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Extramural Papers of the Month

By Jerry Phelps
January 2008

Beyond the Human Genome Sequence: Scientists Map "Silenced Genes"

NIEHS supported researches have identified and mapped a set of about 200 genes that are turned off or silenced and are believed to play a profound role in people's health. This work marks an important step in studying how the environment interacts with genes to help determine why some people get sick and others don't.

Usually, people inherit two alleles or copies of genes, one from each parent. Typically, both copies are active, but if one copy of a gene becomes mutated and quits working properly, often the other copy can compensate. Genetic imprinting turns off or silences the backup copy. Molecular signals, such as DNA methylation, imprint the copy from the other parent to be silent. Until now, only about 40 human imprinted genes had been identified.

The research team reported that many of the newly found imprinted genes are in regions of chromosomes already linked to the development of obesity, diabetes, cancer and some other major diseases - including several cancers and, possibly, epilepsy and bipolar disorder.

Previous research has indicated that imprinted genes accounted for only about 1 percent of the human genome. While scientists must double-check that the newly identified ones are truly silenced, the new map matches that tally.

Citation: Luedi PP, Dietrich FS, Weidman JR, Bosko JM, Jirtle RL, Hartemink AJ. Exit NIEHS ( 2007. Computational and experimental identification of novel human imprinted genes. Genome Res (12):1723-1730.

Bisphenol A Effects on ER? Expression: Implications in Prostate Cancer

Bisphenol A causes down regulation of gene expression for estrogen receptor ? (ER?) and likely regulates cell proliferation in prostate cancer, according to new research from NIEHS grantees at the University of Cincinnati.

Prostate adenocarcinomas are dependent on the androgen receptor for growth and progression. Current therapies are aimed at repressing androgen receptor activity; however, androgen receptor activity can be reactivated through somatic mutations that form mutant receptors. These altered receptors can be activated by alternative ligands including bisphenol A, an endocrine disrupting chemical that is found in many plastics.

Using a prostate cancer cell line containing mutant androgen receptors and employing DNA microarray analysis, the researchers were able to show that bisphenol A dramatically reduced ER? expresson. Since ER? functions to antagonize the androgen receptor function and androgen receptor-dependent cell proliferation, decreasing its expression could likely lead to growth of prostate tumors. Future research in this laboratory will focus on the contribution of ER? on the bisphenol A-induced proliferative response.

Citation: Hess-Wilson JK, Webb SL, Daly HK, Leung YK, Boldison J, Comstock CE, Sartor MA, Ho SM, Knudsen KE. ( Exit NIEHS 2007. Unique bisphenol A transcriptome in prostate cancer: novel effects on ER beta expression that correspond to androgen receptor mutation status. Environ Health Perspect 115(11):1646-1653.

Regular Use of NSAIDS May Reduce the Risk of Parkinson's Disease

Over-the-counter nonsteroidal anti-inflammatory agents (NSAIDS) reduce the risk of Parkinson's disease (PD) by a little more than half among regular users of these common drugs, according to new NIEHS-supported epidemiologic research. Using as few as two pills per week for as little as one month lowered a person's risk of the disease by 20 percent.

Neuroinflammatory markers, such as the presence of microglia, immune cells within the central nervous system and increased levels of proinflammatory cytokines, are frequently found in the brains and cerebrospinal fluids of PD patients. However, the link between anti-inflammatory agents and Parkinson's in humans remains uncertain, although there is a body of evidence in laboratory animal models of PD that NSAIDS exert a protective effect.

The study participants included 579 men and women, about half of whom had PD. A stronger protective effect was seen for regular users of non-aspirin anti-inflammatory agents. Only 44 percent of non-aspirin users who had taken the drugs regularly for more than 24 months developed Parkinson's. Interestingly, a protective effect for regular aspirin use was only seen in women - reducing their risk by about 40 percent.

Future research by this and other research teams will be focused on trying to determine the exact mechanism by which anti-inflammatory drugs exert this effect.

Citation: Wahner AD, Bronstein JM, Bordelon YM, Ritz B. ( Exit NIEHS 2007. Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease. Neurology 69(19):1836-1842.

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