The prenatal period represents a critical window of susceptibility to inorganic arsenic (iAs) exposure from contaminated drinking water. Ingested iAs undergoes hepatic methylation generating mono and di-methyl arsenicals (MMAs and DMAs, respectively), a process that facilitates urinary arsenic (As) elimination. Differences in pregnant women’s metabolism of As as indicated by greater proportions of MMAs and smaller proportions of DMAs in urine are a risk factor for adverse birth outcomes. One carbon metabolism (OCM), the nutritionally-regulated pathway essential for supplying methyl groups, plays a role in As metabolism and is understudied during the prenatal period. In this cross-sectional study from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Gómez Palacio, Mexico, we assessed the relationships among OCM indicators (e.g. maternal serum B12, folate, and homocysteine (Hcys)), and levels of iAs and its metabolites in maternal urine and in neonatal cord serum. The prevalence of folate sufficiency (folate levels > 9 nmol/L) in the cohort was high 99%, and hyperhomocysteinemia (Hcys levels > 10.4 μmol/L) was low (8%). However, 74% of the women displayed a deficiency in B12 (serum levels < 148 pmol/L). Association analyses identified that infants born to mothers in the lowest tertile of serum folate had significantly higher mean levels of %MMA in cord serum relative to folate replete women. In addition, elevated maternal Hcys was associated with total As in maternal urine and cord serum as well as cord serum %MMAs. The results from this study indicate that maternal OCM status may influence the distribution of As metabolites in cord serum.
Subscribe to Journal
Get full journal access for 1 year
only $19.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Huang L, Wu H, van der Kuijp TJ. The health effects of exposure to arsenic-contaminated drinking water: a review by global geographical distribution. Int J Environ Health Res. 2015;25:432–52.
Tseng CH. Arsenic methylation, urinary arsenic metabolites and human diseases: current perspective. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2007;25:1–22.
Naujokas MF, Anderson B, Ahsan H, Aposhian HV, Graziano JH, Thompson C, et al. The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environ Health Perspect. 2013;121:295–302.
Laine JE, Bailey KA, Rubio-Andrade M, Olshan AF, Smeester L, Drobná Z, et al. Maternal arsenic exposure, arsenic methylation efficiency, and birth outcomes in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Mexico. Environ Health Perspect. 2015;123:186–92.
Gilbert-Diamond D, Emond JA, Baker ER, Korrick SA, Karagas MR. Relation between in utero arsenic exposure and birth outcomes in a cohort of mothers and their newborns from New Hampshire. Environ Health Perspect. 2016;124:1299–307.
Jansen RJ, Argos M, Tong L, Li J, Rakibuz-Zaman M, Islam MT, et al. Determinants and consequences of arsenic metabolism efficiency among 4794 individuals: demographics, lifestyle, genetics, and toxicity. Cancer Epidemiol Biomark Prev. 2016;25:381–90.
Rodrigues EG, Kile M, Hoffman E, Quamruzzaman Q, Rahman M, Mahiuddin G, et al. GSTO and AS3MT genetic polymorphisms and differences in urinary arsenic concentrations among residents in Bangladesh. Biomarkers. 2012;17:240–7.
Lindberg AL, Kumar R, Goessler W, Thirumaran R, Gurzau E, Koppova K, et al. Metabolism of low-dose inorganic arsenic in a central European population: influence of sex and genetic polymorphisms. Environ Health Perspect. 2007;115:1081–6.
Vahter M. Mechanisms of arsenic biotransformation. Toxicology. 2002;181-2:211–7.
Karagas MR, Stukel TA, Morris JS, Tosteson TD, Weiss JE, Spencer SK, et al. Skin cancer risk in relation to toenail arsenic concentrations in a US population-based case-control study. Am J Epidemiol. 2001;153:559–65.
Vahter ME. Interactions between arsenic-induced toxicity and nutrition in early life. J Nutr. 2007;137:2798–804.
Peters BA, Hall MN, Liu X, Parvez F, Sanchez TR, van Geen A, et al. Folic acid and creatine as therapeutic approaches to lower blood arsenic: a randomized controlled trial. Environ Health Perspect. 2015;123:1294–301.
Hall MN, Gamble MV. Nutritional manipulation of one-carbon metabolism: effects on arsenic methylation and toxicity. J Toxicol. 2012;2012:595307.
Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, Wu J, et al. Targeted disruption of the methionine synthase gene in mice. Mol Cell Biol. 2001;21:1058–65.
Hall M, Gamble M, Slavkovich V, Liu X, Levy D, Cheng Z, et al. Determinants of arsenic metabolism: blood arsenic metabolites, plasma folate, cobalamin, and homocysteine concentrations in maternal-newborn pairs. Environ Health Perspect. 2007;115:1503–9.
Li L, Ekström EC, Goessler W, Lönnerdal B, Nermell B, Yunus M, et al. Nutritional status has marginal influence on the metabolism of inorganic arsenic in pregnant Bangladeshi women. Environ Health Perspect. 2008;116:315–21.
Gardner RM, Nermell B, Kippler M, Grandér M, Li L, Ekström EC, et al. Arsenic methylation efficiency increases during the first trimester of pregnancy independent of folate status. Reprod Toxicol. 2011;31:210–8.
Devesa V, Maria Del Razo L, Adair B, Drobna Z, Waters SB, Hughes MF, et al. Comprehensive analysis of arsenic metabolites by pH-specific hydride generation atomic absorption spectrometry. J Anal At Spectrom. 2004;19:1460–7.
Hernandez-Zavala A, Matousek T, Drobna Z, Paul DS, Walton F, Adair BM, et al. Speciation analysis of arsenic in biological matrices by automated hydride generation-cryotrapping-atomic absorption spectrometry with multiple microflame quartz tube atomizer (multiatomizer). J Anal Spectrom. 2008;23:342–51.
Hernandez-Zavala A, Drobna Z, Styblo M, Thomas DJ. Analysis of arsenical metabolites in biological samples. Curr Protoc Toxicol. 2009;42:4.33. 31–34.33.17.
Matoušek T, Currier JM, Trojánková N, Saunders RJ, Ishida MC, González-Horta C, et al. Selective hydride generation- cryotrapping- ICP-MS for arsenic speciation analysis at picogram levels: analysis of river and sea water reference materials and human bladder epithelial cells. J Anal Spectrom. 2013;28:1456–65.
Fukai Y, Hirata M, Ueno M, Ichikawa N, Kobayashi H, Saitoh H, et al. Clinical pharmacokinetic study of arsenic trioxide in an acute promyelocytic leukemia (APL) patient: speciation of arsenic metabolites in serum and urine. Biol Pharm Bull. 2006;29:1022–7.
Skalny AV, Simashkova NV, Klyushnik TP, Grabeklis AR, Radysh IV, Skalnaya MG, et al. Assessment of serum trace elements and electrolytes in children with childhood and atypical autism. J Trace Elem Med Biol. 2017;43:9–14.
Gamble MV, Ahsan H, Liu X, Factor-Litvak P, Ilievski V, Slavkovich V, et al. Folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh. Am J Clin Nutr. 2005;81:1372–7.
de Benoist B. Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies. Food Nutr Bull. 2008;29:S238–44.
Howe CG, Niedzwiecki MM, Hall MN, Liu X, Ilievski V, Slavkovich V, et al. Folate and cobalamin modify associations between S-adenosylmethionine and methylated arsenic metabolites in arsenic-exposed Bangladeshi adults. J Nutr. 2014;144:690–7.
Swearinge CJ, Melguizo Castro MS, Bursac Z. Modeling percentage outcomes: the %beta_regression macro. In proceedings of the SAS Global Forum, Las Vegas NV, 2011, paper 335:1-12.
Sukumar N, Rafnsson SB, Kandala NB, Bhopal R, Yajnik CS, Saravanan P. Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis. Am J Clin Nutr. 2016;103:1232–51.
Shamah-Levy T, Villalpando S, Mejía-Rodríguez F, Cuevas-Nasu L, Gaona-Pineda EB, Rangel-Baltazar E, et al. Prevalence of iron, folate, and vitamin B12 deficiencies in 20 to 49 years old women: Ensanut 2012. Salud Publica Mex. 2015;57:385–93.
Ray JG, Goodman J, O'Mahoney PR, Mamdani MM, Jiang D. High rate of maternal vitamin B12 deficiency nearly a decade after Canadian folic acid flour fortification. QJM. 2008;101:475–7.
Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr. 2001;85(Suppl 2):S109–13.
Molloy AM, Kirke PN, Brody LC, Scott JM, Mills JL. Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr Bull. 2008;29:S101–111. discussionS112-05
Shane B, Stokstad EL. Vitamin B12-folate interrelationships. Annu Rev Nutr. 1985;5:115–41.
Concha G, Vogler G, Lezcano D, Nermell B, Vahter M. Exposure to inorganic arsenic metabolites during early human development. Toxicol Sci. 1998;44:185–90.
Environmental Protection Agency (EPA). Fact sheet: Drinking Water Standard for arsenic. Washington, DC: Office of Water, U.S. Environmental Protection Agency; 2001.
Forges T, Monnier-Barbarino P, Alberto JM, Guéant-Rodriguez RM, Daval JL, Guéant JL. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007;13:225–38.
Park H, Kim YJ, Ha EH, Kim KN, Chang N. The risk of folate and vitamin B(12) deficiencies associated with hyperhomocysteinemia among pregnant women. Am J Perinatol. 2004;21:469–75.
Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S, Fisher DJ, et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia. 2008;51:29–38.
Gamble MV, Liu X, Ahsan H, Pilsner R, Ilievski V, Slavkovich V, et al. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh. Environ Health Perspect. 2005;113:1683–8.
Steegers-Theunissen RP, Wathen NC, Eskes TK, van Raaij-Selten B, Chard T. Maternal and fetal levels of methionine and homocysteine in early human pregnancy. Br J Obstet Gynaecol. 1997;104:20–24.
Cikot RJ, Steegers-Theunissen RP, Thomas CM, de Boo TM, Merkus HM, Steegers EA. Longitudinal vitamin and homocysteine levels in normal pregnancy. Br J Nutr. 2001;85:49–58.
Spratlen MJ, Gamble MV, Grau-Perez M, Kuo CC, Best LG, Yracheta J, et al. Arsenic metabolism and one-carbon metabolism at low-moderate arsenic exposure: Evidence from the Strong Heart Study. Food Chem Toxicol. 2017;105:387–97.
Koebnick C, Heins UA, Dagnelie PC, Wickramasinghe SN, Ratnayaka ID, Hothorn T, et al. Longitudinal concentrations of vitamin B(12) and vitamin B(12)-binding proteins during uncomplicated pregnancy. Clin Chem. 2002;48:928–33.
Hall M, Chen Y, Ahsan H, Slavkovich V, van Geen A, Parvez F, et al. Blood arsenic as a biomarker of arsenic exposure: results from a prospective study. Toxicology. 2006;225:225–33.
Kingsley G, Schaffert R, Harris WW. Microdetermination of arsenic and its application to biological material. Anal Chem. 1951;23:914–9.
This research was supported by grants from the National Institute of Environmental Health Sciences (P42-ES005948, R01-ES019315, and T32-ES07018).
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
About this article
Cite this article
Laine, J.E., Ilievski, V., Richardson, D. et al. Maternal one carbon metabolism and arsenic methylation in a pregnancy cohort in Mexico. J Expo Sci Environ Epidemiol 28, 505–514 (2018). https://doi.org/10.1038/s41370-018-0041-1
- Pregnancy Cohort
- Dimethyl Arsenic (DMAs)
- Maternal Urine
- Hcy Levels
- Cord Serum