Researchers identify genetic variants and processes linked to arsenic metabolism and toxicity

Exposure to inorganic arsenic is a global health issue, affecting over 100 million people worldwide. Chronic exposure, even at low doses, is linked to health issues such as cancer, cardiorespiratory disease and other illnesses.

In a study published in the April 1 issue of PLOS Genetics, a University of Chicago-based team working with collaborators in Bangladesh identified a new genetic variant linked to arsenic metabolism and toxicity. Using DNA samples from 1,660 Bangladeshi individuals, the researchers performed a genome-wide association study (GWAS) to look for genetic differences that vary with arsenic content in urine and arsenical skin lesions, one of the early signs of arsenic toxicity and a risk factor for arsenic-induced cancer. They found that a single-nucleotide difference in a gene known as FTCD was closely associated with less efficient arsenic metabolism and increased risk of skin lesions.

“Understanding the genetic basis of how an individual responds to arsenic exposure can help us develop intervention strategies for those with the highest risk for health complications,” said Brandon Pierce, PhD, associate professor in Public Health Sciences and Human Genetics at UChicago and lead author on the study.

Arsenic metabolism

After inorganic arsenic is ingested, it is absorbed into the bloodstream and processed in the liver. There, an enzyme known as AS3MT, or arsenite methyltransferase, converts arsenic into mono- and di-methylated forms (MMA and DMA). DMA is thought to be the least toxic form of arsenic. It is more easily removed from the body in urine, and a greater percentage of DMA in urine is associated with reduced risk of skin lesions and cancer.

In an earlier GWAS study conducted by the same UChicago team, certain variants of the AS3MT gene were found to support more efficient conversion of inorganic arsenic and MMA into DMA. However, few other genetic variants affecting arsenic metabolism have been identified.

“When we saw that a variant in the FTCD gene showed the same association with all three arsenic types, we knew we had found something interesting,” said Pierce, who is also the co-leader of the Cancer Prevention and Control Research Program at the University of Chicago’s Comprehensive Cancer Center.

FTCD codes for an enzyme involved in histidine catabolism, a cellular process upstream of both folate and arsenic metabolism. Pierce says that “The folate cycle supplies methyl groups to AS3MT. Histidine catabolism can contribute methyl groups to this cycle, so our finding suggests that histidine could be an important source of methyl groups for arsenic metabolism.” When these processes are inefficient, arsenic is converted into DMA and excreted at a slower rate, increasing the proportion of more toxic arsenic forms that linger in the body.

The low efficiency allele of FTCD is characterized by a single-nucleotide change in its coding sequence. That change introduces a potential new start site for protein translation. The authors think that it could produce a short, or truncated, form of the FTCD protein. This is important given that FTCD works in units of eight, binding to itself multiple times to form a larger functional structure. Truncated forms of the protein may be less likely to form these larger units, impacting enzyme function and lowering its efficiency.

Mitigating arsenic toxicity

Arsenic occurs naturally in rocks and soil, where it can seep into drinking water and contaminate agricultural products. In Bangladesh alone, over 50 million people are exposed to arsenic at levels over 10 ug/L, making groundwater contamination a public health issue.

Habibul Ahsan, MBBS, MMedSc, senior author on this study, and his colleagues have been conducting research on arsenic exposure in Bangladesh for nearly 20 years. Their initial studies, funded by the National Institute of Environmental and Health Sciences, were an urgent response to the discovery in the 1990s of widespread arsenic exposure in Bangladesh. Most of the damage stemmed from shallow tubewells that drew naturally-contaminated drinking water.

In 2009, Pierce started working with Ahsan, the Louis Block Distinguished Professor of Public Health Sciences, Medicine, and Human Genetics and director of Institute for Population and Precision Health at the University of Chicago. Since then, their research has helped provide a clearer picture of the genetic and environmental factors that affect arsenic metabolism and toxicity.

For example, in another study published May 28, 2019, in the journal Environmental Health Perspectives, the team studied the association between exposure to arsenic and methylation of DNA, a process where chemical molecules are added to DNA in a way that affects its activity without changing the underlying sequence. They identified more than 30 locations in the human genome where exposure to arsenic is likely to modify DNA methylation. These epigenetic alterations, as they are called, can be further investigated as potential mediators in arsenic toxicity and as biomarkers of exposure and effect in exposed populations.

Their ongoing research also has implications for treatment. Dietary folate supplementation has been shown to improve excretion of arsenic as DMA, protecting against its toxic side effects. “By identifying this genetic variant in FTCD,” Pierce said, “we have provided new evidence supporting the well-established hypothesis that modifying folate intake can boost arsenic metabolism and reduce toxicity risk.”

Behavioral changes, too, could help lower toxic effects for at-risk populations in Bangladesh. “Our team is currently conducting research to determine if participants want to receive information on their genetic susceptibility to arsenic,” said Pierce.

In the future, they plan to measure the impact of providing this information to high-risk individuals. The hope, Pierce said, is that this knowledge will “motivate individuals to take exposure-reducing measures, such as switching their drinking source from high arsenic to low arsenic wells and urging their health care providers to enhance surveillance of arsenic-related diseases.” Such actions could help mitigate health risks from arsenic exposure in Bangladesh and beyond.