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Extramural Papers of the Month

By Jerry Phelps
June 2009


Alzheimer's Disease Linked to Mitochondrial Damage

New research findings suggest that preventing S-nitrosylation of the mitochondrial protein Drp1 by the free radical nitric oxide may reduce or even prevent neurodegeneration in Alzheimer's patients.

The NIEHS-supported research team found that S-nitrosylated Drp1facilitates mitochondrial fragmentation, which leads to synaptic injury and eventual nerve cell death. This finding helps to explain how beta-amyloid protein causes neurodegeration. Beta-amyloid protein is the source of the nitric oxide, which reacts with Drp1. By identifying Drp1 as the protein responsible for the synaptic injury, the investigators have discovered a new target for developing drugs that may stop or slow the progression of Alzheimer's.

Drp1 is an enzyme that mediates fission or fragmentation of mitochondria. The team showed that excessive nitric oxide production caused damage to Drp1 which leads to excessive mitochondrial fragmentation in cultured nerve cells. Elevated levels of S-nitrosylated Drp1 were also found in the brains of Alzheimer's patients, but not in those with Parkinson's disease or controls who didn't have neurodegenerative disease, adding additional evidence to the in vitro findings.

Finally, experiments to decrease Drp1 activity, either using RNA interference or a mutation that prevented Drp1 activity, inhibited excess mitochondrial damage and protected the neurons. These findings suggest that drugs or interventions to prevent damage to Drp1could prove to be effective prevention or treatment strategies for Alzheimer's disease.

Citation: Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. (http://www.ncbi.nlm.nih.gov/pubmed/19342591?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS 2009. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324(5923):102-105.

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Swine Flu Susceptibility Linked to Arsenic Exposure

Low-level exposure to arsenic at concentrations found commonly in U.S. drinking water compromises the initial immune response to H1N1 or swine flu infection according to NIEHS-supported scientists. The study, conducted in laboratory mice, suggests that people exposed to arsenic in their drinking water may be at increased risk for more serious illness or death in response to infection from the virus.

The arsenic-exposed mice initially showed a weak immune response to the virus, and when the immune response fully developed, it was "too robust and too late," according to the study's senior author, Josh Hamilton. The late influx of immune cells to the lung and the inflammatory response caused lung damage and bleeding not seen in the control animals. Over the course of the infection, the death rate in arsenic-exposed animals was much higher than the non-exposed mice.

The current U.S. EPA drinking water standard is 10 parts per billion; however, 100 parts per billion levels are commonly found in well water in areas where arsenic is geologically abundant such as New England, Florida, large portions of the Midwest, the Southwest and the Rocky Mountains. The authors also point out that high levels of arsenic in drinking water are common in the areas of Mexico where swine flu was initially reported.

Citation: Kozul CD, Ely KH, Enelow RI, Hamilton JW. (http://ehp.niehs.nih.gov/0900911/) 2009. Low dose arsenic compromises the immune response to influenza A infection in vivo. Environ Health Perspect. doi: 10.1289/ehp.0900911

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Gene May Be Linked to Lung Cancer

Recent research from the Environmental Health Sciences Center at the University of Cincinnati indicates that a gene found on chromosome 6 known as RGS17 may be a lung cancer susceptibility gene. The researchers found a significant association between three single nucleotide polymorphisms in the gene and lung cancer susceptibility. These results were confirmed in two separate familial lung cancer populations with a combined total of 380 lung cancer cases and 638 controls.

In addition to the human studies, transgenic mouse experiments were conducted as well. The animal studies showed inhibition of lung tumor cell proliferation and the development of tumors in mice when RGS17 gene expression was decreased.

Cigarette smoking is the number one cause of lung cancer. However, only 15-18 percent of heavy smokers develop lung cancer and some people who never smoke develop the disease. These studies point to a genetic link that may help to explain both phenomena and could lead to new prevention strategies to decrease the occurrence of lung cancer and to identify people who are at increased risk of developing the disease.

Citation: You M, Wang D, Liu P, Vikis H, James M, Lu Y, Wang Y, Wang M, Chen Q, Jia D, Liu Y, Wen W, Yang P, Sun Z, Pinney SM, Zheng W, Shu XO, Long J, Gao YT, Xiang YB, Chow WH, Rothman N, Petersen GM, de Andrade M, Wu Y, Cunningham JM, Wiest JS, Fain PR, Schwartz AG, Girard L, Gazdar A, Gaba C, Rothschild H, Mandal D, Coons, T, Lee J, Kupert E, Seminara D, Minna J, Bailey-Wilson JE, Amos CI, Anderson MW. (http://www.ncbi.nlm.nih.gov/pubmed/19351763?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS 2009. Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene. Clin Cancer Res 15(8):2666-2674.

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Phthalate Exposure May Extend Pregnancy

A multi-state epidemiologic study, funded in part by NIEHS, reports that women at the upper range of exposure to the plasticizing agent di-(2-ethylhexyl) phthalate (DEHP), had a two day longer gestation than women at the lower range of exposure. The highly exposed women also had higher odds for caesarian section delivery and delivery at 41 weeks of gestation or later, as well as decreased odds for preterm delivery. These findings suggest that DEHP may interfere with the hormonally controlled signaling that initiates birth.

Phthalates are used in a wide variety of products including food and beverage containers, pharmaceutical pills and nutritional supplements, gelling agents, personal care products, medical devices, detergents, children's toys and nail polish. As of 2004, manufacturers produced 800 million pounds of phthalates each year.

When added to plastics, phthalates allow the long polyvinyl molecules to slide against one another. Phthalates are easily released into the environment because there is no covalent bond between the phthalates and plastics in which they are mixed. As plastics age and break down, the release of phthalates accelerates. Because phthalates are subject to biodegradation, photo-degradation and anaerobic degradation, they do not generally persist in the outdoor environment.

Citation: Adibi JJ, Hauser R, Williams PL, Whyatt RM, Calafat AM, Nelson H, Herrick R,Swan SH. (http://www.ncbi.nlm.nih.gov/pubmed/19251754?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS 2009. Maternal urinary metabolites of di-(2-ethylhexyl) phthalate in relation to the timing of labor in a US multicenter pregnancy cohort study. Am J Epidemiol 169(8):1015-1024.

(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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