level (r 0.33; P < 0.0001). There was no association between Hg level and fetal growth in the whole sample of women, except for an early negative relationship with biparietal diameter. A positive association was found between seafood intake and fetal growth in overweight women only which remained unchanged after adjustment for Hg level (birth weight: +101 g for a difference of 1 sd in seafood consumption; P = 0.008). Although seafood intake was associated with Hg contamination in French pregnant women, the contamination level was low. There was no consistent association between Hg level and fetal growth. Taking into account Hg level did not modify associations between seafood intake and fetal growth.

Monoamine oxidase activity in placenta in relation to manganese, cadmium, lead, and mercury at delivery.

BACKGROUND: Environmental prenatal exposure to potentially neurotoxic metals poses a particular challenge with regard to the study of early toxic effects. Monoamine oxidase activity, shown to be influenced by metals in experimental studies, could be a useful biomarker in humans. OBJECTIVE: To examine the relationship between blood metal concentrations at delivery and placenta MAO activity. METHODS: The study was performed in 163 pregnancies. Maternal and cord blood samples were obtained for manganese (Mn), lead (Pb), and cadmium (Cd) determination. Mercury (Hg) was also analysed in maternal hair. Placental samples were stored immediately after expulsion and total MAO activity was measured. RESULTS: MAO activity was significantly positively correlated with maternal and cord blood Mn concentrations in subjects with high MAO activity. In subjects with low MAO activity, maternal hair Hg was negatively correlated with MAO. CONCLUSION: Our results suggest the use of placental MAO as a potential surrogate marker of Mn toxicity in the newborn and its correlation with psychomotor development should be further investigated.

Maternal blood lead levels and the risk of pregnancy-induced hypertension: the EDEN cohort study.

BACKGROUND: Prior studies revealed associations of environmental lead exposure with risks of hypertension and elevated blood pressure. OBJECTIVE: We examined the effect of blood lead levels on blood pressure and the incidence of pregnancy-induced hypertension (PIH) in the second and third trimesters of pregnancy. METHODS: One thousand seventeen pregnant women were enrolled in two French municipalities between 2003 and 2005 for the EDEN (Etude des Déterminants pré et post natals du développement et de la santé de l' Enfant) cohort study. Blood lead concentrations were measured by atomic absorption spectrometry in mothers between 24 and 28 weeks of gestation. RESULTS: PIH was diagnosed in 106 subjects (10.9%). Age, parity, weight gain, alcohol, smoking habits, and calcium supplementation were comparable between hypertensive and nonhypertensive women. Lead levels were significantly higher in PIH cases (mean +/- SD, 2.2 +/- 1.4 microg/dL) than in normotensive patients (1.9 +/- 1.2 microg/dL; p = 0.02). Adjustment for potential confounder effects slightly attenuated but did not eliminate the significant association between blood lead levels and the risk of PIH (adjusted odds ratio of PIH = 3.3; 95% confidence interval, 1.1-9.7). We also observed geographic differences in lead exposure and in the incidence of PIH and found significant correlations between blood lead levels and unadjusted as well as adjusted systolic and diastolic blood pressures after 24 weeks of gestation. CONCLUSIONS: These findings confirm the relationship between blood lead levels at mid-pregnancy and blood pressure and suggest that environmental lead exposure may play an etiologic role in PIH.

Biomarkers of selenium status in the Amazonian context: blood, urine and sequential hair segments.

Selenium (Se) is an essential element and deficit or excess of dietary Se is associated with health disorders. Relatively elevated Se levels have been reported in the Brazilian Amazon, where there are also important annual variations in the availability of different foods. The present study was conducted among six riparian communities of the Tapajós River to evaluate seasonal variations in blood and sequential hair cm Se concentrations, and to examine the relationships between Se in blood and hair, and blood and urine. Two cross-sectional studies were conducted, at the descending water (DWS, n=259) and the rising water (RWS, n=137) seasons, with repeated measures for a subgroup (n=112). Blood Se (B-Se), hair Se (H-Se) and urine Se (U-Se) were determined. Match-paired analyses were used for seasonal comparisons and the method of best fit was used to describe the relationships between biomarkers. B-Se levels presented a very large range (142-2447 microg/l) with no overall seasonal variation (median 284 and 292 microg/l, respectively). Sequential analysis of 13 cm hair strands showed significant variations over time: Se concentrations at the DWS were significantly lower compared with the rising water season (medians: 0.7 and 0.9 microg/g; ranges: 0.2-4.3 microg/g and 0.2-5.4 microg/g, respectively). At both seasons, the relationships between B-Se and H-Se were linear and highly significant (r(2)=67.9 and 63.6, respectively), while the relationship between B-Se and U-Se was best described by a sigmoid curve. Gender, age, education and smoking did not influence Se status or biomarker relationships. Variations in H-Se suggest that there may be seasonal availability of Se sources in local food. For populations presenting a large range and/or elevated Se exposure, sequential analyses of H-Se may provide a good reflection of variations in Se status.

Hair mercury negatively correlates with calcium pump activity in human term newborns and their mothers at delivery.

BACKGROUND: Calcium homeostasis is a known target of several environmental toxicants including lead and mercury. OBJECTIVE: Our goal was to determine the relationship between Hg exposure and erythrocyte Ca pump activity in women at delivery and in their newborns. METHODS: We determined total Hg as well as Pb concentrations in 81 hair and blood samples obtained at delivery. Basal and calmodulin-stimulated Ca pump activity was measured in red blood cells from cord blood and maternal erythrocyte plasma membranes. RESULTS: Maternal hair Hg negatively correlates with Ca pump activity in maternal and cord blood erythrocytes. Pb and Hg both independently correlate negatively with Ca pump activity without any statistically significant interaction. After adjustment for potential confounders, Pb and Hg explain about 30% and 7% of total variance of Ca pump activity in newborns and mothers, respectively. CONCLUSION: Our findings confirm results reported in previous experimental studies and support the use of biomarkers in newborns from general population.

Effect of maternal manganese blood levels on erythrocyte calcium-pump activity in newborns.

UNLABELLED: Manganese (Mn) is widely distributed in the biosphere but occurs in only trace amounts in animal tissues. Although Mn deficiency and toxicity both have pathological consequences, the underlying biochemical lesions have not been well defined. In vitro studies suggest that transport proteins are affected by Mn, lead (Pb), and selenium (Se). Among these transport proteins, the calmodulin-regulated calcium pump (Ca(2+)Mg(2+)ATPase) could be inhibited by Mn. In order to understand Mn biochemical pathways, we examined the relationships between Mn blood levels and red blood cell Ca-pump activity among 248 mothers and newborns, environmentally exposed to Mn, Pb, and Se. POPULATION AND METHODS: 248 mother-newborn pairs were recruited at Robert Debré University Hospital (Paris). Blood Mn and Pb concentrations were measured by absorption spectrophotometry. Se was measured by fluorometric method. Red blood cell membrane suspensions were obtained for Ca-pump activity measurements. Linear and quadratic regression models and Pearson correlation were performed. RESULTS: A non-linear parabolic relationship between maternal Mn blood levels and newborn Ca-pump activity was discovered from the analysis of the observed data. The peak level of maternal Mn that corresponded to a maximal activity of the newborn Ca-pump was estimated at 23.9 microg/l with a 95% confidence interval of 17.6 to 32.4 microg/l. An inhibition of this enzyme was observed at low and high levels of maternal Mn. The relationships between the newborn Ca-pump activity and maternal Se and Pb levels became non-significant after adjustment on all the co-factors included in the final model. CONCLUSION: Maternal environmental exposure to Mn, as reflected by maternal blood levels of this metal, is associated with a reduced activity of newborn erythrocyte Ca-pump in a non-linear pattern. Mn levels between 17.6 and 32.4 microg/l in maternal blood probably correspond to the optimal physiological concentration for the metabolism of this enzyme in newborns.

Health impact evaluation of boron in drinking water: a geographical risk assessment in Northern France.

OBJECTIVE: To evaluate health impact of boron in drinking water. METHODS: A regional scale geographical study in Northern France was conducted. Assessment of boron blood levels in a group of 180 healthy individuals and correlation with boron content in drinking water were followed by an assessment of health indicators such as birth rates, mortality rates, and sex ratios in zones of different boron content in drinking water. RESULTS: After necessary adjustments, men living in municipalities with more than 0.30 mg/L of boron in drinking water had elevated but not significant boron blood levels compared with those living in municipalities with boron water levels of less than 0.30 mg/L (159.1 versus 123.0 ng/g; p > 0.05). The standardized birth ratio adjusted for the reference geographic zone and calendar time period was 1.07 and 1.28 in the low and high (>0.3 mg/L) boron content municipalities, respectively. The birth rate in municipalities with high boron content in drinking water was higher than that of the reference geographic zone and of the French general population (p < 10(-4)). The standardized mortality ratio adjusted for the reference geographic zone and calendar time period was 0.94 and 0.92 in the low and high boron content municipalities, respectively. The mortality rate in municipalities with high boron content in drinking water was less than that of the reference geographic zone and of the French general population (p < 10(-3)). No statistical difference was noted in the male-female sex ratios between the different municipality zones (p = 0.45). CONCLUSIONS: The results of this study do not support the idea of a deleterious effect of boron on human health, at the boron water level contents found in this specific region. In fact, there is a tendency toward a beneficial effect with low-dose environmental exposure (less than 1 mg/L of boron) in drinking water.

Environmental boron exposure and activity of delta-aminolevulinic acid dehydratase (ALA-D) in a newborn population.

Following boron intake, multiple effects have been observed in animal experiments. However, human data is lacking, and no data is available on the ability of boron to accumulate in fetal tissues. Positive responses in animal species suggest that developmental toxicity may be an area of concern in humans, following exposure to boron. Two hypotheses have seemed to account for the multiple effects described in scientific findings. One hypothesis is that boron is a negative regulator that influences a number of metabolic pathways by competitively inhibiting some key enzyme reactions. The other hypothesis is that boron has a role in ionic membrane transport regulations. To better understand boron potential toxicity, the present study examined the relationship between boron exposure and some key enzymes, well-known for their affinity for mineral elements, such as delta-aminolevulinic acid dehydratase (ALA-D), and two fundamental enzymes having a role in ionic membrane transport regulations (Ca-pump and Na(+)K(+)-ATPase). We investigated the potential effects of an environmental boron exposure on the activity of these enzymes in an urban population of 197 "normal" newborns. Environmental boron exposure was assessed in placental tissue. Because of the well-known inhibiting effect of lead on these enzymes, cord blood and placental lead were also analyzed. After adjustment for potential confounders, including lead, placental boron levels were negatively significantly correlated to ALA-D activity while Ca-pump and Na(+)K(+)-ATPase activities did not seem to be affected by the level of boron exposure. Given boron's ability, as a Lewis acid, to complex with hydroxyl groups, we suggest that such a mechanism would explain the inhibiting effect of boron on ALA-D.

Manganese, monoamine metabolite levels at birth, and child psychomotor development.

Several studies have demonstrated neurobehavioral impairment related to manganese (Mn) exposure in the workplace. Exposure to high doses of manganese is associated with irreversible neurodegenerative disorders resembling idiopathic Parkinson disease. Although there is a risk of Mn accumulation in the foetus during pregnancy, little information exists about developmental effects of environmental low-level exposure in human. For this reason, we conducted a prospective epidemiological study in 247 healthy pregnant women and their babies to determine the long-term effect of in utero Mn levels on child's psychomotor development. Concurrently, we examined the relationship between Mn tissue levels at delivery and foetal plasma monoamine metabolites. Of the newborns, 195 were examined at 9 months, 126 at 3 years and 100 at 6 years. At 9 months, the Brunet-Lézine scales were administered. The McCarthy scales of children's abilities were used at 3 and 6 years. After adjustment for potential confounding co-factors (child's gender, mother's educational level), negative relationships were observed between cord blood Mn levels and several psychomotor sub-scales at age of 3 years: "attention" (partial r=-0.33, P<0.001), "non-verbal memory" (partial r=-0.28, P<0.01), and "hand skills" (partial r=-0.22, P<0.05). No significant relationships were observed between Mn measures at birth and the general psychomotor indices, Brunet-Lézine developmental quotient (DQ) at 9 months or McCarthy general cognitive index (GCI) at 3 and 6 years. Maternal blood Mn levels were negatively associated with foetal plasma HVA and 5-HIAA concentrations (adjusted for labour duration, child's gender, and smoking during pregnancy), but the adjustment for monoamine levels at birth did not change the association between the Mn levels and the psychomotor scores. These results suggest that environmental Mn exposure in utero could affect early psychomotor development.

Could monoamine plasma levels and erythrocyte membrane ATPase activities at birth be predictive for future hand performance?

The monoamine and intracellular calcium systems are two major elements of nervous system functions. However, their role in human brain development is unclear. We studied the association between activity of monoamine and intracellular calcium systems during prenatal life and subsequent psychomotor performances in healthy children. We used prospective data from 247 children followed from birth through 6 y of age. Among those, 195 were examined at 9 mo using the Brunet-Lézine Scales, whereas 126 were examined at 3 y and 100 at 6 y using the McCarthy Scales of Children's Ability. A blood sample was collected from the umbilical cord to measure levels of dopamine and serotonin metabolites (homovanillic acid and 5-hydroxyindoleacetic acid, respectively) and ATPase activities (Na+K+-ATPase and Ca2+Mg2+-ATPase). The hand skill score at 6 y of age was significantly and negatively correlated with ATPase activities and with monoamine metabolite concentrations. No other cognitive score was related to biochemical measures at birth. Results were adjusted for child's sex, mother's educational level, duration of labor, and tea consumption. Composite scores of ATPase activities and monoamine metabolite concentrations measured at birth explained 29% of hand skill score variance at 6 y. Our results demonstrate the importance of prenatal factors on monoaminergic and ATPase activities in early human psychomotor development. This study also suggests that specific psychometric measures such as fine motor tests may be a better developmental measurement to correlate with biochemical factors than general cognitive scales.

Predictive factors of manual dexterity and cognitive performance at 17 years: a 10-year longitudinal study in a rural area of France.

Studies of predictive factors of manual dexterity in adolescents and young adults are lacking. The present longitudinal study reports the relationship between cognitive and behavioural assessments at age 7 years and the schooling, cognitive performance, and manual dexterity at age 17 years. The participants were 65 schoolchildren, 30 boys and 35 girls, from a rural area in France. Assessment at age 7 years included the McCarthy scales and questionnaires measuring the behavior of the child, completed by the mother, the teacher, and the assessing psychologist. Assessment at age 17 years included schooling situation (whether they were in high school or not), cognitive testing (WAIS-R, Trail Making, Verbal Fluency, Cancel H, Stroop, Memory Assessment Scales), and manual dexterity testing (dynamometer, Finger Tapping, Santa Ana Test, Purdue Pegboard). After controlling for effects of parental education and IQ, a negative teachers' rating of children's behaviour and abilities in first-grade (7 years) was correlated with early cessation of schooling, but also, unexpectedly, with higher scores for manual dexterity at 17 years. Manual dexterity was not related to cognitive performance at 17 years. It is suggested that the relationship between manual and cognitive performance varies during development. Although manual exploratory behaviour is an important correlate of early cognitive development, manual dexterity is probably not related to later academic performance.

A comparative study of manganese and lead levels in human umbilical cords and maternal blood from two urban centers exposed to different gasoline additives.

Manganese (Mn) and lead (Pb) are two neurotoxic chemicals and experimental evidence suggests that they can cross the placental barrier. Tetraethyl lead was still in use as an antiknock agent in Paris during the sampling period of the study, while it has been replaced by methylcyclopentadienyl manganese tricarbonyl (MMT) in Canada since 1977. By 1990, MMT was in 100% of gasoline in Canada. In a study of 160 pairs of mothers-neonates in Montreal and 206 pairs in Paris, we compared levels of Mn and Pb in the umbilical cord and in maternal blood. Neonates and mothers had significantly higher Pb levels in Paris where lead additives were still used in gasoline. Geometric mean maternal blood Pb levels were 5.4 microg/dl compared to 2.1 microg/dl in Montreal and cord blood Pb levels were 3.2 microg/dl in Parisian mothers compared to 1.7 microg/dl in Montreal. The prevalence of Paris Pb values superior to the 95th percentile of the Montreal distribution was highly elevated in all media studied. The prevalence of high Mn levels in umbilical cord blood was also significantly higher in Montreal. Surveillance programs are important to limit Pb overexposure and associated neurological effects in neonates where tetraethyl Pb is still in use as a gasoline additive. Since Mn is an essential element and dietary Mn intake may differ between Montreal and Paris, the difference observed with regard to high Mn values between Montreal and Paris cannot, at this time, be attributed to MMT in Montreal's gasoline. Further studies are needed to infer an association between Mn emissions from MMT and prenatal exposure to Mn.