UMaine Research Studies the Effects of Arsenic on the Cell

Science has long known that arsenic is toxic to humans. Exposure to high doses over a brief period can lead rapidly to organ failure and death. At lower doses over a longer time, arsenic exposure is associated with cancer, diabetes, impaired neurological development, behavioral changes and more.

But the mechanism of arsenic’s toxicity is poorly understood. To complicate matters, it appears that some of the same qualities that make it so deadly may actually have a therapeutic effect in specific circumstances. And, importantly, since arsenic is all around us, most people have some exposure.

At the University of Maine’s Department of Molecular and Biomedical Sciences, professors Carol Kim and Julie Gosse are learning more about arsenic and the ways it functions in the body. By advancing scientific understanding of its mechanisms, they hope to promote science-based environmental regulations and medical interventions that can mitigate arsenic’s toxic effects.

Like its elemental cousins lead and mercury, arsenic (As) is found in naturally occurring deposits from which it leaches into water and soils. It also can be released more rapidly into the environment through natural processes, such as volcanic activity and erosion, and through human activity such as mining and agriculture.

Arsenic is found in manufactured products as well, including wood preservatives, paints, dyes, metals, soaps and medicines, and workers in these industries may be exposed. Arsenic-containing waste is present in many landfills and dumps. In some cultures, arsenic in high doses has been used as an effective therapy for acute asthma attacks, although its mechanism has been poorly understood and its therapeutic value is offset by its long-term risks.

In Maine, arsenic is present in many public and private water supplies, most often at levels below the 10 parts per billion (ppb) cap designated as “safe” by the U.S. Environmental Protection Agency, following a 2001 rule change that took effect in 2006. Prior to this change, the EPA’s allowable standard was 50 ppb.

Public water supplies are closely monitored for arsenic and that information is available to the public through individual water utilities and the governmental agencies that oversee them. But private wells are unregulated and may contain much higher levels. Concerns remain that exposure to arsenic over time — even at very low levels, perhaps below the current 10 ppb limit — poses a significant and pernicious risk to human health.

Arsenic contamination from both naturally occurring deposits and human-produced pollution is a problem across the country, but particularly in Maine and New Hampshire, says Carol Kim, director of UMaine’s Graduate School of Biomedical Sciences, who has been conducting research since 1998 on innate immunity and infectious diseases, using zebrafish as a model organism.

Kim’s most recent project studies the effects of low levels of arsenic — like those found in drinking water — on a healthy innate immune response and one compromised by the gene mutation that causes cystic fibrosis. Her study is funded by a $1.8 million grant from the National Institutes of Health, part of an $11 million NIH grant to Dartmouth Medical School. The principal investigator is Jason Moore, a computational geneticist at Dartmouth Medical School.

The project draws on the strength of two major milestones in Kim’s lab: the development of a zebrafish model for studying cystic fibrosis, funded in 2005 with an NIH grant of more than $405,000; and a 2007 discovery showing that arsenic exposure at levels deemed safe in human drinking water suppressed the overall innate immune health of zebrafish, causing increased susceptibility to viral and bacterial infections.

“We’re trying to understand how arsenic exacerbates cystic fibrosis and the extent to which this effect is brought about by exposure to arsenic as an environmental toxicant,” Kim says.

Cystic fibrosis is the most common fatal genetic disease in the United States, according to NIH’s National Human Genome Research Institute. An estimated 30,000 people in the U.S. have the disease, which is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR). Approximately 10 million Americans carry the defective CFTR gene.

In normal cells, the CFTR protein serves as a channel, allowing cells to release chloride and water into the lungs. However, in people with cystic fibrosis, the protein is defective and the cells do not release the chloride, resulting in an improper salt balance and less water on the lung surfaces, producing abnormally thick mucus.

The gene mutations cause increased susceptibility to Pseudomonas aeruginosa, a common bacterium in water and soil. P. aeruginosa is the cause of chronic infection and irreparable lung tissue scarring in 80 percent of cystic fibrosis patients in their late teens, Kim says. Yet the bacterium is not a common lung pathogen in people with healthy immune systems.

“We’re trying to understand how arsenic exacerbates cystic fibrosis and the extent to which this effect is brought about by exposure to arsenic as an environmental toxicant.” Carol Kim

Kim’s research has shown that the zebrafish’s ability to resist bacterial and viral infection is compromised by exposure to arsenic. She hopes to identify genes and pathways involved in modulating innate immunity in response to arsenic exposure, as well as CFTR modulation. Her data will be shared with a Dartmouth-based biostatistician and a bioinformatics specialist to help identify sets of human genes and signaling pathways that contribute to the innate immune response, respond to arsenic and are influenced by CFTR.

With the NIH grant, Dartmouth Medical School will establish an NIH Center of Biomedical Research Excellence to advance biomedical research and foster collaboration among scientists from UMaine, Harvard, Jackson Laboratory, Mount Desert Island Biological Laboratory, Maine Medical Center, University of New Hampshire, University of Southern Maine and University of Vermont.

“There is real potential to find genes associated with CF and to identify potential drug targets that could reduce or eliminate many of the debilitating effects of the disease,” Kim says.

There have been a lot of recent studies about arsenic, says Julie Gosse, “but we need to fill in some of the gaps.” Gosse specializes in the study of biochemical, molecular and cellular toxicology with the long-term goal of protecting humans from environmental health risks. At UMaine, she and her students are examining arsenic’s molecular activity and its impact on the immune system.

Gosse is looking at mast cells, a type of immune cell found in most bodily tissues that plays a key role in triggering allergies, asthma and inflammation. Mast cells also protect the body from certain types of parasites. By treating rat mast cells with arsenic, Gosse has determined that exposure inhibits the mast cell process known as degranulation, in which the cells release histamine and other chemicals into blood and tissue.

The result of normal degranulation is localized swelling, warmth, redness, itching and pain. In humans, degranulation can cause allergic reactions, such as asthma and eczema. But degranulation also triggers a healthy immune response that helps fight off parasites and other human pathogens.

Since arsenic is a known endocrine disrupter, Gosse says, it may inhibit normal degranulation by blocking estrogen signaling involved in histamine release. Or, as recent data suggest, the process may be taking place at an early step in the signaling pathway, such as by inhibition of tyrosine phosphorylation, an important signaling process in mast cells.

“We don’t fully understand the molecular mechanism yet,” Gosse says. She and her students continue to work with rat mast cells and now with human mast cells. In the future, Gosse plans to extend her arsenic research into zebrafish.

It is much too early to apply her findings to human health models, but Gosse says her research may help shed some light on the success of traditional Chinese healers in treating acute asthma attacks with high doses of arsenic.

Although the inhibition of degranulation effectively calms swollen and inflamed respiratory tissues, the long-term results of this treatment often include serious chronic illnesses, such as cancer and neurological disorders. And in populations where persistent intestinal parasites cause serious diarrheal diseases and anemia in children, such as in Bangladesh, consistently elevated levels of arsenic in drinking water supplies may be suppressing healthy immune response and promoting generalized muscle wasting and related disorders.

Gosse came to UMaine in 2008 after completing her post-doctoral work at Dartmouth Medical School. Her work here, funded by the PhRMA Foundation, the Maine Agricultural and Forest Experiment Station, and UMaine start-up funds, builds on recent studies at Dartmouth that first identified arsenic as an endocrine disrupter.

“Someday, this could point to a drug target,” Gosse says of her research. She envisions a safe medical alternative that would mimic arsenic’s valuable suppressive effects for disorders such as asthma or autoimmune disorders, without undermining overall immune response — and without arsenic’s potentially lethal risks.