Arsenic: The missing link?

Researchers have discovered a mechanism that may explain the link between long-term exposure to arsenic in drinking water and cancer of the bladder, lungs, skin, kidney, nasal passages, liver, and prostate. Paradoxically, the mechanism that empowers arsenic as a tumor promoter also seems to be closely linked to arsenic’s effectiveness in the treatment of some forms of leukemia.

The findings could have implications for the U.S. EPA’s new 10 parts-per-billion (ppb) rule for arsenic in drinking water. Although the lowest concentration of arsenic trioxide used in this latest experiment by Wen-Chien Chou of Johns Hopkins University and colleagues was 20 ppb, the researchers say this same mechanism could play a role in chronic exposure to arsenic at very low levels.

Studying arsenic trioxide’s exposure on various cell lines, including leukemia, cervical cancer, and breast cancer, Chou and colleagues observed a marked decrease in telomerase activity. Telomerase is an enzyme that maintains the length of chromosomal ends, or telomeres, which otherwise would become progressively shorter after each cell division. For most advanced tumors, telomere maintenance is essential for continued proliferation. In healthy, noncancerous cells, however, the loss of telomeres could lead to genomic instabilities and the formation of cancerous cells.

The researchers found that arsenic inhibits the transcription of the human gene, hTERT, which in turn inhibits telomerase expression. The inhibition was dose-related and occurred with arsenic concentrations at or lower than those measured in plasma taken from human subjects exposed to the metal in pharmacokinetic studies.

The authors believe that the inhibition of hTERT is the result of decreased activity of c-Myc and Sp1 transcription factors—proteins that promote the conversion of DNA sequences into corresponding RNA—in the exposed cultures. However, this explanation leaves open the questions of why other processes in which Sp1 plays a role are less affected by arsenic and whether the inhibitory effect of arsenic on other genes may also contribute to the decrease in hTERT expression and telomere maintenance. (J. Clin. Invest. 2001, 108, 1541–1547). —KRIS CHRISTEN