The toxic metals arsenic and uranium may interact to contribute to the development of diabetes in American Indians, according to NIEHS-funded research. The study, published Aug. 5 in the journal Environment International, is unique because it reveals how co-exposure to multiple metals may affect metabolism in humans.

“This study presents an atlas of metal exposure on human metabolites and provides important preliminary evidence toward the identification of metabolic signatures of metal mixtures,” said first author Tiffany Sanchez, Ph.D., from Columbia University.

Among her other research efforts, Sanchez aims to identify early molecular signs of disease resulting from exposure to metals. (Photo courtesy of Tiffany Sanchez)

“Understanding the biochemical networks underlying metabolic homeostasis and their association with exposure to multiple metals may help identify novel biomarkers, pathways of disease, and potential signatures of environmental metal exposure,” she noted.

Solving the metal-metabolism mystery

People are exposed to different levels of metals through food, water, and air. Some metals, such as molybdenum, selenium, and zinc, are essential for performing normal biological functions but can be toxic at high levels. In contrast, metals such as arsenic, cadmium, lead, and uranium are non-essential and play a role in the development of cardiovascular disease, kidney disease, neurological problems, and certain types of cancer.

Previous research has revealed how interactions between two metals affect biological pathways, but the effects of exposure to multiple metals have not been clear. This uncertainty extends to metabolism, according to Sanchez.

“While past studies have shown how individual metals affect metabolites, the interactive effects of metals have largely been a mystery,” she noted.

To help fill this knowledge gap, Sanchez and her collaborators leveraged data from the Strong Heart Family Study. Funded by the National Institutes of Health, the study has provided extensive information on the health effects of metals in American Indians living in rural and small-town communities in the United States.

Other NIEHS grantees have investigated longstanding arsenic and uranium exposure in the Navajo Nation. (Photo courtesy of Autumn’s Memories / Shutterstock.com)

The researchers analyzed metals in urine samples and metabolites in blood samples from 145 study participants. Specifically, they examined the relationship between 8,810 metabolic features and urinary levels of antimony, cadmium, lead, molybdenum, selenium, tungsten, uranium, zinc, and four different forms of arsenic.

Overall, the metals affected three main metabolic pathways related to fatty acids, amino acids, and energy. Most metals were associated with distinct subsets of metabolites. However, inorganic arsenic and uranium were clustered together through shared metabolites among the 50 participants who developed diabetes five years later. This interaction was not present in participants who did not develop diabetes.

Past research in humans has shown that arsenic is associated with type 2 diabetes, but the role of uranium in this disease has been less clear. In the new study, participants who developed diabetes had higher arsenic levels, as expected. However, their uranium levels were not higher than those of participants without diabetes, which suggested that the health effects of uranium may be exacerbated by co-exposure to other metals such as arsenic.

“The findings highlight the complexity of metabolism, which involves thousands of connected chemical reactions,” Sanchez said. “Because the results differed across metals, future studies with larger populations will be needed to confirm the metal-metal interactions we detected.”

Citation: Sanchez TR, Hu X, Zhao J, Tran V, Loiacono N, Go YM, Goessler W, Cole S, Umans J, Jones DP, Navas-Acien A, Uppal K. 2021. An atlas of metallome and metabolome interactions and associations with incident diabetes in the Strong Heart Family Study. Environ Int 157:106810.

(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)