Public health experts estimate that more than 200 million people worldwide are exposed to arsenic through contaminated drinking water. Scientists know long-term exposure to arsenic is associated with increased risk of chronic illnesses like cancer and cardiovascular disease, but there hasn't been a reliable way to track these exposures and fully understand their effects on the body and the mechanisms behind them.
A new study led by researchers at the University of Chicago addresses this challenge, shedding light on how arsenic leaves its mark on human DNA and offering a potential new tool for exposure assessment. In the International Journal of Epidemiology , the researchers describe a robust DNA methylation-based biomarker associated with arsenic exposure that can predict toxicity risk and serve as a model for developing other epigenetic biomarkers to help track — and potentially mitigate — the health effects of environmental toxins.
Studying a large, high-exposure population
The researchers analyzed blood samples from over 1,100 adults in Bangladesh, where arsenic contamination in well water presents a serious and persistent public health challenge. Using advanced DNA methylation arrays, the team scanned more than 700,000 sites across the genome, searching for patterns that correlated with arsenic levels measured in participants' urine.
"This was a significant leap in scale and resolution," said lead author James Li, PhD , a UChicago MD/PhD student. "Our large sample size and wide range of exposure levels enabled us to identify more sites in the epigenome linked to arsenic exposure than any previous study in adults."
The team found 1,177 sites in the genome that were significantly associated with arsenic exposure, most of which hadn't been identified before. Going a step further, they employed an analytical approach called Mendelian randomization to assess whether arsenic exposure causally impacts DNA methylation at these sites in the epigenome, rather than merely showing correlation. This kind of statistical analysis is important because there is no ethical way to study something potentially harmful like arsenic exposure in a classic randomized trial.
"Mendelian randomization helped us rule out other variables, allowing us to say not just that arsenic and DNA methylation are associated, but that the way someone's body metabolizes arsenic is likely to cause these changes in DNA methylation," said senior author Brandon Pierce, PhD , incoming Chair of the Department of Public Health Sciences at UChicago.
Developing and validating an epigenetic biomarker
The researchers then set out to distill their genome-wide findings into a measurable signature of DNA methylation that could estimate an individual's arsenic exposure from a blood sample. Using 255 of the sites they identified, they could robustly predict urinary arsenic levels, arsenical skin lesions — blemishes that are a clinically visible sign of how arsenic poisons the body — and overall mortality.
"Arsenic has a relatively short half-life in the body after someone drinks contaminated water, so exposure levels measured in urine samples may be liable to fluctuations," Li said. "DNA methylation changes are thought to be more stable, so building a biomarker lets us capture more information about biological effects over time."
This biomarker proved to be predictive even outside the original Bangladeshi cohort. When tested in an entirely different population in the United States, where overall arsenic exposures are much lower, it still succeeded in estimating arsenic exposure, albeit with reduced precision. To date, it proved to be the best-performing epigenetic marker for exposure to a single toxin, including those developed for alcohol consumption and lead exposure.
"I was surprised at how well the predictor worked, even in a completely different population with much lower exposures," Pierce said. "This gives us hope that epigenetic biomarkers are a promising avenue for estimating historical exposure to environmental chemicals."
Many of the genome sites the researchers identified as most closely associated with arsenic exposure matched up very closely with sites that had been previously linked to chronic conditions like heart disease, type 2 diabetes, and various cancers, aligning with known health effects associated with arsenic exposure.
"While it doesn't definitively prove that DNA methylation directly causes these downstream health effects, we're showing very strong evidence that these epigenetic changes may help explain the link between arsenic and associated health conditions," Li said.
Pierce added, "It's an important reminder that environmental exposures really do 'get under your skin,' leaving an imprint on you via changes in how your genome functions."
" The impact of arsenic exposure on DNA methylation in humans: building an epigenetic biomarker of exposure across three independent cohorts " was published in the International Journal of Epidemiology in April 2026. Co-authors are James L Li, Niyati Jain, Lizeth I Tamayo, Lin Tong, Kathryn Demanelis, Farzana Jasmine, Muhammad G Kibriya, Lin S Chen, Arce Domingo-Relloso, Anne K Bozack, Ana Navas-Acien, Habibul Ahsan & Brandon L Pierce.
