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Extramural Papers of the Month

By Jerry Phelps
February 2009

Selenium May Prevent High-Risk Bladder Cancer

NIEHS grantees at Dartmouth Medical School report in a new study that selenium may help prevent high-risk bladder cancer. The study found that women, moderate smokers and people with p53-positive tumors showed significant reductions in bladder cancer with higher selenium intake.

In the U.S., bladder cancer is the fourth most common cancer among men and the twelfth most common among women with approximately 67,000 cases being diagnosed each year. About 13,000 deaths are expected this year from bladder cancer. Bladder cancer develops through different pathways, but one of the major paths is through alterations in the p53 gene. These cancers are associated with more advanced disease.

The study involved 857 people with newly diagnosed bladder cancer. Selenium intake was measured by analyzing toenail clippings. Cancer risk was reduced 30 to 50 percent in the three groups as selenium intake increased.

The exact mechanism by which selenium inhibits carcinogenesis is unknown, but it may occur through several mechanisms, including reducing oxidative stress and inflammation, enhanced immune responses and activation of DNA repair genes. The results of this study may provide clues on how to prevent tumors from developing and potentially lead to new chemotherapeutic agents.

Citation: Wallace K, Kelsey KT, Schned A, Morris JS, Andrew AS, Karagas MR. ( Exit NIEHS 2009. Selenium and risk of bladder cancer: a population-based case-control study. Cancer Prev Res (Phila Pa) 2(1):70-73.

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Gene Packaging is Important in Cancer

New NIEHS-supported research suggests that the packaging of genes may be as important as the genes themselves when it comes to the development and treatment of cancer. The findings point to the three dimensional chromatin packaging around genes formed by tight loops of polycomb group (PcG) proteins. Chromatin packaging is a complex combination of DNA and proteins that compresses the DNA to fit inside the cell nucleus and keep genes in a low expression state.

The researchers compared embryonic cells to adult colon cancer cells. The gene studied, GATA-4, is packaged by PcG proteins. In the embryonic cells the gene is in a low expression state and has no methylation. When the gene received signals for the cells to mature, the protein structures were disrupted and the gene was highly expressed. However, when the same gene was methylated, as is the case in the colon cancer cells, the PcG protein packaging loops were tighter and there was no gene expression. When the researchers removed the methylation, the cancer cells behaved similarly to the embryonic cells.

When the normal processes are disrupted and some genes are improperly methylated, important tumor suppressing cell functions can shut down. This research suggests that for therapies that remove abnormal DNA methylation from genes to be fully effective, researchers may need to search for agents that disrupt the PcG protein loops.

Citation: Tiwari VK, McGarvey KM, Licchesi JD, Ohm JE, Herman JG, Schübeler D, Baylin SB. ( Exit NIEHS 2008. PcG proteins, DNA methylation, and gene repression by chromatin looping. PLoS Biol 6(12):2911-2927.

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Dopamine Transmission Impaired by Manganese

NIEHS grantees report that manganese exposure inhibits dopamine neurotransmission from the substantia nigra region of the brain, leading to motor activity impairments resembling those seen in Parkinson's disease. These results follow on previous studies from their laboratory using cynomolgus macaques. Previous research has shown that these monkeys show cognitive and fine motor deficits in response to manganese exposure.

The debilitating neurological condition manganism results from chronic high-dose exposure to the essential trace mineral manganese. Manganese-induced parkinsonism most often results from high exposure in industrial settings related to steel production; however, other sources include the impairment of manganese excretion in some liver diseases, high doses of manganese from parenteral nutrition, illicit psychostimulant drugs and, possibly, ambient concentrations generated from gasoline containing the additive methylcyclopentadienyl manganese tricarbonyl.

The monkeys were treated weekly with manganese doses ranging from 3.3-10 milligrams per kilogram body weight from seven up to 59 weeks. They received PET scans prior to the beginning of dosing and at one or two time points during the exposure. The researchers found that amphetamine-induced dopamine release was markedly reduced in the manganese-exposed animals. They concluded that the manganese exposure is responsible for the motor deficits documented in the monkeys. These findings may have implications for the prevention and treatment of symptoms of parkinsonism.

Citation: Guilarte TR, Burton NC, McGlothan JL, Verina T, Zhou Y, Alexander M, Pham L, Griswold M, Wong DF, Syversen T, Schneider JS. ( Exit NIEHS 2008. Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): implications to manganese-induced parkinsonism. J Neurochem (5):1236-1247.

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Dioxin Disrupts Prostate Development

Researchers at the University of Wisconsin in Madison have determined the mechanism by which dioxin disrupts prostate gland formation in laboratory mice. They found that when dioxin is administered maternally at days 15 and 16 of gestation, the chemical inhibits the formation of certain prostate buds in two different regions (ventral and dorsolateral).

Members of this research team have previously shown that dioxin exposure during the fetal and neonatal periods inhibits prostate budding, thereby reducing the number of prostate ducts and causing a reduction in prostate size. There is also a growing body of scientific evidence that dioxin exposure in humans causes prostate cancer.

Experimental results show that hyperactivation of the aryl hydrocarbon receptor signaling pathway changes the patterning of the fetal urogenital sinus, disrupting where prostate buds develop and where prostate lobes are formed. The current study presents a new paradigm of how in utero dioxin exposure disrupts prostate formation, suggesting this same mechanism may in part explain how dioxin impairs the development of other organs and tissues.

Citation: Vezina CM, Allgeier SH, Moore RW, Lin TM, Bemis JC, Hardin HA, Gasiewicz TA, Peterson RE ( Exit NIEHS. 2008. Dioxin causes ventral prostate agenesis by disrupting dorsoventral patterning in developing mouse prostate. Toxicol Sci 106(2):488-96.

(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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