Person:

Ettinger, Adrienne

Background: Given the association between iron deficiency and lead absorption, we hypothesized that variants in iron metabolism genes would predict higher blood lead levels in young children. Objective: We examined the association between common missense variants in the hemochromatosis (HFE) and transferrin (TF) genes and blood lead levels in 422 Mexican children. Methods: Archived umbilical cord blood samples were genotyped for HFE (H63D and C282Y) and TF (P570S) variants. Blood lead was measured at 24, 30, 36, 42, and 48 months of age. A total of 341 subjects had at least one follow-up blood lead level available and data available on covariates of interest for inclusion in the longitudinal analyses. We used random-effects models to examine the associations between genotype (HFE, TF, and combined HFE + TF) and repeated measures of blood lead, adjusting for maternal blood lead at delivery and child’s concurrent anemia status. Results: Of 422 children genotyped, 17.7, 3.3, and 18.9% carried the HFE H63D, HFE C282Y, and TF P570S variants, respectively. One percent of children carried both the HFE C282Y and TF P570S variants, and 3% of children carried both the HFE H63D and TF P570S variants. On average, carriers of either the HFE (β = 0.11, p = 0.04) or TF (β = 0.10, p = 0.08) variant had blood lead levels that were 11% and 10% higher, respectively, than wild-type subjects. In models examining the dose effect, subjects carrying both variants (β = 0.41, p = 0.006) had blood lead 50% higher than wild-type subjects and a significantly higher odds of having a blood lead level > 10 μg/dL (odds ratio = 18.3; 95% confidence interval, 1.9–177.1). Conclusions: Iron metabolism gene variants modify lead metabolism such that HFE variants are associated with increased blood lead levels in young children. The joint presence of variant alleles in the HFE and TF genes showed the greatest effect, suggesting a gene-by-gene-by-environment interaction.

Nursing infants may be exposed to lead from breast milk, but relatively few data exist with which to evaluate and quantify this relationship. This route of exposure constitutes a potential infant hazard from mothers with current ongoing exposure to lead as well as from mothers who have been exposed previously due to the redistribution of cumulative maternal bone lead stores. We studied the relationship between maternal breast milk lead and infant blood lead levels among 255 mother–infant pairs exclusively or partially breast-feeding through 1 month of age in Mexico City. A rigorous, well-validated technique was used to collect, prepare, and analyze the samples of breast milk to minimize the potential for environmental contamination and maximize the percent recovery of lead. Umbilical cord and maternal blood lead were measured at delivery; 1 month after delivery (± 5 days) maternal blood, bone, and breast milk and infant blood lead levels were obtained. Levels of lead at 1 month postpartum were, for breast milk, 0.3–8.0 μg/L (mean ± SD, 1.5 ± 1.2); maternal blood lead, 2.9–29.9 μg/dL (mean ± SD, 9.4 ± 4.5); and infant blood lead, 1.0–23.1 μg/dL (mean ± SD, 5.5 ± 3.0). Infant blood lead at 1 month postpartum was significantly correlated with umbilical cord (Spearman correlation coefficient rS = 0.40, p < 0.0001) and maternal (rS = 0.42, p < 0.0001) blood lead at delivery and with maternal blood (rS = 0.67, p < 0.0001), patella (rS = 0.19, p = 0.004), and breast milk (rS = 0.32, p < 0.0001) lead at 1 month postpartum. Adjusting for cord blood lead, infant weight change, and reported breast-feeding status, a difference of approximately 2 μg/L (ppb; from the midpoint of the lowest quartile to the midpoint of the highest quartile) breast milk lead was associated with a 0.82 μg/dL increase in blood lead for breast-feeding infants at 1 month of age. Breast milk lead accounted for 12% of the variance of infant blood lead levels, whereas maternal blood lead accounted for 30%. Although these levels of lead in breast milk were low, they clearly have a strong influence on infant blood lead levels over and above the influence of maternal blood lead. Additional information on the lead content of dietary alternatives and interactions with other nutritional factors should be considered. However, because human milk is the best and most complete nutritional source for young infants, breast-feeding should be encouraged because the absolute values of the effects are small within this range of lead concentrations.

Background: Fetal lead exposure is associated with adverse pregnancy outcomes and developmental and cognitive deficits; however, the mechanism(s) by which lead-induced toxicity occurs remains unknown. Epigenetic fetal programming via DNA methylation may provide a pathway by which environmental lead exposure can influence disease susceptibility. Objective: This study was designed to determine whether prenatal lead exposure is associated with alterations in genomic methylation of leukocyte DNA levels from umbilical cord samples. Methods: We measured genomic DNA methylation, as assessed by Alu and LINE-1 (long interspersed nuclear element-1) methylation via pyrosequencing, on 103 umbilical cord blood samples from the biorepository of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study group. Prenatal lead exposure had been assessed by measuring maternal bone lead levels at the mid-tibial shaft and the patella using a spot-source 109Cd K-shell X-ray fluorescence instrument. Results: We found an inverse dose–response relationship in which quartiles of patella lead correlated with cord LINE-1 methylation (p for trend = 0.01) and and tibia lead correlated with Alu methylation (p for trend = 0.05). In mixed effects regression models, maternal tibia lead was negatively associated with umbilical cord genomic DNA methylation of Alu (β= −0.027; p = 0.01). We found no associations between cord blood lead and cord genomic DNA methylation. Conclusions: Prenatal lead exposure is inversely associated with genomic DNA methylation in cord blood. These data suggest that the epigenome of the developing fetus can be influenced by maternal cumulative lead burden, which may influence long-term epigenetic programming and disease susceptibility throughout the life course.

Background: Neonatal growth is a complex process involving genetic and environmental factors. Polymorphisms in the hemochromatosis (HFE) iron regulatory genes have been shown to modify transport and toxicity of lead which is known to affect birth weight. Methods: We investigated the role of HFE C282Y, HFE H63 D, and transferrin (TF) P570 S gene variants in modifying the association of lead and infant birthweight in a cohort of Mexican mother-infant pairs. Subjects were initially recruited between 1994-1995 from three maternity hospitals in Mexico City and 411 infants/565 mothers had archived blood available for genotyping. Multiple linear regression models, stratified by either maternal/infant HFE or TF genotype and then combined with interaction terms, were constructed examining the association of lead and birthweight after controlling for covariates. Results: 3.1%, 16.8% and 17.5% of infants (N = 390) and 1.9%, 14.5% and 18.9% of mothers (N = 533) carried the HFE C282Y, HFE H63D, and TF P570 S variants, respectively. The presence of infant HFE H63 D variants predicted 110.3 g (95% CI -216.1, -4.6) decreases in birthweight while maternal HFE H63 D variants predicted reductions of 52.0 g (95% CI -147.3 to 43.2). Interaction models suggest that both maternal and infant HFE H63 D genotype may modify tibia lead's effect on infant birthweight in opposing ways. In our interaction models, maternal HFE H63 D variant carriers had a negative association between tibia lead and birthweight. Conclusions: These results suggest that the HFE H63 D genotype modifies lead's effects on infant birthweight in a complex fashion that may reflect maternal-fetal interactions with respect to the metabolism and transport of metals.

Background: The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure. Objective: We studied prenatal lead exposure’s impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels. Methods: We measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose. Results: Maternal lead levels were moderately high with a first-trimester blood lead mean (± SD) value of 7.1 ± 5.1 μg/dL and 14% of values ≥10 μg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p less than 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores. Conclusions: Fetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood.

Background: Prenatal lead exposure is associated with deficits in fetal growth and neurodevelopment. Calcium supplementation may attenuate fetal exposure by inhibiting mobilization of maternal bone lead and/or intestinal absorption of ingested lead. Objective: Our goal was to evaluate the effect of 1,200 mg dietary calcium supplementation on maternal blood lead levels during pregnancy. Methods: In a double-blind, randomized, placebo-controlled trial conducted from 2001 through 2003 in Mexico City, we randomly assigned 670 women in their first trimester of pregnancy to ingest calcium (n = 334) or placebo (n = 336). We followed subjects through pregnancy and evaluated the effect of supplementation on maternal blood lead, using an intent-to-treat analysis by a mixed-effects regression model with random intercept, in 557 participants (83%) who completed follow-up. We then conducted as-treated analyses using similar models stratified by treatment compliance. Results: Adjusting for baseline lead level, age, trimester of pregnancy, and dietary energy and calcium intake, calcium was associated with an average 11% reduction (0.4 μg/dL) in blood lead level relative to placebo (p = 0.004). This reduction was more evident in the second trimester (−14%, p lesss than 0.001) than in the third (−8%, p = 0.107) and was strongest in women who were most compliant (those who consumed ≥ 75% calcium pills; −24%, p less than 0.001), had baseline blood lead greater than 5 μg/dL (−17%, p less than 0.01), or reported use of lead-glazed ceramics and high bone lead (−31%, p less than 0.01). Conclusion: Calcium supplementation was associated with modest reductions in blood lead when administered during pregnancy and may constitute an important secondary prevention effort to reduce circulating maternal lead and, consequently, fetal exposure.

Despite the many well-recognized benefits of breast-feeding for both mothers and infants, detectable levels of lead in breast milk have been documented in population studies of women with no current environmental or occupational exposures. Mobilization of maternal bone lead stores has been suggested as a potential endogenous source of lead in breast milk. We measured lead in breast milk to quantify the relation between maternal blood and bone lead levels and breast-feeding status (exclusive vs. partial) among 310 lactating women in Mexico City, Mexico, at 1 month postpartum. Umbilical cord and maternal blood samples were collected at delivery. Maternal breast milk, blood, and bone lead levels were obtained at 1 month postpartum. Levels of lead in breast milk ranged from 0.21 to 8.02 microg/L (ppb), with a geometric mean (GM) of 1.1 microg/L; blood lead ranged from 1.8 to 29.9 microg/dL (GM = 8.4 microg/dL); bone lead ranged from less than 1 to 67.2 microg/g bone mineral (patella) and from less than 1 to 76.6 microg/g bone mineral (tibia) at 1 month postpartum. Breast milk lead was significantly correlated with umbilical cord lead [Spearman correlation coefficient (r(_S)) = 0.36, p less than 0.0001] and maternal blood lead (r(_S)= 0.38, p less than 0.0001) at delivery and with maternal blood lead (r(_S) = 0.42, p less than 0.0001) and patella lead (r(_S)= 0.15, p less than 0.01) at 1 month postpartum. Mother's age, years living in Mexico City, and use of lead-glazed ceramics, all predictive of cumulative lead exposure, were not significant predictors of breast milk lead levels. Adjusting for parity, daily dietary calcium intake (milligrams), infant weight change (grams), and breast-feeding status (exclusive or partial lactation), the estimated effect of an interquartile range (IQR) increase in blood lead (5.0 microg/dL) was associated with a 33% increase in breast milk lead [95% confidence interval (CI), 24 to 43%], whereas an IQR increase in patella lead (20 microg/g) was associated with a 14% increase in breast milk lead (95% CI, 5 to 25%). An IQR increase in tibia lead (12.0 microg/g) was associated with a 5% increase in breast milk lead (95% CI, -3% to 14%). Our results indicate that even among a population of women with relatively high lifetime exposure to lead, levels of lead in breast milk are low, influenced both by current lead exposure and by redistribution of bone lead accumulated from past environmental exposures.

Background: Most toxicologic studies focus on a single agent, although this does not reflect real-world scenarios in which humans are exposed to multiple chemicals. Objectives: We prospectively studied manganese–lead interactions in early childhood to examine whether manganese–lead coexposure is associated with neurodevelopmental deficiencies that are more severe than expected based on effects of exposure to each metal alone. Methods: Four hundred fifty-five children were enrolled at birth in an longitudinal cohort study in Mexico City, provided blood samples, and were followed until 36 months of age. We measured lead and manganese at 12 and 24 months and assessed neurodevelopment at 6-month intervals from 12 to 36 months of age using Bayley Scales of Infant Development–II. Results: Mean (± SD) blood concentrations at 12 and 24 months were, respectively, 24.7 ± 5.9 μg/L and 21.5 ± 7.4 μg/L for manganese and 5.1 ± 2.6 μg/dL and 5.0 ± 2.9 μg/dL for lead. Mixed-effects models, including Bayley scores at five time points, showed a significant interaction over time: highest manganese quintile × continuous lead; mental development score, β = –1.27 [95% confidence interval (CI): –2.18, –0.37]; psychomotor development score, β = –0.92 (95% CI: –1.76, –0.09). Slopes for the estimated 12-month lead effect on 18-month mental development and 24- through 36-month psychomotor development scores were steeper for children with high manganese than for children with midrange manganese levels. Conclusions: We observed evidence of synergism between lead and manganese, whereby lead toxicity was increased among children with high manganese coexposure. Findings highlight the importance of understanding health effects of mixed exposures, particularly during potentially sensitive developmental stages such as early childhood.