Analysis of maternal polymorphisms in arsenic (+3 oxidation state)-methyltransferase AS3MT and fetal sex in relation to arsenic metabolism and infant birth outcomes: Implications for risk analysis

Drobná, Zuzana; Martin, Elizabeth M.; Kim, Kyung Soo; Smeester, Lisa; Bommarito, Paige A.; Rubio-Andrade, Marisela; Garcı́a-Vargas, Gonzalo G.; Stýblo, Miroslav; Zou, Fei; Fry, Rebecca C.

doi:10.1016/j.reprotox.2016.02.017

Cited by 27 publications

(13 citation statements)

References 55 publications

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“…). The AS3MT minor allele frequencies in this population were similar to previously published studies from Mexico [Drobná et al, ], Bangladesh [Engström et al, ], and Mongolia [Chen et al, ] (Fig. ).…”

Section: Resultssupporting

confidence: 90%

“…A more recent in vitro investigation confirmed that N6AMT1 is involved in MMA III methylation, but its effects were secondary to AS3MT [Zhang et al, 2015]. Although several epidemiology studies have found associations between AS3MT polymorphisms and the proportion of MMA in urine [Engstr€ om et al, 2011[Engstr€ om et al, , 2007Pierce et al, 2012;Drobn a et al, 2016], few have examined cancer risk in the same study population [Chung et al, 2009;Engstr€ om et al, 2015], and only two have assessed the role of N6AMT1 polymorphisms in arsenic metabolism [Harari et al, 2013;Chen et al, 2017].…”

Section: Introductionmentioning

confidence: 99%

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Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N‐6 adenine‐specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

Rosa

Steinmaus

Akers

et al. 2017

Environ and Mol Mutagen

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Inter-individual differences in arsenic metabolism have been linked to arsenic-related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic iAs metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = −1.9%, 95% CI: −3.3, −0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR=0.3; 95% CI: 0.1–0.6) and lung cancer (OR=0.6; 95% CI: 0.2–1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N‐6 adenine‐specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

Rosa

Steinmaus

Akers

et al. 2017

Environ and Mol Mutagen

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show abstract

“…The inflammatory response in women pregnant with a male infant was much more robust than that observed in women pregnant with a female infant. These results provide molecular support for previous research demonstrating that iAs-associated diseases may be more severe in male infants and children that experience in utero iAs exposure [10,14,49]. The genes identified as differentially expressed in association with urinary arsenic species were also significantly associated with birth outcomes, namely gestational age, birth weight, birth length, and ponderal index.…”

Section: Discussionsupporting

confidence: 86%

“…This highlights that women pregnant with male infants may experience a more robust inflammatory response to iAs exposure. This is supported by research demonstrating that males may experience greater risk of certain diseases associated with prenatal iAs exposure compared to females [14,23,49]. These differentially expressed genes are involved in Toll-like receptor signaling and tumor necrosis factor (TNF) production.…”

Section: Discussionmentioning

confidence: 92%

Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire

Bommarito

Martin

Smeester

et al. 2017

Reproductive Toxicology

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Exposure to inorganic arsenic (iAs) during pregnancy is associated with adverse health outcomes present both at birth and later in life. A biological mechanism may include epigenetic and genomic alterations in fetal genes involved in immune functioning. To investigate the role of the maternal immune response to in utero iAs exposure, we conducted an analysis of the expression of immune-related genes in pregnant women from the New Hampshire Birth Cohort Study. A set of 31 genes was identified with altered expression in association with levels of urinary total arsenic, urinary iAs, urinary monomethylated arsenic and urinary dimethylated arsenic. Notably, maternal gene expression signatures differed when stratified on fetal sex, with a more robust inflammatory response observed in male pregnancies. Moreover, the differentially expressed genes were also related to birth outcomes. These findings highlight the sex-dependent nature of the maternal iAs-induced inflammatory response in relationship to fetal outcomes.

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“…However, in Maine, exposure to drinking water levels greater than only 5 μg/L iAs is associated with a decrease of 5–6 Full Scale IQ, Verbal Comprehension, Working Memory, and Perceptual Reasoning IQ points in children 27 . The disparity in these results may be related to several factors, including (1) nutritional differences between these populations 76 , (2) potential differences in susceptibility between populations with respect to the particular effects of iAs 77 , and possibly (3) difficulties in quantifying and comparing neurodevelopmental indicators, such as IQ, between culturally different populations. The differences between the magnitude of these effects and possible underlying factors represent the challenge presented by identifying the critical dose ranges for iAs-associated health outcomes.…”

Section: Discussionmentioning

confidence: 99%

Developmental windows of susceptibility to inorganic arsenic: a survey of current toxicologic and epidemiologic data

Bommarito

Fry

2016

Toxicol. Res.

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Globally, millions of people are exposed to elevated levels of inorganic arsenic (iAs) via drinking water. Exposure to iAs is associated with a wide range of negative health outcomes, including cancers, skin lesions, neurological impairment, cardiovascular diseases, and an increased susceptibility to infection. Among those exposed to iAs, the developing fetus and young children represent particularly sensitive subpopulations. Specifically, it has been noted in animal models and human populations that prenatal and early life iAs exposures are associated with diseases occurring during childhood and later in life. Recent epidemiologic and toxicologic studies have also demonstrated that epigenetic alterations may play a key mechanistic role underlying many of the iAs-associated health outcomes, including the carcinogenic and immunologic effects of exposure. This review summarizes some of the key studies related to prenatal and early life iAs exposure and highlights the complexities in isolating the precise developmental windows of exposure associated with these health outcomes.

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Analysis of maternal polymorphisms in arsenic (+3 oxidation state)-methyltransferase AS3MT and fetal sex in relation to arsenic metabolism and infant birth outcomes: Implications for risk analysis

Cited by 27 publications

References 55 publications

Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N‐6 adenine‐specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N‐6 adenine‐specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire

Developmental windows of susceptibility to inorganic arsenic: a survey of current toxicologic and epidemiologic data

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