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      Polymorphisms in ABC Transporter Genes and Concentrations of Mercury in Newborns – Evidence from Two Mediterranean Birth Cohorts

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          Abstract

          Background

          The genetic background may influence methylmercury (MeHg) metabolism and neurotoxicity. ATP binding cassette (ABC) transporters actively transport various xenobiotics across biological membranes.

          Objective

          To investigate the role of ABC polymorphisms as modifiers of prenatal exposure to MeHg.

          Methods

          The study population consisted of participants (n = 1651) in two birth cohorts, one in Italy and Greece (PHIME) and the other in Spain (INMA). Women were recruited during pregnancy in Italy and Spain, and during the perinatal period in Greece. Total mercury concentrations were measured in cord blood samples by atomic absorption spectrometry. Maternal fish intake during pregnancy was determined from questionnaires. Polymorphisms (n = 5) in the ABC genes ABCA1, ABCB1, ABCC1 and ABCC2 were analysed in both cohorts.

          Results

          ABCB1 rs2032582, ABCC1 rs11075290, and ABCC2 rs2273697 modified the associations between maternal fish intake and cord blood mercury concentrations. The overall interaction coefficient between rs2032582 and log2-transformed fish intake was negative for carriers of GT (β = −0.29, 95%CI −0.47, −0.12) and TT (β = −0.49, 95%CI −0.71, −0.26) versus GG, meaning that for a doubling in fish intake of the mothers, children with the rs2032582 GG genotype accumulated 35% more mercury than children with TT. For rs11075290, the interaction coefficient was negative for carriers of TC (β = −0.12, 95%CI −0.33, 0.09), and TT (β = −0.28, 95%CI −0.51, −0.06) versus CC. For rs2273697, the interaction coefficient was positive when combining GA+AA (β = 0.16, 95%CI 0.01, 0.32) versus GG.

          Conclusion

          The ABC transporters appear to play a role in accumulation of MeHg during early development.

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          Most cited references 28

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          Measuring inconsistency in meta-analyses.

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            Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense.

            In tumor cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins. ABC proteins that confer drug resistance include (but are not limited to) P-glycoprotein (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and the breast cancer resistance protein (BCRP, gene symbol ABCG2). In addition to their role in drug resistance, there is substantial evidence that these efflux pumps have overlapping functions in tissue defense. Collectively, these proteins are capable of transporting a vast and chemically diverse array of toxicants including bulky lipophilic cationic, anionic, and neutrally charged drugs and toxins as well as conjugated organic anions that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products. P-glycoprotein, MRP1, MRP2, and BCRP/ABCG2 are expressed in tissues important for absorption (e.g., lung and gut) and metabolism and elimination (liver and kidney). In addition, these transporters have an important role in maintaining the barrier function of sanctuary site tissues (e.g., blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier or placenta). Thus, these ABC transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics. In this review, the role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed. Species variations in substrate specificity and tissue distribution of these transporters are also addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.
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              The International HapMap Project Web site.

              The HapMap Web site at http://www.hapmap.org is the primary portal to genotype data produced as part of the International Haplotype Map Project. In phase I of the project, >1.1 million SNPs were genotyped in 270 individuals from four worldwide populations. The HapMap Web site provides researchers with a number of tools that allow them to analyze the data as well as download data for local analyses. This paper presents step-by-step guides to using those tools, including guides for retrieving genotype and frequency data, picking tag-SNPs for use in association studies, viewing haplotypes graphically, and examining marker-to-marker LD patterns.
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                Author and article information

                Affiliations
                [1 ]Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO, Valencia, Spain
                [2 ]Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
                [3 ]Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden
                [4 ]School of Nursing, University of Valencia, Valencia, Spain
                [5 ]Unit of Hygiene and Epidemiology, University of Udine, Udine, Italy
                [6 ]Department of Environmental Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
                [7 ]Medicine Department, Jaume I University, Castelló de la Plana, Spain
                [8 ]Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
                [9 ]Hospital del Mar Research Institute (IMIM), Barcelona, Spain
                [10 ]Center for Genomic Regulation (CRG), Barcelona, Spain
                [11 ]Pompeu Fabra University (UPF), Barcelona, Spain
                [12 ]Department of Social and Developmental Paediatrics Institute of Child Health, Athens, Greece
                [13 ]Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                Kagoshima University Graduate School of Medical and Dental Sciences, Japan
                Author notes

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

                Analyzed the data: SL KE MM MB KB. Wrote the paper: SL KB. Conception and design of this work: SL FBE MR JS KE KB. Planning and execution of the study: SL KE FBE MR JS KB. Recruitment of the study participants: SL SN IA EA ASK FB FP AP. Genetic analysis: KE EF AA MB. Mercury analysis in PHIME participants: DM MH JT. Interpretation of results: SL KE MM MB KB. Participated with comments to the final version of the manuscript: SL KE FBE EF AA FP JT DM MM MR MB JS ASK AP EA IA SN FB MH KB.

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                15 May 2014
                : 9
                : 5
                24831289 4022503 PONE-D-13-50685 10.1371/journal.pone.0097172

                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.

                Counts
                Pages: 9
                Funding
                This study was funded by The European Union 6th and 7th framework projects PHIME NEWGENERIS, the Swedish Research Council for Health, Working Life and Welfare, the Swedish Research Council FORMAS. The INMA study was funded by grants from the Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0031), UE (FP7-ENV-2011 DENAMIC cod 282957 and HEALTH.2010.2.4.5-1), Spanish Ministry of Health (FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, 11/02591, 04/1436, 04/2018, 09/02311, 06/0867, 08/1151, 11/02038, CP11/00178), Conselleria de Sanitat Generalitat Valenciana, Generalitat de Catalunya (CIRIT 1999SGR 00241), Fundació La marató de TV3 (090430) and European Union Sixth Framework Project (NEWGENERIS FP6-2003-Food-3-A-016320). National funding for the PHIME project in Slovenia was provided by the programme ARRS P1-0143. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Blood Chemistry
                Computational Biology
                Evolutionary Biology
                Population Genetics
                Genetic Polymorphism
                Genetics
                Epigenetics
                Human Genetics
                Nutrition
                Population Biology
                Toxicology
                Toxic Agents
                Toxins
                Heavy Metals
                Neurotoxicology
                Medicine and Health Sciences
                Women's Health
                Maternal Health
                Pregnancy
                Obstetrics and Gynecology
                Physical Sciences
                Chemistry
                Environmental Chemistry
                Pollutants
                Research and Analysis Methods
                Research Design
                Clinical Research Design
                Cohort Studies

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