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Association of plasma folate, vitamin B12 levels, and arsenic methylation capacity with developmental delay in preschool children in Taiwan

  • Inorganic Compounds
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Abstract

Developmental delay has been associated with inefficient arsenic methylation capacity in preschool children. Folate and vitamin B12 are important nutrients that produce s-adenosylmethionine during single-carbon metabolism and provide methyl groups for arsenic methylation. The aim of the present study was to explore whether plasma folate and vitamin B12 levels influence arsenic methylation capacity and in turn are related to developmental delay in preschool children. A case–control study was conducted in 178 children with developmental delay and 88 normal children, who were recruited from Shin Kong Wu Ho-Su Memorial Teaching Hospital from August 2010 to March 2014. Arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) in the urine was determined by high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Plasma folate and vitamin B12 levels were measured using a SimulTRAC-SNB radioassay. The results show that the combination of high plasma folate and high vitamin B12 levels were correlated with efficient arsenic methylation capacity (low MMAV %, low InAs %, and high DMAV %). High MMAV % significantly increased and high DMAV % and secondary methylation index decreased the odds ratio (OR) of developmental delay in a dose-dependent manner in both low plasma folate and low vitamin B12 (low/low) groups; the multivariate OR and 95% confidence interval were 5.01 (0.83–30.06), 0.21 (0.04–1.23), and 0.20 (0.03–1.20), respectively. This is the first study to show that the combination of high plasma folate and high vitamin B12 levels increases arsenic methylation capacity and indirectly decreases the OR of developmental delay in preschool children.

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References

  • Beck WS (1991) Neuropsychiatric consequences of cobalamin deficiency. Adv Intern Med 36:33–56

    CAS  PubMed  Google Scholar 

  • Bozack AK, Hall MN, Liu X, Ilievski V, Lomax-Luu AM, Parvez F, Siddique AB, Shahriar H, Uddin MN, Islam T, Graziano JH, Gamble MV (2019) Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh. Am J Clin Nutr 109:380–391

    Article  PubMed  Google Scholar 

  • Caramaschi D, Sharp GC, Nohr EA, Berryman K, Lewis SJ, Davey SG, Relton CL (2017) Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child’s IQ at age 8, cognitive performance and educational attainment: a two-step Mendelian randomization study. Hum Mol Genet 26:3001–3013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan W, Almasieh M, Catrinescu MM, Levin LA (2018) Cobalamin-associated superoxide scavenging in neuronal cells is a potential mechanism for Vitamin B12-deprivation optic neuropathy. Am J Pathol 188:160–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang H, Zhang T, Zhang Z, Bao R, Fu C, Wang Z, Bao Y, Li Y, Wu L, Zheng X, Wu J (2011) Tissue-specific distribution of aberrant DNA methylation associated with maternal low-folate status in human neural tube defects. J Nutr Biochem 22:1172–1177

    Article  CAS  PubMed  Google Scholar 

  • Dominguez-Salas P, Moore SE, Baker MS, Bergen AW, Cox SE, Dyer RA, Fulford AJ, Guan Y, Laritsky E, Silver MJ, Swan GE, Zeisel SH, Innis SM, Waterland RA, Prentice AM, Hennig BJ (2014) Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun 5:3746

    Article  CAS  PubMed  Google Scholar 

  • Dosman CF, Andrews D, Goulden KJ (2012) Evidence-based milestone ages as a framework for developmental surveillance. Paediatr Child Health 17:561–568

    Article  PubMed  PubMed Central  Google Scholar 

  • Du X, Tian M, Wang X, Zhang J, Huang Q, Liu L, Shen H (2018) Cortex and hippocampus DNA epigenetic response to a long-term arsenic exposure via drinking water. Environ Pollut 234:590–600

    Article  CAS  PubMed  Google Scholar 

  • Eichner ER, Hillman RS (1971) The evolution of anemia in alcoholic patients. Am J Med 50:218–232

    Article  CAS  PubMed  Google Scholar 

  • Froese DS, Fowler B, Baumgartner MR (2019) Vitamin B12, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. J Inherit Metab Dis 42:673–685

    Article  CAS  PubMed  Google Scholar 

  • Gamble MV, Liu X, Ahsan H, Pilsner JR, Ilievski V, Slavkovich V, Parvez F, Chen Y, Levy D, Factor-Litvak P, Graziano JH (2006) Folate and arsenic metabolism: a double-blind, placebo-controlled folic acid-supplementation trial in Bangladesh. Am J Clin Nutr 84:1093–1101

    Article  CAS  PubMed  Google Scholar 

  • Gamboa-Loira B, Hernandez-Alcaraz C, Gandolfi AJ, Cebrian ME, Burguete-Garcia A, Garcia-Martinez A, Lopez-Carrillo L (2018) Arsenic methylation capacity in relation to nutrient intake and genetic polymorphisms in one-carbon metabolism. Environ Res 164:18–23

    Article  CAS  PubMed  Google Scholar 

  • Gueant JL, Caillerez-Fofou M, Battaglia-Hsu S, Alberto JM, Freund JN, Dulluc I, Adjalla C, Maury F, Merle C, Nicolas JP, Namour F, Daval JL (2013) Molecular and cellular effects of vitamin B12 in brain, myocardium and liver through its role as co-factor of methionine synthase. Biochimie 95:1033–1040

    Article  CAS  PubMed  Google Scholar 

  • Hall MN, Gamble MV (2012) Nutritional manipulation of one-carbon metabolism: effects on arsenic methylation and toxicity. J Toxicol 2012:595307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamadani JD, Tofail F, Nermell B, Gardner R, Shiraji S, Bottai M, Arifeen SE, Huda SN, Vahter M (2011) Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study. Int J Epidemiol 40:1593–1604

    Article  CAS  PubMed  Google Scholar 

  • Homberg JR, Kyzar EJ, Scattoni ML, Norton WH, Pittman J, Gaikwad S, Nguyen M, Poudel MK, Ullmann JF, Diamond DM, Kaluyeva AA, Parker MO, Brown RE, Song C, Gainetdinov RR, Gottesman II, Kalueff AV (2016) Genetic and environmental modulation of neurodevelopmental disorders: translational insights from labs to beds. Brain Res Bull 125:79–91

    Article  PubMed  Google Scholar 

  • Hsieh RL, Huang YL, Shiue HS, Huang SR, Lin MI, Mu SC, Chung CJ, Hsueh YM (2014) Arsenic methylation capacity and developmental delay in preschool children in Taiwan. Int J Hyg Environ Health 217:678–686

    Article  CAS  PubMed  Google Scholar 

  • Hsieh RL, Su CT, Shiue HS, Chen WJ, Huang SR, Lin YC, Lin MI, Mu SC, Chen RJ, Hsueh YM (2017) Relation of polymorphism of arsenic metabolism genes to arsenic methylation capacity and developmental delay in preschool children in Taiwan. Toxicol Appl Pharmacol 321:37–47

    Article  CAS  PubMed  Google Scholar 

  • Hsueh YM, Huang YL, Huang CC, Wu WL, Chen HM, Yang MH, Lue LC, Chen CJ (1998) Urinary levels of inorganic and organic arsenic metabolites among residents in an arseniasis-hyperendemic area in Taiwan. J Toxicol Environ Health A 54:431–444

    Article  CAS  PubMed  Google Scholar 

  • Kvestad I, Hysing M, Shrestha M, Ulak M, Thorne-Lyman AL, Henjum S, Ueland PM, Midttun O, Fawzi W, Chandyo RK, Shrestha PS, Strand TA (2017) Vitamin B-12 status in infancy is positively associated with development and cognitive functioning 5 year later in Nepalese children. Am J Clin Nutr 105:1122–1131

    Article  CAS  PubMed  Google Scholar 

  • Lai DC, Tseng YC, Guo HR (2018) Characteristics of young children with developmental delays and their trends over 14 years in Taiwan: a population-based nationwide study. BMJ Open 8:e020994

    Article  PubMed  PubMed Central  Google Scholar 

  • Lintas C (2019) Linking genetics to epigenetics: the role of folate and folate-related pathways in neurodevelopmental disorders. Clin Genet 95:241–252

    Article  CAS  PubMed  Google Scholar 

  • McGarel C, Pentieva K, Strain JJ, McNulty H (2015) Emerging roles for folate and related B-vitamins in brain health across the lifecycle. Proc Nutr Soc 74:46–55

    Article  CAS  PubMed  Google Scholar 

  • Moore CL, Flanigan TJ, Law CD, Loukotkova L, Woodling KA, da Costa GG, Fitzpatrick SC, Ferguson SA (2019) Developmental neurotoxicity of inorganic arsenic exposure in Sprague-Dawley rats. Neurotoxicol Teratol 72:49–57

    Article  CAS  PubMed  Google Scholar 

  • Rush EC, Katre P, Yajnik CS (2014) Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease. Eur J Clin Nutr 68:2–7

    Article  CAS  PubMed  Google Scholar 

  • Singh M (2004) Role of micronutrients for physical growth and mental development. Indian J Pediatr 71:59–62

    Article  PubMed  Google Scholar 

  • Styblo M, Del Razo LM, Vega L, Germolec DR, LeCluyse EL, Hamilton GA, Reed W, Wang C, Cullen WR, Thomas DJ (2000) Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Arch Toxicol 74:289–299

    Article  CAS  PubMed  Google Scholar 

  • Su CT, Hsieh RL, Chung CJ, Huang PT, Lin YC, Ao PL, Shiue HS, Chen WJ, Huang SR, Lin MI, Mu SC, Hsueh YM (2019) Plasma selenium influences arsenic methylation capacity and developmental delays in preschool children in Taiwan. Environ Res 171:52–59

    Article  CAS  PubMed  Google Scholar 

  • Suren P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T, Schjolberg S, Davey SG, Oyen AS, Susser E, Stoltenberg C (2013) Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA 309:570–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ulak M, Chandyo RK, Thorne-Lyman AL, Henjum S, Ueland PM, Midttun O, Shrestha PS, Fawzi WW, Graybill L, Strand TA (2016) Vitamin status among breastfed infants in Bhaktapur, Nepal. Nutrients 8:149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vahter M (2000) Genetic polymorphism in the biotransformation of inorganic arsenic and its role in toxicity. Toxicol Lett 112–113:209–217

    Article  PubMed  Google Scholar 

  • Veena SR, Krishnaveni GV, Srinivasan K, Wills AK, Muthayya S, Kurpad AV, Yajnik CS, Fall CH (2010) Higher maternal plasma folate but not vitamin B-12 concentrations during pregnancy are associated with better cognitive function scores in 9- to 10-year-old children in South India. J Nutr 140:1014–1022

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Shangguan S, Xin Y, Chang S, Wang Z, Lu X, Wu L, Niu B, Zhang T (2017) Folate deficiency disturbs hsa-let-7 g level through methylation regulation in neural tube defects. J Cell Mol Med 21:3244–3253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang B, Liu J, Liu B, Liu X, Yu X (2018) Prenatal exposure to arsenic and neurobehavioral development of newborns in China. Environ Int 121:421–427

    Article  CAS  PubMed  Google Scholar 

  • Wasserman GA, Liu X, Parvez F, Chen Y, Factor-Litvak P, Loiacono NJ, Levy D, Shahriar H, Uddin MN, Islam T, Lomax A, Saxena R, Gibson EA, Kioumourtzoglou MA, Balac O, Sanchez T, Kline JK, Santiago D, Ellis T, van Geen A, Graziano JH (2018) A cross-sectional study of water arsenic exposure and intellectual function in adolescence in Araihazar, Bangladesh. Environ Int 118:304–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Li X, Sun Q, He B, Jia Y, Cai D, Zhao R (2016) Folate deprivation induces cell cycle arrest at G0/G1 phase and apoptosis in hippocampal neuron cells through down-regulation of IGF-1 signaling pathway. Int J Biochem Cell Biol 79:222–230

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciate the assistance with the recruitment of study subjects provided by Drs. Tseng-Chen Sung, Cheng Hui Lin, and Ling-Jen Wang of the Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital. The present study was supported by grants from Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (SKH-TMU-102-10, SKH-TMU-100-06, and SKH-TMU-99-03), the National Science Council (NSC 100-2314-B-038 -026, NSC 101-2314-B-038 -051-MY3 (1-3), NSC 101-2314-B-038 -051-MY3 (2-3), NSC 101-2314-B-038 -051-MY3 (3-3)), and the Ministry of Science and Technology of the Republic of China (MOST103-2314-B-038-021-MY2 (1-2), MOST103-2314-B-038-021-MY2 (2-2), MOST 105-2314-B-038-082, MOST 106-2314-B-038-066, and MOST 107-2314-B-038-073).

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Lin, YC., Chung, CJ., Huang, YL. et al. Association of plasma folate, vitamin B12 levels, and arsenic methylation capacity with developmental delay in preschool children in Taiwan. Arch Toxicol 93, 2535–2544 (2019). https://doi.org/10.1007/s00204-019-02540-4

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