Researchers have found a new oncogenic（致瘤的） signaling pathway by which the environmental toxin¹（毒素，毒质） arsenic²（砒霜，砷） may lead to adverse³（不利的，相反的） health effects, including bladder（膀胱） cancer. These study results are published in Cancer Research, a journal of the American Association for Cancer Research. "In a collaborative investigation⁴ we found that arsenic, at environmentally relevant levels, is capable of activating⁵ the Hedgehog pathway and may represent a novel pathway of arsenic-associated diseases, such as bladder cancer," said Margaret R. Karagas, Ph.D., professor in the Department of Community and Family Medicine at Dartmouth Medical School.

"We provide important insight into the etiology（病因学，病原学） of arsenic-induced disease, potentially relevant to the millions of people worldwide who are exposed to arsenic," she said.

Arsenic is a well-known environmental toxin and carcinogen（致癌物质） . Studies to date have shown that individuals who live in arsenic contaminated areas of the world exhibit an elevated cancer rate. In many regions of the world, notably⁶（显著地，尤其） Taiwan, Bangladesh（孟加拉国） and Argentina, high levels of arsenic are detected in drinking water, according to Karagas. Here in the United States, Karagas said that arsenic concentrations above the current maximum contaminant level of 10 μg/L are often found in private, unregulated drinking water systems.

While the correlation⁷（相关，关联） between exposure to arsenic resulting in human tumors such as those derived⁸ from bladder, lung and skin is well established, the molecular⁹ mechanisms¹¹ driving this connection is unclear.

Karagas and colleagues examined the hypothesis that the secreted¹² protein called Hedgehog, a key oncogenic signaling pathway, might be activated¹³ by arsenic. Activation¹⁴ might underlie¹⁵ the mechanism¹⁰ by which arsenic acts as a co-carcinogen.

Using experimental data from cell cultures and results of epidemiologic studies, the researchers found that arsenic activates¹⁶ the Hedgehog（刺猬） signaling by decreasing the stability of the repressor form of GLI3, which is one of the transcription factors that regulate Hedgehog activity. Also, Karagas and colleagues found high levels of arsenic exposure associated with high levels of Hedgehog activity.

"Constitutive Hedgehog signaling has been implicated¹⁷ in a wide spectrum¹⁸ of solid tumors," said Anthony Capobianco, Ph.D., editorial board member of Cancer Research. "This group observed increased Hedgehog activity in a large set of human bladder tumors. Interestingly, they also detected a strong correlation between high-level Hedgehog activity and arsenic exposure in this cohort of bladder cancer patients, supporting their mechanistic findings."

Capobianco is director of the Molecular Oncology Research Program in the Division of Surgical¹⁹ Oncology at the Sylvester Comprehensive Cancer Center, University of Miami, and was not associated with this study.

"This report is the first to link arsenic exposure to activation of the signaling pathway and its potential mediator²⁰（均氧还电势物质，电位介体） of arsenic-driven tumors," he said.