Maitreyi Mazumdar

Low-level environmental lead exposure in childhood and adult intellectual function: a follow-up study

BackgroundEarly life lead exposure might be a risk factor for neurocognitive impairment in adulthood.ObjectivesWe sought to assess the relationship between early life environmental lead exposure and intellectual function in adulthood. We also attempted to identify which time period blood-lead concentrations are most predictive of adult outcome.MethodsWe recruited adults in the Boston area who had participated as newborns and young children in a prospective cohort study that examined the relationship between lead exposure and childhood intellectual function. IQ was measured using the Wechsler Abbreviated Scale of Intelligence (WASI). The association between lead concentrations and IQ scores was examined using linear regression.ResultsForty-three adults participated in neuropsychological testing. Childhood blood-lead concentration (mean of the blood-lead concentrations at ages 4 and 10 years) had the strongest relationship with Full-Scale IQ (β = -1.89 ± 0.70, p = 0.01). Full-scale IQ was also significantly related to blood-lead concentration at age 6 months (β = -1.66 ± 0.75, p = 0.03), 4 years (β = -0.90 ± 0.41, p = 0.03) and 10 years (β = -1.95 ± 0.80, p = 0.02). Adjusting for maternal IQ altered the significance of the regression coefficient.ConclusionsOur study suggests that lead exposure in childhood predicts intellectual functioning in young adulthood. Our results also suggest that school-age lead exposure may represent a period of increased susceptibility. Given the small sample size, however, the potentially confounding effects of maternal IQ cannot be excluded and should be evaluated in a larger study.

X-linked creatine transporter defect: A report on two unrelated boys with a severe clinical phenotype

SummaryWe report two unrelated boys with the X-linked creatine transporter defect (CRTR) and clinical features more severe than those previously described with this disorder. These two boys presented at ages 12 and 30 months with severe mental retardation, absent speech development, hypotonia, myopathy and extra-pyramidal movement disorder. One boy has seizures and some dysmorphic features; he also has evidence of an oxidative phosphorylation defect. They both had classical absence of creatine peak on brain magnetic resonance spectroscopy (MRS). In one, however, this critical finding was overlooked in the initial interpretation and was discovered upon subsequent review of the MRS. Molecular studies showed large genomic deletions of a large part of the 3′ end of the complete open reading frame of the SLC6A8 gene. This report emphasizes the importance of MRS in evaluating neurological symptoms, broadens the phenotypic spectrum of CRTR and adds knowledge about the pathogenesis of creatine depletion in the brain and retina.

Bayesian kernel machine regression for estimating the health effects of multi-pollutant mixtures

Because humans are invariably exposed to complex chemical mixtures, estimating the health effects of multi-pollutant exposures is of critical concern in environmental epidemiology, and to regulatory agencies such as the U.S. Environmental Protection Agency. However, most health effects studies focus on single agents or consider simple two-way interaction models, in part because we lack the statistical methodology to more realistically capture the complexity of mixed exposures. We introduce Bayesian kernel machine regression (BKMR) as a new approach to study mixtures, in which the health outcome is regressed on a flexible function of the mixture (e.g. air pollution or toxic waste) components that is specified using a kernel function. In high-dimensional settings, a novel hierarchical variable selection approach is incorporated to identify important mixture components and account for the correlated structure of the mixture. Simulation studies demonstrate the success of BKMR in estimating the exposure-response function and in identifying the individual components of the mixture responsible for health effects. We demonstrate the features of the method through epidemiology and toxicology applications.

Prenatal lead levels, plasma amyloid β levels, and gene expression in young adulthood.

Background: Animal studies suggest that early-life lead exposure influences gene expression and production of proteins associated with Alzheimer’s disease (AD). Objectives: We attempted to assess the relationship between early-life lead exposure and potential biomarkers for AD among young men and women. We also attempted to assess whether early-life lead exposure was associated with changes in expression of AD-related genes. Methods: We used sandwich enzyme-linked immunosorbent assays (ELISA) to measure plasma concentrations of amyloid β proteins Aβ40 and Aβ42 among 55 adults who had participated as newborns and young children in a prospective cohort study of the effects of lead exposure on development. We used RNA microarray techniques to analyze gene expression. Results: Mean plasma Aβ42 concentrations were lower among 13 participants with high umbilical cord blood lead concentrations (≥ 10 μg/dL) than in 42 participants with lower cord blood lead concentrations (p = 0.08). Among 10 participants with high prenatal lead exposure, we found evidence of an inverse relationship between umbilical cord lead concentration and expression of ADAM metallopeptidase domain 9 (ADAM9), reticulon 4 (RTN4), and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) genes, whose products are believed to affect Aβ production and deposition. Gene network analysis suggested enrichment in gene sets involved in nerve growth and general cell development. Conclusions: Data from our exploratory study suggest that prenatal lead exposure may influence Aβ-related biological pathways that have been implicated in AD onset. Gene network analysis identified further candidates to study the mechanisms of developmental lead neurotoxicity.

Preventing stroke among children with sickle cell anemia: an analysis of strategies that involve transcranial Doppler testing and chronic transfusion.

BACKGROUND. Transcranial Doppler ultrasonography can identify children with sickle cell anemia who are at elevated risk of stroke and may benefit from chronic transfusions. Uncertainty about the risk/benefit trade-offs of chronic transfusion has led some clinicians to decide not to offer transcranial Doppler ultrasonography screening. OBJECTIVES. Our goals were to (1) compare the projected benefits and risks of 6 primary stroke-prevention strategies, (2) estimate the optimal frequency of screening, and (3) identify key assumptions that influence the risk/benefit relationship. METHODS. We designed a decision model to compare 6 primary stroke-prevention strategies: (1) annual transcranial Doppler ultrasonography screening until age 16 with children at high risk of stroke receiving monthly transfusion for life; (2) annual transcranial Doppler ultrasonography until age 16 with transfusions until age 18; (3) biannual transcranial Doppler ultrasonography until age 16 with transfusions until age 18; (4) annual transcranial Doppler ultrasonography until age 10 with transfusion until age 18; (5) 1-time screening at age 2 with transfusion until age 18; and (6) no intervention. Assumptions were derived from the published literature. RESULTS. For a hypothetical cohort of 2-year-old children, the optimal strategy was transcranial Doppler ultrasonography screening annually until age 10 with children at high risk receiving monthly transfusions until age 18. The optimal strategy would prevent 32% of strokes predicted to occur without intervention. The optimal strategy led to benefits similar to more intensive screening and transfusion strategies but resulted in fewer adverse events. All the intervention strategies resulted in net losses in life expectancy, because the projected mortality averted by stroke prevention was outweighed by the projected increase in mortality from transfusion. Results were sensitive to adherence rates to iron-chelation therapy. CONCLUSIONS. The optimal stroke-prevention strategy was projected to be annual transcranial Doppler ultrasonography screening until age 10 with transfusion for children at high risk until age 18. Better adherence to chelation therapy would improve life expectancy in all intervention strategies.

Estimating Effects of Arsenic Exposure During Pregnancy on Perinatal Outcomes in a Bangladeshi Cohort

Background: The relationship between arsenic and birth weight is not well understood. The objective was to evaluate the causal relationship between prenatal arsenic exposure and birth weight considering the potential mediation effects of gestational age and maternal weight gain during pregnancy using structural equation models. Methods: A prospectively enrolled cohort of pregnant women was recruited in Bangladesh from 2008 to 2011. Arsenic was measured in personal drinking water at the time of enrollment (gestational age <16 weeks, N = 1,140) and in toenails collected ⩽1 month postpartum (N = 624) using inductively coupled plasma mass spectrometry. Structural equation models estimated the direct and indirect effects of arsenic on birth weight with gestational age and maternal weight gain considered as mediating variables. Results: Every unit increase in natural log water arsenic was indirectly associated with decreased birth weight (&bgr; = −19.17 g, 95% confidence interval [CI]: −24.64, −13.69) after adjusting for other risk factors. This association was mediated entirely through gestational age (&bgr; = −17.37 g, 95% CI: −22.77, −11.98) and maternal weight gain during pregnancy (&bgr; = −1.80 g, 95% CI: −3.72, 0.13). When exposure was modeled using toenail arsenic concentrations, similar results were observed. Every increase in natural log toenail arsenic was indirectly associated with decreased birth weight (&bgr; = −15.72 g, 95% CI: −24.52, −6.91) which was mediated through gestational age (&bgr; = −13.59 g, 95% CI: −22.10, −5.07) and maternal weight gain during pregnancy (&bgr; = −2.13 g, 95% CI: −5.24, 0.96). Conclusion: Arsenic exposure during pregnancy was associated with lower birth weight. The effect of arsenic on birth weight appears to be mediated mainly through decreasing gestational age and to a lesser extent by lower maternal weight gain during pregnancy.

Contaminated Turmeric Is a Potential Source of Lead Exposure for Children in Rural Bangladesh

Background. During the conduct of a cohort study intended to study the associations between mixed metal exposures and child health outcomes, we found that 78% of 309 children aged 20–40 months evaluated in the Munshiganj District of Bangladesh had blood lead concentrations ≥5 µg/dL and 27% had concentrations ≥10 µg/dL. Hypothesis. Environmental sources such as spices (e.g., turmeric, which has already faced recalls in Bangladesh due to high lead levels) may be a potential route of lead exposure. Methods. We conducted visits to the homes of 28 children randomly selected from among high and low blood lead concentration groups. During the visits, we administered a structured questionnaire and obtained soil, dust, rice, and spice samples. We obtained water samples from community water sources, as well as environmental samples from neighborhood businesses. Results. Lead concentrations in many turmeric samples were elevated, with lead concentrations as high as 483 ppm. Analyses showed high bioaccessibility of lead. Conclusions. Contamination of turmeric powder is a potentially important source of lead exposure in this population.

The Joint Effect of Prenatal Exposure to Metal Mixtures on Neurodevelopmental Outcomes at 20–40 Months of Age: Evidence from Rural Bangladesh

Background: Exposure to chemical mixtures is recognized as the real-life scenario in all populations, needing new statistical methods that can assess their complex effects. Objectives: We aimed to assess the joint effect of in utero exposure to arsenic, manganese, and lead on children’s neurodevelopment. Methods: We employed a novel statistical approach, Bayesian kernel machine regression (BKMR), to study the joint effect of coexposure to arsenic, manganese, and lead on neurodevelopment using an adapted Bayley Scale of Infant and Toddler Development™. Third Edition, in 825 mother–child pairs recruited into a prospective birth cohort from two clinics in the Pabna and Sirajdikhan districts of Bangladesh. Metals were measured in cord blood using inductively coupled plasma-mass spectrometry. Results: Analyses were stratified by clinic due to differences in exposure profiles. In the Pabna district, which displayed high manganese levels [interquartile range (IQR): 4.8, 18μg/dl], we found a statistically significant negative effect of the mixture of arsenic, lead, and manganese on cognitive score when cord blood metals concentrations were all above the 60th percentile (As≥0.7μg/dl, Mn≥6.6μg/dl, Pb≥4.2μg/dl) compared to the median (As=0.5μg/dl, Mn=5.8μg/dl, Pb=3.1μg/dl). Evidence of a nonlinear effect of manganese was found. A change in log manganese from the 25th to the 75th percentile when arsenic and manganese were at the median was associated with a decrease in cognitive score of −0.3 (−0.5, −0.1) standard deviations. Our study suggests that arsenic might be a potentiator of manganese toxicity. Conclusions: Employing a novel statistical method for the study of the health effects of chemical mixtures, we found evidence of neurotoxicity of the mixture, as well as potential synergism between arsenic and manganese. https://doi.org/10.1289/EHP614

Polymorphisms in maternal folate pathway genes interact with arsenic in drinking water to influence risk of myelomeningocele

BACKGROUND Arsenic induces neural tube defects in many animal models. Additionally, studies have shown that mice with specific genetic defects in folate metabolism and transport are more susceptible to arsenic-induced neural tube defects. We sought to determine whether 14 single-nucleotide polymorphisms in genes involved in folate metabolism modified the effect of exposure to drinking water contaminated with inorganic arsenic and posterior neural tube defect (myelomeningocele) risk. METHODS Fifty-four mothers of children with myelomeningocele and 55 controls were enrolled through clinical sites in rural Bangladesh in a case-control study of the association between environmental arsenic exposure and risk of myelomeningocele. We assessed participants for level of myelomeningocele, administered questionnaires, conducted biological and environmental sample collection, and performed genotyping. Inductively coupled plasma mass spectrometry was used to measure inorganic arsenic concentration in drinking water. Candidate single-nucleotide polymorphisms were identified through review of the literature. RESULTS Drinking water inorganic arsenic concentration was associated with increased risk of myelomeningocele for participants with 4 of the 14 studied single-nucleotide polymorphisms in genes involved in folate metabolism: the AA/AG genotype of rs2236225 (MTHFD1), the GG genotype of rs1051266 (SLC19A1), the TT genotype of rs7560488 (DNMT3A), and the GG genotype of rs3740393 (AS3MT) with adjusted odds ratio of 1.13, 1.31, 1.20, and 1.25 for rs2236225, rs1051266, rs7560488, and rs3740393, respectively. CONCLUSION Our results support the hypothesis that environmental arsenic exposure increases the risk of myelomeningocele by means of interaction with folate metabolic pathways.

Elevated sweat chloride levels due to arsenic toxicity.

A study of a population with arsenic in drinking water shows that arsenic toxicity leads to changes in sweat chloride that are similar to those seen in cystic fibrosis.