Arsenic is a naturally occurring metalloid found in groundwater, soil, and certain crops across much of the world, and chronic exposure is well established as a risk factor for cardiovascular disease, cancers, and skin lesions. Once absorbed, inorganic arsenic does not simply accumulate unchanged. The body metabolizes it in two successive methylation steps, enzymatically attaching methyl groups to convert inorganic arsenic into monomethylated arsenic, or MMA, and then into dimethylated arsenic, or DMA. These methylated forms are excreted in urine, and for decades the methylation process was considered detoxifying, since the fully dimethylated product is generally less reactive at the cellular level than its predecessors. But this conventional wisdom has been increasingly challenged by studies hinting that trivalent intermediates formed along the pathway may be more toxic than the parent compound itself.

The MANOS research team, led by Margaret Quaid of Boston University School of Public Health together with collaborators at institutions in the United States, El Salvador, and Nicaragua, set out to examine whether specific arsenic metabolism profiles were associated with blood pressure among working men in a region where both arsenic exposure and an unexplained kidney disease overlap. The study included 393 male participants drawn from the broader occupational cohort, and the researchers measured the concentrations of inorganic arsenic, MMA, and DMA in urine samples, expressing each species as a percentage of the total inorganic and methylated arsenic. Blood pressure outcomes included systolic pressure, diastolic pressure, pulse pressure, and mean arterial pressure, all adjusted for age, body mass index, worksite, pesticide use, smoking status, and water consumption.

The results revealed a pattern that at first glance seems counterintuitive. Participants with higher percentages of DMA, the end product of complete arsenic methylation, tended to have higher systolic blood pressure and wider pulse pressure. In the conventional models, each percentage point increase in DMA was associated with a 0.17 millimeter of mercury increase in systolic pressure and a 0.14 millimeter of mercury increase in pulse pressure. Conversely, participants with higher percentages of MMA, indicating incomplete methylation, showed lower systolic and pulse pressures, with each percentage point increase in MMA corresponding to a 0.37 and 0.31 millimeter of mercury decrease respectively. In other words, the men whose bodies pushed arsenic metabolism further along the detoxification pathway were the ones showing elevated cardiovascular readings, not those who stalled at an intermediate step.

Because the three urinary metabolite percentages are mathematically interdependent, the researchers took care to disentangle their individual contributions using two additional analytical strategies. In leave-one-out models, they evaluated the relative effect of two species while statistically holding the third constant. These models reinforced the initial findings: higher DMA at the expense of MMA was associated with increased systolic blood pressure, with an effect estimate of 0.33 millimeters of mercury per percentage point, and increased pulse pressure of 0.29 millimeters of mercury per percentage point. A third approach using principal components analysis, a statistical technique that compresses correlated variables into independent axes representing the two methylation steps, provided converging evidence. The component capturing the second methylation step, the conversion of MMA to DMA, was associated with a 0.93 millimeter of mercury increase in systolic pressure and a 0.74 millimeter of mercury increase in pulse pressure.

The consistency of the effect across three distinct modeling frameworks lends weight to the authors’ conclusion that efficient methylation of inorganic arsenic all the way to DMA is associated with higher blood pressure compared with partial methylation to MMA. This finding complicates the simplistic narrative of methylation as unambiguously protective. It aligns instead with a growing body of research suggesting that the methylation process may generate intermediate trivalent species, such as monomethylarsinous acid, which are highly reactive and can disrupt cellular signaling, endothelial function, and oxidative stress pathways. If the second methylation step is inefficient at clearing these intermediates, or if individuals who methylate rapidly accumulate different arsenic species in tissues, the downstream cardiovascular consequences could differ in ways that conventional toxicity rankings fail to capture.

The biological mechanisms linking arsenic metabolism to blood pressure remain under active investigation, but several plausible pathways have been proposed. Arsenic exposure has been associated with impaired nitric oxide signaling, increased oxidative stress, vascular inflammation, and alterations in arterial stiffness, all of which can elevate systolic pressure and widen pulse pressure, a marker of arterial aging. The methylation process itself consumes methyl groups supplied by S-adenosyl methionine, drawing on one-carbon metabolism, a biochemical network that also regulates homocysteine levels and DNA methylation. Variation in the arsenite methyltransferase gene, known as AS3MT, and in nutritional factors such as folate and B vitamins can shift an individual’s metabolic profile substantially, meaning that two people exposed to identical arsenic levels may carry very different internal arsenic species distributions. The MANOS findings suggest these individual differences are not mere biochemical trivia but may carry meaningful cardiovascular consequences.

The context of the study population adds an important dimension to the findings. MesoAmerican nephropathy, also referred to as chronic kidney disease of unknown etiology, is an epidemic affecting agricultural workers along the Pacific coast of Central America, and arsenic exposure has been proposed among the candidate causes, alongside heat stress, dehydration, and pesticide exposures. By focusing on working men in sugarcane communities in El Salvador and Nicaragua, the MANOS investigators examined arsenic metabolism in a real-world setting of intense occupational and environmental stressors, rather than in a general population survey. The cross-sectional design means the study captures a single moment in time and cannot establish whether arsenic metabolism patterns cause the blood pressure differences or reflect some underlying physiological state. The authors are careful to frame the results as an association, and reverse causation or residual confounding cannot be excluded, particularly in a workforce with high rates of kidney impairment that could alter arsenic excretion.

Nevertheless, the study carries practical implications for how researchers and clinicians think about arsenic risk. Most environmental health surveillance measures total urinary arsenic, treating exposure as a single number. The MANOS results argue that the speciation profile, meaning the relative proportions of inorganic arsenic, MMA, and DMA, conveys additional information about cardiovascular vulnerability that total exposure alone would miss. If future longitudinal studies confirm that the second methylation step is genuinely associated with elevated blood pressure, then arsenic metabolism biomarkers could become part of cardiovascular risk assessment in exposed populations, helping to identify individuals who, despite similar exposure levels, face different health trajectories. Such work would also sharpen the search for modifiable factors, such as nutrition and one-carbon metabolism support, that shape methylation capacity and might therefore mediate arsenic’s cardiovascular effects.

For now, the study stands as a reminder that the body’s handling of a poison can be as consequential as the poison itself. In the cane fields of Central America, where arsenic, kidney disease, and hypertension intersect in an unfolding public health crisis, understanding the chemistry of methylation may prove essential to protecting the hearts and kidneys of the people who live and labor there. The researchers emphasize the importance of arsenic metabolism profiles in cardiovascular risk assessment, and their findings open a clear path for follow-up studies that follow exposed workers over time, track their metabolic profiles, and test whether the blood pressure patterns observed here translate into hypertension, arterial disease, and cardiovascular events in the years ahead.

Subject of Research: The association between arsenic metabolism profiles and blood pressure in MesoAmerican agricultural workers

Article Title: The association of arsenic metabolism and blood pressure: a cross-sectional analysis in the MesoAmerican Nephropathy Occupational Study (MANOS)

Article References: Quaid, M., Rodgers, K., Velázquez, J. J. A., García-Trabanino, R., Jarquin, E., Lopez-Pilarte, D., Leibler, J., Brooks, D., Glabonjat, R. A., Navas-Acien, A., Argos, M., & Scammell, M. K. (2026). The association of arsenic metabolism and blood pressure: a cross-sectional analysis in the MesoAmerican Nephropathy Occupational Study (MANOS). Environmental Health. https://doi.org/10.1186/s12940-026-01333-4

Image Credits: AI Generated

DOI: 10.1186/s12940-026-01333-4

Keywords: arsenic, arsenic metabolism, blood pressure, methylation, MMA, DMA, hypertension, MesoAmerican nephropathy, El Salvador, Nicaragua, environmental health, cardiovascular risk