Associations between Methylated Metabolites of Arsenic and Selenium in Urine of Pregnant Bangladeshi Women and Interactions between the Main Genes Involved

Abstract

Background:It has been proposed that interactions between selenium and arsenic in the body may affect their kinetics and toxicity. However, it is unknown how the elements influence each other in humans.Objectives:We aimed to investigate potential interactions in the methylation of selenium and arsenic.Methods:Urinary selenium (U-Se) and arsenic (U-As) were measured using inductively coupled plasma mass spectrometry (ICPMS) in samples collected from pregnant women (n=226) in rural Bangladesh at gestational weeks (GW) 8, 14, 19, and 30. Urinary concentrations of trimethyl selenonium ion (TMSe) were measured by HPLC–vapor generation–ICPMS, as were inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA). Methylation efficiency was assessed based on relative amounts (%) of arsenic and selenium metabolites in urine. Genotyping for the main arsenite and selenium methyltransferases, AS3MT and INMT, was performed using TaqMan probes or Sequenom.Results:Multivariable-adjusted linear regression analyses indicated that %TMSe (at GW8) was positively associated with %MMA (β=1.3, 95% CI: 0.56, 2.0) and U-As, and inversely associated with %DMA and U-Se in producers of TMSe (INMT rs6970396 AG+AA, n=74), who had a wide range of urinary TMSe (12–42%). Also, %TMSe decreased in parallel to %MMA during pregnancy, especially in the first trimester (−0.58 %TMSe per gestational week). We found a gene–gene interaction for %MMA (p-interaction=0.076 for haplotype 1). In analysis stratified by INMT genotype, the association between %MMA and both AS3MT haplotypes 1 and 3 was stronger in women with the INMT GG (TMSe nonproducers, 5th–95th percentile: 0.2–2%TMSe) vs. AG+AA genotype.Conclusions:Our findings for Bangladeshi women suggest a positive association between urinary %MMA and %TMSe. Genes involved in the methylation of selenium and arsenic may interact on associations with urinary %MMA. https://doi.org/10.1289/EHP1912

Production of a Urinary Selenium Metabolite, Trimethylselenonium, by Thiopurine S-Methyltransferase and Indolethylamine N-Methyltransferase

“…Animals may have a redundant metabolic system against the biologically and toxicologically ambivalent nutrient, Se. The genetic polymorphism of INMT was also reported. , Our findings support the literature addressing that the amount of TMSe in urine is dependent on the genetic polymorphism of INMT and suggest that INMT is actually required in Se excretion in humans.…”

“…Indolethylamine N -methyltransferase (INMT) is another methyltransferase that catalyzes double methylation of tryptamine to produce N , N -dimethyltryptamine . The TMSe concentration in blood and urine correlated with single nucleotide polymorphisms in the INMT gene by a genome wide association study between the TMSe-producing and nonproducing individuals. , Previous works suggested that mouse and human INMT proteins drove the methylation of dimethylsulfide, dimethylselenide, and dimethyltelluride as substrates. , However, it is still unclear how INMT commits to produce TMSe for urinary Se excretion.…”

Association between Arsenic Methylation in Early Pregnancy and Gestational Diabetes Mellitus: A Prospective Cohort Study

“…The metabolism of arsenic changes throughout the course of pregnancy. 25,26 The first trimester was suggested to be the critical period of arsenic exposure in the etiology of GDM. 15,27 Thus, it is important to investigate arsenic species and methylation capacity in the first trimester to adequately explore the relationship between arsenic methylation and GDM.…”

“…Two studies compared the methylation indices between GDM and non-GDM groups and found no significant differences. , These studies, however, have only focused on urine samples collected in the second trimester when an oral glucose tolerance test (OGTT) was taken. The metabolism of arsenic changes throughout the course of pregnancy. , The first trimester was suggested to be the critical period of arsenic exposure in the etiology of GDM. , Thus, it is important to investigate arsenic species and methylation capacity in the first trimester to adequately explore the relationship between arsenic methylation and GDM.…”