title: Interaction of plasma glutathione redox and folate deficiency on arsenic methylation capacity in Bangladeshi adults.
abstract: Inorganic arsenic(As) is metabolized through a series of methylation reactions catalyzed by arsenic(III)-methyltransferase (AS3MT), resulting in the generation of monomethylarsonic (MMAs) and dimethylarsinic acids (DMAs). AS3MT activity requires the presence of the methyl donor S-adenosylmethionine, a product of folate-dependent one-carbon metabolism, and a reductant. Although glutathione (GSH), the primary endogenous antioxidant, is not required for As methylation, GSH stimulates As methylation rates in vitro. However, the relationship between GSH redox and As methylation capacity in humans is unknown. We wished to test the hypothesis that a more oxidized plasma GSH redox status is associated with decreased As methylation capacity and examine whether these associations are modified by folate nutritional status. Concentrations of plasma GSH and GSSG, plasma folate, total blood As (bAs), total urinary As (uAs), and uAs metabolites were assessed in a cross-sectional study of n=376 Bangladeshi adults who were chronically exposed to As in drinking water. We observed that a decreased plasma GSH/GSSG ratio (reflecting a more oxidized redox state) was significantly associated with increased urinary %MMA, decreased urinary %DMA, and increased total bAs in folate-deficient individuals (plasma folate ≤ 9.0 nmol/L). Concentrations of plasma GSH and GSSG were independently associated with increased and decreased As methylation capacity, respectively. No significant associations were observed in folate-sufficient individuals, and interactions by folate status were statistically significant. Our findings suggest that GSH/GSSG redox regulation might contribute to the large interindividual variation in As methylation capacity observed in human populations.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Niedzwiecki
authors.affiliation: Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Vesna
authors.initials: V
authors.lastname: Slavkovich
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Vesna
authors.initials: V
authors.lastname: Ilievski
authors.affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Levy
authors.affiliation: Columbia University Arsenic Project in Bangladesh, Dhaka, Bangladesh.
authors.forename: Shafiul
authors.initials: S
authors.lastname: Alam
authors.affiliation: Columbia University Arsenic Project in Bangladesh, Dhaka, Bangladesh.
authors.forename: Abu B
authors.initials: AB
authors.lastname: Siddique
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Faruque
authors.initials: F
authors.lastname: Parvez
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Graziano
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. Electronic address: mvg7@columbia.edu.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Gamble
mesh_terms: D000328:Adult; D000368:Aged; D001151:Arsenic / Q000737:chemistry / Q000378:metabolism*; D001152:Arsenicals / Q000652:urine*; D001459:Bangladesh; D002101:Cacodylic Acid / Q000652:urine*; D003430:Cross-Sectional Studies; D060766:Drinking Water; D004781:Environmental Exposure; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005494:Folic Acid Deficiency / Q000097:blood; D005978:Glutathione / Q000097:blood* / Q000737:chemistry; D019803:Glutathione Disulfide / Q000097:blood; D006801:Humans; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D010084:Oxidation-Reduction; D012436:S-Adenosylmethionine / Q000737:chemistry
chemical_list: D001152:Arsenicals; D060766:Drinking Water; D012436:S-Adenosylmethionine; D005492:Folic Acid; D002101:Cacodylic Acid; D008780:Methyltransferases; C505756:AS3MT protein, human; D005978:Glutathione; C020300:monomethylarsonic acid; D001151:Arsenic; D019803:Glutathione Disulfide
keywords: Arsenic; Arsenic methylation; Bangladesh; Folate; Free radicals; Glutathione; Glutathione disulfide; Oxidative stress; Redox
references.citation: Arch Environ Occup Health. 2010 Jul-Sep;65(3):140-7
references.pmid: 20705574
references.citation: Environ Sci Technol. 2005 Jan 1;39(1):299-303
references.pmid: 15667109
references.citation: Environ Health Perspect. 2007 Jul;115(7):1081-6
references.pmid: 17637926
references.citation: Analyst. 2001 Jul;126(7):1011-7
references.pmid: 11478628
references.citation: Cancer Causes Control. 2007 Feb;18(1):7-27
references.pmid: 17186419
references.citation: Theor Biol Med Model. 2008 Apr 28;5:8
references.pmid: 18442411
references.citation: J Biol Chem. 2012 Nov 9;287(46):38790-9
references.pmid: 22955273
references.citation: Biochimie. 2010 Oct;92(10):1397-406
references.pmid: 20621156
references.citation: Int J Hyg Environ Health. 2002 Oct;205(6):505-8
references.pmid: 12455273
references.citation: J Biol Chem. 2012 Sep 14;287(38):32195-205
references.pmid: 22798075
references.citation: Chem Res Toxicol. 2004 Mar;17(3):404-9
references.pmid: 15025511
references.citation: Theor Biol Med Model. 2011 Aug 26;8:31
references.pmid: 21871107
references.citation: Adv Enzymol Relat Subj Biochem. 1951;12:429-91
references.pmid: 14885024
references.citation: Mutat Res. 1997 Jun;386(3):197-207
references.pmid: 9219558
references.citation: Chem Res Toxicol. 2001 Jun;14(6):651-6
references.pmid: 11409934
references.citation: Chem Res Toxicol. 2001 May;14(5):517-22
references.pmid: 11368549
references.citation: Toxicol Appl Pharmacol. 2008 Oct 1;232(1):142-9
references.pmid: 18640141
references.citation: Chem Res Toxicol. 2003 Dec;16(12):1507-13
references.pmid: 14680363
references.citation: Annu Rev Public Health. 2009;30:107-22
references.pmid: 19012537
references.citation: Metallomics. 2012 Jan;4(1):91-100
references.pmid: 22028001
references.citation: Toxicol Appl Pharmacol. 2010 Dec 15;249(3):217-23
references.pmid: 20887743
references.citation: Toxicol Sci. 2009 Feb;107(2):309-11
references.pmid: 19074764
references.citation: Chem Res Toxicol. 2004 Dec;17(12):1621-9
references.pmid: 15606138
references.citation: J Environ Monit. 2010 Jun;12(6):1247-54
references.pmid: 20532380
references.citation: Science. 2007 Jan 19;315(5810):387-9
references.pmid: 17234949
references.citation: Environ Health Perspect. 2013 Sep;121(9):1068-74
references.pmid: 23792557
references.citation: Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E260-9
references.pmid: 19401458
references.citation: Toxicology. 2006 Aug 15;225(2-3):225-33
references.pmid: 16860454
references.citation: FASEB J. 1996 Mar;10(4):471-80
references.pmid: 8647346
references.citation: Am J Physiol Cell Physiol. 2008 Oct;295(4):C849-68
references.pmid: 18684987
references.citation: J Toxicol Environ Health A. 2007 Jan 15;70(2):159-70
references.pmid: 17365577
references.citation: Toxicol Appl Pharmacol. 2012 Oct 1;264(1):121-30
references.pmid: 22868225
references.citation: Chem Res Toxicol. 1997 Jan;10(1):27-33
references.pmid: 9074799
references.citation: Environ Res. 2010 Jul;110(5):463-8
references.pmid: 20045512
references.citation: Anal Bioanal Chem. 2004 Jun;379(3):512-8
references.pmid: 15098084
references.citation: J Environ Sci Health A Tox Hazard Subst Environ Eng. 2007 Oct;42(12):1729-40
references.pmid: 17952774
references.citation: Mol Nutr Food Res. 2013 Apr;57(4):628-36
references.pmid: 23143835
references.citation: Free Radic Biol Med. 2007 Sep 15;43(6):883-98
references.pmid: 17697933
references.citation: Biochem Pharmacol. 1995 Mar 30;49(7):971-7
references.pmid: 7741769
references.citation: Arch Toxicol. 2005 Apr;79(4):183-91
references.pmid: 15526190
references.citation: J Inorg Biochem. 2012 Mar;108:141-9
references.pmid: 22197475
references.citation: Environ Health Perspect. 2007 Apr;115(4):599-605
references.pmid: 17450230
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1270-8
references.pmid: 17548696
references.citation: Environ Health Perspect. 2009 Nov;117(11):1724-9
references.pmid: 20049124
references.citation: Free Radic Biol Med. 2002 Nov 1;33(9):1290-300
references.pmid: 12398937
references.citation: Exp Biol Med (Maywood). 2007 Jan;232(1):3-13
references.pmid: 17202581
references.citation: J Anal At Spectrom. 2013 Jun 1;28(6):843-852
references.pmid: 23687401
references.citation: Cancer Causes Control. 2010 Oct;21(10):1605-13
references.pmid: 20532609
references.citation: Mutat Res. 2003 Dec 10;533(1-2):37-65
references.pmid: 14643412
references.citation: Toxicol Sci. 2005 Mar;84(1):157-66
references.pmid: 15601678
references.citation: FEBS Lett. 2013 Jul 11;587(14):2232-40
references.pmid: 23742935
references.citation: Scand J Clin Lab Invest. 1965;17(4):381-7
references.pmid: 5838275
references.citation: Arch Toxicol. 2000 Aug;74(6):289-99
references.pmid: 11005674
references.citation: Pharmacol Toxicol. 2001 Jul;89(1):1-5
references.pmid: 11484904
references.citation: Science. 2006 Dec 15;314(5806):1687-8
references.pmid: 17170279
references.citation: IARC Monogr Eval Carcinog Risks Hum Suppl. 1987;7:1-440
references.pmid: 3482203
references.citation: Clin Chim Acta. 1998 Jul 28;275(2):175-84
references.pmid: 9721075
references.citation: J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2007 Jan-Mar;25(1):1-22
references.pmid: 17365340
references.citation: J Biol Chem. 2002 Mar 29;277(13):10795-803
references.pmid: 11790780