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Extramural Papers of the Month

By Jerry Phelps
July 2008

Risks of Coarse Particulate Air Pollution

A nationwide study of coarse particulate air pollution, defined as 2.5-10 microns in diameter, found some evidence of an association with hospital admissions for cardiovascular disease and no evidence of an association for respiratory disease. Researchers at Johns Hopkins University, supported by NIEHS, conducted the study, the largest on record, for both public health and regulatory purposes.

The study examined associations between daily changes in hospital admission rates for cardiovascular and respiratory outcomes and daily changes in coarse and fine particulate matter concentrations in ambient air in 108 urban counties across the U.S. The study included over 12 million people enrolled in Medicare from 1999-2005.

The Environmental Protection Agency (EPA) regulates the level of fine particulate matter pollution, defined as particles less than 2.5 microns in diameter, but does not currently regulate coarse particulates. Fine particles are generally the result of combustion from automobiles and coal burning power plants. Coarse particles are produced by processes such as mechanical grinding, windblown dust and agricultural practices.

Previous investigation into fine particulate matter pollution by this research team demonstrated a strong link to hospitalization for cardiovascular and respiratory illnesses. According to the researchers, the coarse particle association found in the current study warrants the attention of EPA regulators when the agency readdresses its standard for particles in the air.

Citation: Peng RD, Chang HH, Bell ML, McDermott A, Zeger SL, Samet JM, Dominici F( Exit NIEHS Website. 2008. Coarse particulate matter air pollution and hospital admissions for cardiovascular and respiratory diseases among Medicare patients. JAMA 299(18):2172-9.

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Social Isolation and Possible Implications for Breast Cancer

NIEHS-supported scientists report that social isolation early in life in laboratory rats is linked to a higher incidence of mammary tumors in mid-life. Their research focused on assessing the effects of isolation on patterns of ovarian development.

Four-week-old rats were housed either in groups of five or in single cages. The isolated rats developed regular ovarian cycles more quickly than the group-housed rats; however, their cycles were shorter than the cycles of the group-housed rats. These differences resulted in more periovulatory surges of estrogen for the isolated rats and a "higher ratio of estrogenized to nonestrogenized days between 60 and 75 days of age when mammary tissue is receptor positive," even though their mammary development was delayed.

These results suggest that social isolation disassociates two components of puberty by accelerating the maturation of the ovaries while delaying mammary tissue development. At 15 months of age, 100 percent of the isolated animals had tumors as compared to only 33 percent of the group-housed animals.

The researchers suggest that their findings relate to the growing literature on the adverse health outcomes related to girls reaching puberty and experiencing breast development earlier in life than previous generations, possibly leading to an increased risk of certain forms of breast cancer later in life.

Citation: Hermes GL, McClintock MK( Exit NIEHS Website. 2008. Isolation and the timing of mammary gland development, gonadarche, and ovarian senescence: implications for mammary tumor burden. Dev Psychobiol 50(4):353-360.

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Mapping Gene Expression in the Human Liver

A large multi-investigator research project to map gene expression in the human liver has yielded more than 6,000 associations between single nucleotide polymorphisms and liver gene expression traits. Many of the identified genes have already been associated with human diseases. Results from this genome wide association study also identified new candidate genes for type 1 diabetes, coronary artery disease and the so-called "bad" cholesterol, or low-density lipoprotein cholesterol.

Genome-wide association study, also known as a GWAS, is a laboratory approach involving the rapid scanning of markers across complete genomes of many people to find genetic variations associated with particular diseases. Once new genetic associations are identified, researchers can use the information to develop better strategies to detect, treat and prevent the disease.

Four hundred individual human liver samples were used in this study. The researchers profiled more than 39,000 gene transcripts and genotyped 782,476 unique single nucleotide polymorphisms. GWAS reporting associations to disease traits often lack supporting data on the roles candidate susceptibility genes play in disease development. However the NIEHS-backed study provides direct evidence of how integrating genotypic and expression data in mice and humans provides functional support for candidate susceptibility genes.

Citation: Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C, Zhu J, Millstein J, Sieberts S, Lamb J, GuhaThakurta D, Derry J, Storey JD, Avila-Campillo I, Kruger MJ, Johnson JM, Rohl CA, van Nas A, Mehrabian M, Drake TA, Lusis AJ, Smith RC, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich R( Exit NIEHS Website. 2008. Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6(5):e107.

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Enzyme Variant Identified as a Susceptibility Factor for Heart Failure

Researchers from Germany and the U.S. have identified variations in a gene that contributes to heart failure in people with hypertension. The gene, Ephx2, codes for the enzyme soluble epoxide hydrolase, which normally degrades specific epoxides.

The third most common cause of death in Western countries, heart failure commonly results from coronary disease and hypertension. It usually develops over a long period of time and is therefore commonly seen in older individuals. When the heart is no longer able to pump enough blood to meet the body's requirements, the heart muscle enlarges in an effort to compensate. Often the heart does not overcome the increased burden and becomes weakened further, especially in cases of pre-existing hypertension.

Using two strains of laboratory rats, one susceptible to hypertension and stroke and the other susceptible to hypertension and heart failure, the researchers observed that the heart failure rats possessed a single nucleotide polymorphism in the Ephx2 gene that is not present in the stroke prone rats. They conclude that the role of Ephx2 in the initial stages of heart disease in laboratory animals and humans suggests "a potential avenue for developing new heart failure treatments."

Citation: Monti J, Fischer J, Paskas S, Heinig M, Schulz H, Gösele C, Heuser A, Fischer R, Schmidt C, Schirdewan A, Gross V, Hummel O, Maatz H, Patone G, Saar K, Vingron M, Weldon SM, Lindpaintner K, Hammock BD, Rohde K, Dietz R, Cook SA, Schunck WH, Luft FC, Hubner N(ttp:// Exit NIEHS Website. 2008. Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nat Genet 40(5):529-537.

(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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