Early-Life Arsenic Exposure, Nutritional Status, and Adult Diabetes Risk

Abstract

Purpose of review: In utero influences, including nutrition and environmental chemicals, may induce long-term metabolic changes and increase diabetes risk in adulthood. This review evaluates the experimental and epidemiological evidence on the association of early-life arsenic exposure on diabetes and diabetes-related outcomes, as well as the influence of maternal nutritional status on arsenic-related metabolic effects.

Recent findings: Five studies in rodents have evaluated the role of in utero arsenic exposure with diabetes in the offspring. In four of the studies, elevated post-natal fasting glucose was observed when comparing in utero arsenic exposure with no exposure. Rodent offspring exposed to arsenic in utero also showed elevated insulin resistance in the 4 studies evaluating it as well as microRNA changes related to glycemic control in 2 studies. Birth cohorts of arsenic-exposed pregnant mothers in New Hampshire, Mexico, and Taiwan have shown that increased prenatal arsenic exposure is related to altered cord blood gene expression, microRNA, and DNA methylation profiles in diabetes-related pathways. Thus far, no epidemiologic studies have evaluated early-life arsenic exposure with diabetes risk. Supplementation trials have shown B vitamins can reduce blood arsenic levels in highly exposed, undernourished populations. Animal evidence supports that adequate B vitamin status can rescue early-life arsenic-induced diabetes risk, although human data is lacking. Experimental animal studies and human evidence on the association of in utero arsenic exposure with alterations in gene expression pathways related to diabetes in newborns, support the potential role of early-life arsenic exposure in diabetes development, possibly through increased insulin resistance. Given pervasive arsenic exposure and the challenges to eliminate arsenic from the environment, research is needed to evaluate prevention interventions, including the possibility of low-cost, low-risk nutritional interventions that can modify arsenic-related disease risk.

Keywords: Arsenic; Diabetes; Early-life exposures; Nutrition; One-carbon metabolism.

Fig 1.. One-carbon metabolism.

Folic acid is reduced to dihydrofolate and tetrahydrofolate (THF). A one-carbon unit is transferred from serine to THF to form 5,10-methylene-THF which is used for thymidylate synthesis or reduced to 5-methyl-THF. Dietary folate can enter one-carbon metabolism as 5-mTHF. The one-carbon unit is transferred to homocysteine by methionine synthase using the cofactor vitamin B12, forming methionine and THF. Homocysteine can also be remethylated using betaine as the methyl donor. Methionine is activated to S-adenosylmethionine (SAM), which serves as the methyl donor for reactions including arsenic methylation. Methylation reactions generate the methylated product and S-adenosylhomocysteine (SAH), an inhibitor of methyltransferase enzymes. SAH is hydrolyzed to homocysteine, and can be remethylated or be used in the transsulfuration pathway.

Fig 2.. Folate/B12 supplementation.

Diets supplemented with higher folate + vitamin B12 supplementation rescued elevated fasting glucose levels induced by arsenic in utero as compared with an adequate (normal) diet. (Adapted from Huang et al.).

Fig 3.. Major dietary sources of one-carbon metabolism (OCM) related nutrients.

Foods listed under OCM nutrients are considered to be high dietary sources of that nutrient (provide 20% or more of the daily value). (Modified from Spratlen MJ et al.).