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Extramural Papers of the Month

By Jerry Phelps
October 2008

Arsenic and Type 2 Diabetes

New research findings from the National Health and Nutrition Examination Survey (NHANES) suggest that exposure to levels of arsenic commonly found in drinking water may be a risk factor for type 2 diabetes - suggesting that millions of Americans may be at increased risk.

Data on the nearly 800 participants in the study for which urinary arsenic concentrations were available, indicated that urine levels of arsenic were significantly associated with the prevalence of type 2 diabetes. After splitting the subjects into 5 groups based on the level of arsenic in their urine, the researchers determined that those in the highest category were more than three and one-half times more likely to have diabetes.

Inorganic arsenic in drinking water at concentrations higher than 100 parts per million has been linked to type 2 diabetes in countries where drinking water is commonly contaminated with high levels of arsenic. The U.S. drinking water standard is currently 10 parts per million. However, the researchers estimate that about 13 million Americans live in areas where public water systems exceed the EPA standard for arsenic and this number does not included private wells and water systems.

Animal studies have shown that arsenic affects the production of glucose, insulin secretion and can cause insulin resistance.

Citation: Navas-Acien A, Silbergeld EK, Pastor-Barriuso R, Guallar E. ( Exit NIEHS 2008. Arsenic exposure and prevalence of type 2 diabetes in US adults. JAMA 300(7):814-822.

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Connection Between Built Environment and Obesity

People living in neighborhoods with a high density of fast food restaurants, few sidewalks and no parks are more likely to be part of the estimated 34 percent of the U.S. population aged 20 years or more who are obese, according to NIEHS-supported research by the Oregon Research Institute. In contrast, people living in neighborhoods with higher mixed-land use, high street connectivity, better access to public transportation and more green and open spaces are more likely to engage in some form of neighborhood-based walking program.

This study focused on the baby boom population aged 50-75, which will become the major demographic group in healthcare utilization in the next 20 years. Finding and ameliorating built environment limitations on physical activity are important in keeping this population healthy and reducing the health care burden.

The research findings point to access to unhealthy food and lack of accessibility to spaces for exercise as contributing factors for the rise in obesity. The researchers point out that zoning and development policies need to be altered to enable people to lead healthier lifestyles.

The researchers examined 120 neighborhoods in Portland, Oregon. More than 1,200 residents in these neighborhoods completed questionnaires providing basic demographic data along with information on exercise and eating habits.

Citation: Li F, Harmer PA, Cardinal BJ, Bosworth M, Acock A, Johnson-Shelton D, Moore JM. ( Exit NIEHS 2008. Built environment, adiposity, and physical activity in adults aged 50-75. Am J Prev Med 35(1):38-46.

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p53 Inhibits Cell Growth as well as Cell Proliferation

New research findings by NIEHS grantees indicate that the tumor suppressor gene p53 is involved in regulating the growth of cells as well as the proliferation of cells. The fact that p53 targets genes inhibiting cell proliferation genes had long been known, but its targets for inhibiting cellular growth have not.

The p53 protein acts in the cell nucleus to control the expression of other genes whose products can inhibit the abnormal cell proliferation and growth characteristic of cancer. The researchers discovered that two p53 target genes, known as Sestrin1 and Sestrin2, provide an important link between p53 and a protein kinase called mTOR, a central regulator of cell size. mTOR is the target for the immunosuppressive drug rapamycin, which was recently shown to have anti-cancer activity.

The major tumor suppressor p53 can either inhibit cell proliferation and cell growth or induce cell death. Its different functions are mediated through numerous target genes and depend on the extent of damage to the cell. More than half of all human cancers are either missing p53 expression or express a defective version of the protein. Understanding the mechanisms by which p53 suppresses tumors may lead to the development of new cancer preventives and chemotherapeutic agents.

Citation: Budanov AV, Karin M. ( Exit NIEHS 2008. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134(3):451-460.

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The Ah Receptor is Essential for Mediating an Anti-Inflammatory Effect

A research team made up of NIEHS grantees from the University of Rochester and the University of California, Davis has discovered a potentially new role for the Ah receptor in treating inflammatory or immunologic disorders. This research adds new information on the diverse functions of the receptor, including xenobiotic metabolism, involvement in proper blood vessel formation and now immune responses.

The team happened upon this discovery while investigating a low-molecular-weight compound with potent anti-inflammatory activity known as VAF347. The compound is a drug candidate that inhibits allergic lung inflammation. The team demonstrated that VAF347 interacts with the Ah receptor, resulting in stimulation of its signaling pathway. Additional experiments in Ah receptor-deficient mice confirmed the connection. These mice are resistant to the compound's ability to block allergic lung inflammation. The data indicate that the Ah receptor protein is an important target of VAF347 and is important in mediating the anti-inflammatory effects of the compound.

Although the importance of the Ah receptor in mediating the toxicity of various organic compounds is well known, this finding suggests that harnessing the biological activity of the receptor for therapeutic purposes is possible and suggests a new tool for the treatment of inflammatory and immunologic disorders.

Citation: Lawrence BP, Denison MS, Novak H, Vorderstrasse BA, Harrer N, Neruda W, Reichel C, Woisetschl├Ąger M. ( Exit NIEHS 2008. Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound. Blood 112(4):1158-1165.

(Jerry Phelps is a program analyst in the Program Analysis Branch of the NIEHS Division of Extramural Research and Training. Each month, he contributes summaries of extramural papers to the Environmental Factor.)

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