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Extramural Papers of the Month

By Jerry Phelps
December 2009

Chronic Glucocorticoid Use Raises Risk of Bladder Cancer

The most recent study by NIEHS grantee Margaret Karagas at Dartmouth University reports that chronic use of glucocorticoid drugs is a risk factor for bladder cancer. The findings appear in the British Journal of Cancer.

Glucocorticoids are often prescribed for immunosuppressive therapy for organ transplant patients, asthma sufferers, or people with an autoimmune disorder such as rheumatoid arthritis. The study matched 786 bladder-cancer patients to 1,083 control subjects. The risk of bladder cancer was three-fold higher for people who had taken glucocorticoids for more than five years.

These results raise the possibility of an increased risk of bladder cancer from long-term use of glucocorticoids and a potential role of immunological effects in bladder cancer etiology.

Citation: Dietrich K, Schned A, Fortuny J, Heaney J, Marsit C, Kelsey KT, Karagas MR. ( NIEHS 2009. Glucocorticoid therapy and risk of bladder cancer. Br J Cancer 101(8):1316-1320.

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Discovery in Aflatoxin Formation

A Nature article by NIEHS grantee Craig Townsend reports advances in the understanding of how the fungal toxin aflatoxin is synthesized, opening new avenues that might lead to possible methods to prevent the formation of the toxin and its harmful effects.

Aflatoxin is produced by molds in the aspergillus family. They are ubiquitous and are found in many crops such as corn, rice, wheat and peanuts. The toxin is consumed directly by eating contaminated crops or by drinking milk from cows fed contaminated food stuffs. The toxin is a known human carcinogen causing liver cancer.

Using x-ray crystallography, the research team determined the three-dimensional structure of an enzyme in the polyketide synthase family, which is a component of the multi-step process of toxin synthesis. They discovered a region known as the product template domain responsible for producing a precursor of the toxin. The researchers hope to further their discoveries and possibly develop a method to prevent the formation of aflatoxin.

Citation: Crawford JM, Korman TP, Labonte JW, Vagstad AL, Hill EA, Kamari-Bidkorpeh O,Tsai SC, Townsend CA. ( NIEHS 2009. Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization. Nature 461(7267):1139-43.

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Bacterial Toxin Linked to Parkinson's

NIEHS-funded researchers in Alabama discovered that a common soil bacterium produces a metabolite that disrupts a protein degradation pathway associated with Parkinson's disease. This finding suggests that exposures to metabolites from common bacteria may contribute to the development of Parkinson's disease.

Parkinson's disease is a progressive neurodegenerative disorder involving the loss of dopamine producing neurons from the substantia nigra region of the brain. For the past several years, scientists have speculated that environmental causes of the disease are more important than genetics because studies in twins suggest that genetic predisposition is only possibly responsible for the disease occurrence. A clinical hallmark of the disease is misfolding and accumulation of proteins, such as α-synuclein, in inclusions called Lewy Bodies.

In the current study, funded through an exploratory R21 grant, Alabama scientists discovered that a common streptomyces bacterium found in soil produces a natural proteosome inhibitor that blocks protein degradation and causes gradual degeneration of all neuronal cells examined. Dopamine neurons were particularly vulnerable to the metabolites effects. The studies were carried out in a Parkinson's disease model using the nematode C. elegans.

Citation: Caldwell KA, Tucci ML, Armagost J, Hodges TW, Chen J, Memon SB, Blalock JE, DeLeon SM, Findlay RH, Ruan Q, Webber PJ, Standaert DG, Olson JB, Caldwell GA. ( NIEHS 2009. Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration. PLoS One 4(10):e7227.

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Social Isolation Speeds Breast Tumor Growth

A socially-isolated and stressful environment may speed up the growth of breast tumors according to NIEHS-supported researchers at the University of Chicago. The effects are believed to be caused by changes in gene expression in mammary glands.

Previous human epidemiologic studies have shown a link between cancer and stress. The current study was conducted in a strain of laboratory mice genetically susceptible to breast cancer. Mice are generally very social animals and social isolation is recognized as a severe stressor for them. Mice were randomly assigned to be isolated at a very early age. The isolated mice developed larger and more breast cancers than the group-housed mice.

Gene expression changes in mammary tissue were also measured in the mice. Genes involved in metabolism were turned on and off in the isolated mice in a very reproducible manner. Certain metabolic pathways and changes are known to contribute to the increased growth of breast cancer. The isolated mice also had much higher stress hormone levels than their group-housed counterparts.

These findings are preliminary, but suggest that reducing stress and increasing social activity may be important factors in the prevention and treatment of breast cancer in women.

Citation: Williams JB, Pang D, Delgado B, Kocherginsky M, Tretiakova M, Krausz T, Pan D, He J, McClintock MK, Conzen SD. ( NIEHS 2009. A model of gene-environment interaction reveals altered mammary gland gene expression and increased tumor growth following social isolation. Cancer Prev Res (Phila Pa). 2(10):850-61.

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

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