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      Arsenic Exposure Affects Plasma Insulin-Like Growth Factor 1 (IGF-1) in Children in Rural Bangladesh

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          Exposure to inorganic arsenic (As) through drinking water during pregnancy is associated with lower birth size and child growth. The aim of the study was to assess the effects of As exposure on child growth parameters to evaluate causal associations.


          Children born in a longitudinal mother-child cohort in rural Bangladesh were studied at 4.5 years (n=640) as well as at birth (n=134). Exposure to arsenic was assessed by concurrent and prenatal (maternal) urinary concentrations of arsenic metabolites (U-As). Associations with plasma concentrations of insulin-like growth factor 1 (IGF-1), calcium (Ca), vitamin D (Vit-D), bone-specific alkaline phosphatase (B-ALP), intact parathyroid hormone (iPTH), and phosphate (PO 4) were evaluated by linear regression analysis, adjusted for socioeconomic factor, parity and child sex. Child U-As (per 10 µg/L) was significantly inversely associated with concurrent plasma IGF-1 (β=-0.27; 95% confidence interval: -0.50, -0.0042) at 4.5 years. The effect was more obvious in girls (β=-0.29; -0.59, 0.021) than in boys, and particularly in girls with adequate height (β=-0.491; -0.97, -0.02) or weight (β=-0.47; 0.97, 0.01). Maternal U-As was inversely associated with child IGF-1 at birth (r=-0.254, P=0.003), but not at 4.5 years. There was a tendency of positive association between U-As and plasma PO 4 in stunted boys (β=0.27; 0.089, 0.46). When stratified by % monomethylarsonic acid (MMA, arsenic metabolite) (median split at 9.7%), a much stronger inverse association between U-As and IGF-1 in the girls (β=-0.41; -0.77, -0.03) was obtained above the median split.


          The results suggest that As-related growth impairment in children is mediated, at least partly, through suppressed IGF-1 levels.

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          Most cited references 37

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          To construct growth curves for school-aged children and adolescents that accord with the WHO Child Growth Standards for preschool children and the body mass index (BMI) cut-offs for adults. Data from the 1977 National Center for Health Statistics (NCHS)/WHO growth reference (1-24 years) were merged with data from the under-fives growth standards' cross-sectional sample (18-71 months) to smooth the transition between the two samples. State-of-the-art statistical methods used to construct the WHO Child Growth Standards (0-5 years), i.e. the Box-Cox power exponential (BCPE) method with appropriate diagnostic tools for the selection of best models, were applied to this combined sample. The merged data sets resulted in a smooth transition at 5 years for height-for-age, weight-for-age and BMI-for-age. For BMI-for-age across all centiles the magnitude of the difference between the two curves at age 5 years is mostly 0.0 kg/m(2) to 0.1 kg/m(2). At 19 years, the new BMI values at +1 standard deviation (SD) are 25.4 kg/m(2) for boys and 25.0 kg/m(2) for girls. These values are equivalent to the overweight cut-off for adults (> or = 25.0 kg/m(2)). Similarly, the +2 SD value (29.7 kg/m(2) for both sexes) compares closely with the cut-off for obesity (> or = 30.0 kg/m(2)). The new curves are closely aligned with the WHO Child Growth Standards at 5 years, and the recommended adult cut-offs for overweight and obesity at 19 years. They fill the gap in growth curves and provide an appropriate reference for the 5 to 19 years age group.
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            Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization.

            To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cre-mediated recombination to disrupt selectively in mouse osteoblasts the gene encoding the type 1 IGF receptor (Igf1r). Mice carrying this bone-specific mutation were of normal size and weight but, in comparison with normal siblings, demonstrated a striking decrease in cancellous bone volume, connectivity, and trabecular number, and an increase in trabecular spacing. These abnormalities correlated with a striking decrease in the rate of mineralization of osteoid that occurred despite an unexpected osteoblast and osteoclast hyperactivity, detected from the significant increments in both osteoblast and erosion surfaces. Our findings indicate that IGF1 is essential for coupling matrix biosynthesis to sustained mineralization. This action is likely to be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required.
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              Effects of prenatal micronutrient and early food supplementation on maternal hemoglobin, birth weight, and infant mortality among children in Bangladesh: the MINIMat randomized trial.

              Nutritional insult in fetal life and small size at birth are common in low-income countries and are associated with serious health consequences. To test the hypothesis that prenatal multiple micronutrient supplementation (MMS) and an early invitation to food supplementation would increase maternal hemoglobin level and birth weight and decrease infant mortality, and to assess whether a combination of these interventions would further enhance these outcomes. A randomized trial with a factorial design in Matlab, Bangladesh, of 4436 pregnant women, recruited between November 11, 2001, and October 30, 2003, with follow-up until June 23, 2009. Participants were randomized into 6 groups; a double-masked supplementation with capsules of 30 mg of iron and 400 μg of folic acid, 60 mg of iron and 400 μg of folic acid, or MMS containing a daily allowance of 15 micronutrients, including 30 mg of iron and 400 μg of folic acid, was combined with food supplementation (608 kcal 6 days per week) randomized to either early invitation (9 weeks' gestation) or usual invitation (20 weeks' gestation). Maternal hemoglobin level at 30 weeks' gestation, birth weight, and infant mortality. Under 5-year mortality was also assessed. Adjusted maternal hemoglobin level at 30 weeks' gestation was 115.0 g/L (95% CI, 114.4-115.5 g/L), with no significant differences among micronutrient groups. Mean maternal hemoglobin level was lower in the early vs usual invitation groups (114.5 vs 115.4 g/L; difference, -0.9 g/L; 95% CI, -1.7 to -0.1; P = .04). There were 3625 live births out of 4436 pregnancies. Mean birth weight among 3267 singletons was 2694 g (95% CI, 2680-2708 g), with no significant differences among groups. The early invitation with MMS group had an infant mortality rate of 16.8 per 1000 live births vs 44.1 per 1000 live births for usual invitation with 60 mg of iron and 400 μg of folic acid (hazard ratio [HR], 0.38; 95% CI, 0.18-0.78). Early invitation with MMS group had an under 5-year mortality rate of 18 per 1000 live births (54 per 1000 live births for usual invitation with 60 mg of iron and 400 μg of folic acid; HR, 0.34; 95% CI, 0.18-0.65). Usual invitation with MMS group had the highest incidence of spontaneous abortions and the highest infant mortality rate. Among pregnant women in poor communities in Bangladesh, treatment with multiple micronutrients, including iron and folic acid combined with early food supplementation, vs a standard program that included treatment with iron and folic acid and usual food supplementation, resulted in decreased childhood mortality. Identifier: ISRCTN16581394.

                Author and article information

                [1 ]Centre for Vaccine Sciences, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh
                [2 ]Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden
                [3 ]Department of Clinical Trial and Clinical Epidemiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
                [4 ]International Maternal and Child Health, Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
                Inserm, France
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RR MV. Performed the experiments: SA RSR KBA MD MG AKR. Analyzed the data: SA KBA. Contributed reagents/materials/analysis tools: RR MV YW. Wrote the manuscript: RR MV SA. Revision of manuscript: RR MV SA YW ECE.

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                26 November 2013
                : 8
                : 11
                24303053 3841153 PONE-D-13-24569 10.1371/journal.pone.0081530

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                The study was supported by the Swedish Agency for Research Cooperation with Developing Countries (Sida/SAREC Agreement support; grant GR00599); Grant-in-Aid for Scientific Research of the Japan Society for the Promotion of Science (18256005) and icddr,b. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article



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