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      Placental DNA Methylation Related to Both Infant Toenail Mercury and Adverse Neurobehavioral Outcomes

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          Abstract

          Background

          Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. Because Hg can interfere with placental functioning and cross the placenta to target the fetal brain, prenatal Hg exposure can inhibit fetal growth and development directly and indirectly.

          Objectives

          We examined potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes.

          Methods

          The methylation status of > 485,000 CpG loci was interrogated in 192 placental samples using Illumina’s Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU Network Neurobehavioral Scales (NNNS) in an independent subset of 151 infants.

          Results

          We identified 339 loci with an average methylation difference > 0.125 between any two toenail Hg tertiles. Variation among these loci was subsequently found to be associated with a high-risk neurodevelopmental profile (omnibus p-value = 0.007) characterized by the NNNS. Ten loci had p < 0.01 for the association between methylation and the high-risk NNNS profile. Six of 10 loci reside in the EMID2 gene and were hypomethylated in the 16 high-risk profile infants’ placentas. Methylation at these loci was moderately correlated (correlation coefficients range, –0.33 to –0.45) with EMID2 expression.

          Conclusions

          EMID2 hypomethylation may represent a novel mechanism linking in utero Hg exposure and adverse infant neurobehavioral outcomes.

          Citation

          Maccani JZ, Koestler DC, Lester B, Houseman EA, Armstrong DA, Kelsey KT, Marsit CJ. 2015. Placental DNA methylation related to both infant toenail mercury and adverse neurobehavioral outcomes. Environ Health Perspect 123:723–729;  http://dx.doi.org/10.1289/ehp.1408561

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          Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury.

          P Grandjean, P Weihe, R White … (2015)
          A cohort of 1022 consecutive singleton births was generated during 1986-1987 in the Faroe Islands. Increased methylmercury exposure from maternal consumption of pilot whale meat was indicated by mercury concentrations in cord blood and maternal hair. At approximately 7 years of age, 917 of the children underwent detailed neurobehavioral examination. Neuropsychological tests included Finger Tapping; Hand-Eye Coordination; reaction time on a Continuous Performance Test; Wechsler Intelligence Scale for Children-Revised Digit Spans, Similarities, and Block Designs; Bender Visual Motor Gestalt Test; Boston Naming Test; and California Verbal Learning Test (Children). Clinical examination and neurophysiological testing did not reveal any clear-cut mercury-related abnormalities. However, mercury-related neuropsychological dysfunctions were most pronounced in the domains of language, attention, and memory, and to a lesser extent in visuospatial and motor functions. These associations remained after adjustment for covariates and after exclusion of children with maternal hair mercury concentrations above 10 microgram(s) (50 nmol/g). The effects on brain function associated with prenatal methylmercury exposure therefore appear widespread, and early dysfunction is detectable at exposure levels currently considered safe.
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            Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression.

            Melissa Suter, Jun Ma, Alan H. Harris … (2011)
            Several studies linking alterations in differential placental methylation with pregnancy disorders have implicated (de)regulation of the placental epigenome with fetal programming and later-in-life disease. We have previously demonstrated that maternal tobacco use is associated with alterations in promoter methylation of placental CYP1A1 and that these changes are correlated with CYP1A1 gene expression and fetal growth restriction. In this study we sought to expand our analysis of promoter methylation by correlating it to gene expression on a genome-wide scale. Employing side-by-side IlluminaHG-12 gene transcription with Infinium27K methylation arrays, we interrogated correlative changes in placental gene expression and DNA methylation associated with maternal tobacco smoke exposure at an epigenome-wide level and in consideration of signature gene pathways. We observed that the expression of 623 genes and the methylation of 1024 CpG dinucleotides are significantly altered among smokers, with only 38 CpGs showing significant differential methylation (differing by a methylation level of ≥10%). We identified a significant Pearson correlation (≥0.7 or ≤-0.7) between placental transcriptional regulation and differential CpG methylation in only 25 genes among non-smokers but in 438 genes among smokers (18-fold increase, p < 0.0001), with a dominant effect among oxidative stress pathways. Differential methylation at as few as 6 sites was attributed to maternal smoking-mediated birth weight reduction in linear regression models with Bonferroni correction (p < 1.8 × 10(-6)). These studies suggest that a common perinatal exposure (such as maternal smoking) deregulates placental methylation in a CpG site-specific manner that correlates with meaningful alterations in gene expression along signature pathways.
            Article 0 comments Cited 90 times – based on 0 reviews     Review now
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              Mercury exposure in children: a review.

              S A Counter, Adam H Buchanan (2004)
              Exposure to toxic mercury (Hg) is a growing health hazard throughout the world today. Recent studies show that mercury exposure may occur in the environment, and increasingly in occupational and domestic settings. Children are particularly vulnerable to Hg intoxication, which may lead to impairment of the developing central nervous system, as well as pulmonary and nephrotic damage. Several sources of toxic Hg exposure in children have been reported in biomedical literature: (1) methylmercury, the most widespread source of Hg exposure, is most commonly the result of consumption of contaminated foods, primarily fish; (2) ethylmercury, which has been the subject of recent scientific inquiry in relation to the controversial pediatric vaccine preservative thimerosal; (3) elemental Hg vapor exposure through accidents and occupational and ritualistic practices; (4) inorganic Hg through the use of topical Hg-based skin creams and in infant teething powders; (5) metallic Hg in dental amalgams, which release Hg vapors, and Hg2+ in tissues. This review examines recent epidemiological studies of methylmercury exposure in children. Reports of elemental Hg vapor exposure in children through accidents and occupational practices, and the more recent observations of the increasing use of elemental Hg for magico-religious purposes in urban communities are also discussed. Studies of inorganic Hg exposure from the widespread use of topical beauty creams and teething powders, and fetal/neonatal Hg exposure from maternal dental amalgam fillings are reviewed. Considerable attention was given in this review to pediatric methylmercury exposure and neurodevelopment because it is the most thoroughly investigated Hg species. Each source of Hg exposure is reviewed in relation to specific pediatric health effects, particularly subtle neurodevelopmental disorders.
              Article 0 comments Cited 82 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Environ Health Perspect
                Journal ID (iso-abbrev): Environ. Health Perspect
                Journal ID (publisher-id): EHP
                Title: Environmental Health Perspectives
                Publisher: NLM-Export
                ISSN (Print): 0091-6765
                ISSN (Electronic): 1552-9924
                Publication date (Electronic): 06 March 2015
                Publication date (Print): July 2015
                Volume: 123
                Issue: 7
                Pages: 723-729
                Affiliations
                [1 ]Penn State Tobacco Center of Regulatory Science, Department of Public Health Sciences, College of Medicine, Penn State University, Hershey, Pennsylvania, USA
                [2 ]Department of Biostatistics, University of Kansas Medical Center, The University of Kansas, Kansas City, Kansas, USA
                [3 ]Center for the Study of Children at Risk,
                [4 ]Department of Psychiatry and Human Behavior, and
                [5 ]Department of Pediatrics, The Warren Alpert Medical School of Brown University and Women and Infants Hospital, Providence, Rhode Island, USA
                [6 ]College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon, USA
                [7 ]Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
                [8 ]Department of Pathology and Laboratory Medicine, and
                [9 ]Department of Epidemiology, Brown University, Providence, Rhode Island, USA
                [10 ]Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
                Author notes
                Address correspondence to C.J. Marsit, Departments of Pharmacology and Toxicology and of Epidemiology, Geisel School of Medicine at Dartmouth, HB 7650, Pharmacology and Toxicology, Hanover, NH 03755 USA. Telephone: (603) 650-1825. E-mail: Carmen.J.Marsit@ 123456Dartmouth.edu
                Article
                Publisher ID: ehp.1408561
                DOI: 10.1289/ehp.1408561
                PMC ID: 4492267
                PubMed ID: 25748564
                SO-VID: 2aa55570-eee0-4c31-be38-46a8b3d687b1
                License:

                Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

                History
                Date received : 15 April 2014
                Date accepted : 04 March 2015
                Date: 06 March 2015
                Date: 01 July 2015
                Categories
                Subject: Children's Health

                ScienceOpen disciplines: Public health
                Data availability:
                ScienceOpen disciplines: Public health

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