Early-Life Arsenic Exposure: Methylation Capacity and Beyond

Environ Health Perspect. doi:10.1289/ehp.11276 available via http://dx.doi.org [Online 19 February 2008]

Inorganic arsenic (iAs), a toxic metalloid, affects millions of people worldwide, mainly from drinking contaminated water. Arsenic is a human carcinogen that targets skin, lung, bladder, and possibly other sites. iAs and its methylated metabolites readily cross the placenta and reach the fetus [National Research Council (NRC) 1999], producing effects ranging from developmental toxicity to cancer (NRC 1999; Waalkes et al. 2007). Thus, early-life As exposures are drawing escalating health concerns.

In this issue of Environmental Health Perspectives, Li et al. (2008) report on iAs metabolism in pregnant Bangladeshi women exposed to iAs through contaminated water. iAs is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) for urinary excretion; urinary As speciation is widely used to assess As methylation capacity. Arsenic methylation capacity can be influenced by dietary intake of cysteine, methionine, folic acid, niacin, vitamin B12, and choline (Steinmaus et al. 2005), and dietary folic acid supplementation to malnourished arsenicosis patients can decrease As burden by decreasing blood MMA and increasing urinary DMA (Gamble et al. 2007). However, despite poor micronutrient status and high As exposure, the pregnant Bangladeshi women showed remarkably efficient As methylation. The median percentage of urinary DMA (74%) is in the upper range, and MMA (11%) in the lower range of what is commonly seen in urine of individuals from developed counties with much better nutrition (Vahter 2007). Women during childbearing years are more efficient at As methylation than men (Lindberg et al. 2007), particularly during pregnancy. This is likely due to the de novo synthesis of choline by the phosphatidylethanolamine methyltransferase (PEMT) pathway (Vahter 2007), which can be up-regulated by estrogen. Thus, the PEMT pathway may function in malnourished pregnant women to increase choline production needed for fetal development, and, perhaps fortuitously for As methylation (Vahter 2007).

The remarkable efficiency of As methylation in malnourished pregnant women could also be an adaptive response to As exposure. Such adaptation might increase As methylation, and thereby excretion, during pregnancy, but perhaps at the expense of later toxicity. Methyl groups from S-adenosylmethionine are essential to both As and DNA methylation. DNA methylation status is a well-recognized controlling factor in gene expression. Furthermore, alterations in DNA methylation status are a recognized epigenetic mechanism in As carcinogenesis and are linked with As exposure in various systems (Pilsner et al. 2007; Waalkes et al. 2004). Gestation is a critical period of cell differentiation and genetic programming during development, and a highly sensitive time for initiation of chemical carcinogenesis (Waalkes et al. 2007). Thus, adaptation to As methylation in malnourished pregnant women could impact fetal development via altered gene expression. Activation of the PEMT pathway through estrogen signaling is clearly beneficial for As methylation (Vahter 2007). In contrast, aberrant estrogen signaling is linked with transplacental As carcinogenesis in mice (Waalkes et al. 2004, 2007). Arsenic also has potential synergistic effects with estrogenic carcinogens (Waalkes et al. 2007). Indeed, when in utero As exposure is followed by diethylstilbestrol treatment in newborn mice, tumors at multiple sites show synergistic increases in adulthood, including various estrogen sensitive targets (Waalkes et al. 2007).

Recent data show that early-life As exposure has significant impact on human health (Fry et al. 2007; Smith et al. 2006). In newborns from mothers exposed to iAs through contaminated water in Thailand, altered transcript profiles in cord blood include stress-related genes and breast cancer/estrogen-signature genes (Fry et al. 2007), suggesting an adaptive response to As and pointing toward future health issues. Smith et al. (2006) observed a remarkable increase in lung cancer incidence in young adults in Chile who had been exposed to iAs in utero; this suggests a human transplacental carcinogenic potential for As. Thus, regardless of the immediate temporal tolerance to As during pregnancy, preventing early-life As exposure of the fetus and improving nutritional status of pregnant women may be critical for the health of future generations.

The authors declare they have no competing financial interests.

Michael P. Waalkes
Jie Liu
Laboratory of Comparative Carcinogenesis
National Cancer Institute at the National Institute of Environmental Health Sciences
National Institutes of Health
Department of Health and Human Services
Research Triangle Park, North Carolina
E-mail: waalkes@niehs.nih.gov

Michael P. Waalkes received a Ph.D. in 1981 from West Virginia University, with subsequent postdoctoral work at the University of Kansas. He joined the National Cancer Institute (NCI) in 1983, became chief of the Inorganic Carcinogenesis Section in 1992, and was later detailed to the NIEHS. He has > 300 publications and is now the editor of Toxicology and Applied Pharmacology. He is also on EHP's Advisory Board.

Jie Liu graduated from University of Kansas Medical Center in 1992 and is a staff scientist at the National Cancer Institute. He has been active in metal toxicology and carcinogenesis studies and in molecular mechanism studies of transplacental arsenic carcinogenesis.

References

Fry RC, Navasumrit P, Valiathan C, Svensson JP, Hogan BJ, Luo M, et al. 2007. Activation of inflammation/NF-kappaB signaling in infants born to arsenic-exposed mothers. PLoS Genet 3(11):e207; doi: 10.1371/journal.pgen.0030207.

Gamble MV, Liu X, Slavkovich V, Pilsner JR, Ilievski V, Factor-Litvak P, et al. 2007. Folic acid supplementation lowers blood arsenic. Am J Clin Nutr 86: 1202–1209.

Li L, Ekström E-C, Goessler W, Lönnerdal B, Nermell B, Yunus M, et al. 2008. Nutritional status has marginal influence on the metabolism of inorganic arsenic in pregnant Bangladeshi women. Environ Health Perspect 116:315–321.

Lindberg AL, Kumar R, Goessler W, Thirumaran R, Gurzau E, Koppova K, et al. 2007. Metabolism of low-dose inorganic arsenic in a central European population: influence of sex and genetic polymorphisms. Environ Health Perspect 115:1081–1806.

NRC (National Research Council). 1999. Arsenic in Drinking Water. Washington, DC:National Academy Press.

Pilsner JR, Liu X, Ahsan H, Ilievski V, Slavkovich V, Levy D, et al. 2007. Genomic methylation of peripheral blood leukocyte DNA: influences of arsenic and folate in Bangladeshi adults. Am J Clin Nutr 86: 1179–1186.

Smith AH, Marshall G, Yuan Y, Ferreccio C, Liaw J, von Ehrenstein O, et al. 2006. Increased mortality from lung cancer and bronchiectasis in young adults after exposure to arsenic in utero and in early childhood. Environ Health Perspect 114:1293–1296.

Steinmaus C, Carrigan K, Kalman D, Atallah R, Yuan Y, Smith AH. 2005. Dietary intake and arsenic methylation in a U.S. population. Environ Health Perspect 113: 1153–1159.

Vahter ME. 2007. Interactions between arsenic-induced toxicity and nutrition in early life. J Nutr 137:2798–2804.

Waalkes MP, Liu J, Chen H, Xie Y, Achanzar WE, Zhou YS, et al. 2004. Estrogen signaling in livers of male mice with hepatocellular carcinoma induced by exposure to arsenic in utero. J Natl Cancer Inst 96:466–474.

Waalkes MP, Liu J, Diwan BA. 2007. Transplacental arsenic carcinogenesis in mice. Toxicol Appl Pharmacol 222:271–280.