The complexity of the human genetics that influence arsenic metabolism in people
Arsenic exposure is associated with an array of adverse health effects including several cancers, as well as nerve and heart diseases. While the most important risk factor is the amount and duration of exposure to arsenic, typically in drinking water, the way that an individual’s body processes the arsenic once it is consumed can either add risk or reduce risk. The metabolism of arsenic in certain individuals leads to the accumulation of a particular chemical form of arsenic called monomethylarsonic acid (MMA). Increased MMA levels are associated with greater risk of developing arsenic-associated diseases. In 2005, SRP researcher, Walt Klimecki, published the first data to suggest that variations in the DNA sequence of a gene (called AS3MT) whose product was key in arsenic metabolism were associated with MMA levels in arsenic exposed people. In December of 2009 Klimecki’s group published a follow-up study that verified the association between AS3MT variations and MMA levels, and went on to describe the complicated arrangement of DNA sequence variations around AS3MT on its human chromosome 10. Work on the project was conducted by a collaborative group including SRP-supported doctoral student, Paulina Gomez-Rubio and researchers at the Technical University of Sonora. The effect of this complexity is that a researcher could test a genetic variation 400,000 bases distant from AS3MT and get almost exactly the same result as if they had tested a genetic variant in AS3MT itself! This can trip-up the unwary scientist because they might believe that they were testing a gene completely different from AS3MT, when in fact they were not. Klimecki points out that this study will be critical to guide researchers who want to uncover the cause of this very strong genetic association that was first discovered, and now validated by the UA Superfund program.
Gomez-Rubio P, Meza-Montenegro MM, Cantu-Soto E, Klimecki WT. Genetic association between intronic variants in AS3MT and arsenic methylation efficiency is focused on a large linkage disequilibrium cluster in chromosome 10. J Appl Toxicol. . [Epub ahead of print]PMID: 20014157
Identification of unusual cellular process triggered by arsenic exposure in immune cells.
Using cultures of human immune cell lines known as lymphoblastoid cell lines (LCL), Superfund researcher, Dr. Walt Klimecki and graduate student, Alicia Bolt studied the way toxic concentrations of arsenic brought about the death of these immune cells. The group expected that a process called apoptosis was at work, since several hundred publications have described this effect of arsenic. To their surprise the group found no indication of apoptosis, but instead they saw signs of another cellular process called autophagy. Autophagy is a coordinated response of cells to stress in which certain damaged or redundant parts of the cell are broken down and degraded within small cellular disposal units called lysosomes. Using several complementary approaches, the group showed that autophagy was induced by arsenic and was associated with the resulting toxicity to these immune cells. Klimecki’s report joins only a handful of publications describing autophagy as an effect of arsenic and opens a new line of research that may explain how arsenic targets the critical function of the immune system in exposed populations. In the long- term, the study offers the prospect of identifying cellular targets that could be used to design interventions to the immune system damage caused by environmental arsenic.
Bolt AM, Byrd RM, Klimecki WT. Autophagy is the predominant process induced by arsenite in human lymphoblastoid cell lines. Toxicol Appl Pharmacol. 2010 Feb 10. [Epub ahead of print]PMID: 20153345