A Complex Relationship: Dietary Folate, Arsenic Metabolism, and Insulin Resistance in Mice

Abstract

More than 144 million people worldwide are believed to drink water with inorganic arsenic (iAs) concentrations exceeding the World Health Organization guideline of 10 ppb. Consumption of drinking water with high levels of iAs—more than 100 ppb—has been associated with numerous adverse health outcomes in humans, including diabetes.34 A recent study published in Environmental Health Perspectives highlights the potential complexity of the iAs–diabetes relationship: Investigators reported that, under some conditions, dietary folate may modify both iAs metabolism and diabetes-related outcomes in mice. Previous research and known biochemical processes motivated the animal experiments. Several studies have suggested that the way iAs is metabolized may influence the associated health outcomes, including type 2 diabetes.678 Some of the first evidence that folate supplementation may increase the efficiency of human iAs metabolism came from Bangladesh, where exposure to arsenic-contaminated drinking water is much more common than in the United States. In humans and some animal species, iAs is metabolized in multiple methylation steps. The synthesis of an important methyl donor for these reactions requires folate, an essential micronutrient. The enzyme arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes iAs methylation. “Since we wanted to test whether the influence of folate varies by iAs metabolic efficiency, we used wild-type strains and As3mt-knockout mice with a reduced ability to detoxify iAs,” says Madelyn Huang, a postdoctoral fellow at the National Toxicology Program and first author of the new study. “We also compared the same iAs exposure in male and female animals on a low-fat and high-fat diet.” In their study design, the researchers varied four factors: genetic background (wild-type vs. knockout), folate intake (0:2mg=kg vs: 10mg=kg), iAs in drinking water (0 ppb vs. 100 ppb), and dietary fat content. To minimize background dietary iAs, the mice received a purified low-fat diet. After 24 weeks, all the animals were switched to a high-fat diet to see if the added metabolic stress of an obesogenic regimen would alter the separate and combined effects of iAs and folate.