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DERT Papers of the Month

By Jerry Phelps
April 2007

Prostate Cancer Linked to High Levels of a Mismatch Repair Protein

A Ph.D. candidate at the Wake Forest School of Medicine supported by NIEHS identified an increase in a DNA mismatch repair protein as a marker for prostate cancer. This finding represents the first documented evidence of an increase in a mismatch repair protein being associated with human cancer.

The purpose of the study was to identify new prognostic tools to identify prostate cancer patients at risk for particularly severe life-threatening forms of the disease compared to those who develop slower-growing, less severe forms. The research team analyzed tissue samples from prostatectomies and determined the presence or absence of the key mismatch repair proteins MSH2, MLH1 and PMS2. They found increases in PMS2 in the samples from prostate cancer tissue. Many previous studies have associated deficits in mismatch repair proteins with risks for tumor formation. The results also demonstrated that the PMS2 increase is associated with genetic instability.

The study results imply that the increase in PMS2 and the accompanying genetic instability are early events in the development of prostate cancer. The results also suggest that PMS2 may be used as a prognostic marker for the early detection of aggressive forms of prostate cancer and could be used to direct individual treatment strategies for patients with the marker.

Citation: Norris AM, Woodruff RD, D'Agostino RB Jr, Clodfelter JE, Scarpinato KD( Exit NIEHS. 2007. Elevated levels of the mismatch repair protein PMS2 are associated with prostate cancer. Prostate 67(2):214-225.

Air Pollution and Cardiovascular Disease in Women

New research by NIEHS grantees at the University of Washington shows that the risk of harm from particulate air pollution to the respiratory and cardiovascular systems in post-menopausal women is about three times higher than previously estimated. The scientists found that the greater the level of the fine particulate pollution, the greater the risk of cardiovascular disease and death.

Investigators analyzed the medical records of more than 66,000 postmenopausal women participating in the Women's Health Initiative in 36 cities and followed them for six years. Particulate air pollution was measured by monitors placed near the subjects' homes. The size of the particles measured was smaller than 2.5 microns in diameter. During the study, 1,816 women had heart attacks or strokes or were diagnosed with arterial diseases, and 261 died.

The risk of dying from heart attack or stroke increased 76 percent for each ten microgram increase in particulate pollution. The annual average exposure was 13.5 micrograms per cubic meter of air, lower than the EPA standard of 15 micrograms.

Although the actual biological effects of particulate exposure are unknown, the scientists speculate that the particles cause inflammation in the lungs that spreads to the arteries, increasing arterial disease and the likelihood of heart attack and stroke.

Citation: Miller KA, Siscovick DS, Sheppard L, Shepherd K, Sullivan JH, Anderson GL, Kaufman JD( Exit NIEHS. 2007. Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med 356(5): 447-458.

Exposure to Traffic and Lung Development

University of Southern California researchers with support from NIEHS report that children living within 500 meters of a freeway in California had reduced lung-function compared to children living 1,500 meters or more from freeways. This finding is important because it shows that within certain communities, some children are at higher risk than others for adverse respiratory effects resulting from environmental pollution.

The study included 3,677 children aged 10-18 from twelve Southern California communities. Over an eight-year period, researchers gave the children early lung-function tests including forced expiratory volume and maximum midexpiratory flow rate. Results showed significant deficits in lung function for children living within 500 meters of the freeway.

The research team pointed to diesel exhaust as an important component of the impaired lung function. Diesel exhaust is known to contain a high fraction of particulate matter of a size that is readily inhaled deep into the respiratory system. Other human exposure studies show that breathing dilute diesel exhaust produces extensive inflammation in the bronchial walls and adverse effects associated with oxidative stress, activation of protein kinases and transcription factors, and perturbations in cell function by the chemical and physical properties of diesel exhaust particles.

Citation: Gauderman WJ, Vora H, McConnell R, Berhane K, Gilliland F, Thomas D, Lurmann F, Avol E, Kunzli N, Jerrett M, Peters J( Exit NIEHS. 2007. Effect of exposure to traffic on lung development from 10 to 18 years of age: a cohort study. Lancet 369(9561):571-577.

In Utero Bisphenol A Exposure Leads to Abnormal Egg Development in Mice

Recent experiments in pregnant mice exposed to the purported endocrine disrupting chemical bisphenol A (BPA) at doses comparable to the range of common human exposures resulted in chromosomal abnormalities in the eggs of the exposed fetuses.

The NIEHS-funded research found that exposure to BPA at early stages of development disturbs the growth and division of the eggs in the unborn female fetuses. When the fetuses reach adulthood, the perturbations lead to increases in chromosomally abnormal eggs and embryos. The results indicate that as many as 40 percent of the eggs and embryos from females exposed to the chemical may be affected compared to the background rate of less than one percent.

BPA is a component of polycarbonate plastics, resins that line food and beverage containers, and additives in a variety of consumer products. Humans are exposed to trace amounts of it by eating or drinking products stored in these plastics. Other human health effects that have been associated with BPA exposure include a variety of reproductive effects in males and females, increased susceptibility to prostate cancer, alterations in mammary gland organization, and deficits in neurological development. Emerging research is beginning to link exposure with the prevalence of obesity and other endocrine disorders.

Citation: Susiarjo M, Hassold TJ, Freeman E, Hunt PA( Exit NIEHS. 2007. Bisphenol A exposure in utero disrupts early oogenesis in the mouse. PLoS Genet 3(1):e5.

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