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Extramural Papers of the Month

By Jerry Phelps
March 2008

New In Vitro Test May Replace Some Animal Testing

NIEHS-supported scientists have developed a new in vitro screening tool that may reduce the number of animals needed in drug testing. The test system consists of two glass slides - one containing 1,080 individual human cell cultures encapsulated in collagen or other matrices and the other coated with P450 metabolic enzymes.

The product was developed by Jonathan Dordick and Douglas Clark of Solidus Biosciences in part through a Small Business Innovative Research Grant from NIEHS. The cell culture slide, known as the DataChip, has been tested with human bladder, liver, kidney, heart, skin, or lung cells. The enzyme containing slide is called the MetaChip. When the two slides are sandwiched together and incubated, they mimic the body's reaction to compounds. If the cells stop growing, appear sick or die, it's an indication that a toxin is present.

While the investigators don't think their product will replace the use of live laboratory animals in drug testing, they do think that it could reduce the total number of animals used to in bringing new products to the marketplace and provide a more rapid screening tool for weeding out highly toxic or unpromising compounds.

Citation: Lee MY, Kumar RA, Sukumaran SM, Hogg MG, Clark DS, Dordick JS. Exit NIEHS Website( 2008. Three-dimensional cellular microarray for high-throughput toxicology assays. Proc Natl Acad Sci U S A 105(1):59-63.

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Early-life Exposure to Lead Causes Alzheimer's Like Changes in Older Monkeys

Alzheimer's-like symptoms were seen in a group of older long-tailed macaque monkeys given low levels of lead in infant formula during the first 400 days of life at a non-NIH facility. The findings suggest that Alzheimer's disease is influenced by early-life exposures to environmental triggers. NIEHS grantees and intramural scientists collaborated on the study.

The monkeys' blood lead levels at the end of the exposure period were in the range of 19-26 micrograms/deciliter and resembled the levels seen in many inner city children. After they had reached adulthood, their blood lead levels were the same as the control group, indicating that any significant exposure was confined to the developmental and adolescent periods. No health problems were found in any of the monkeys during the 23-year study.

The researchers discovered amyloid protein plaques differences and changes in gene expression in the lead-exposed monkeys. All of the adult monkeys were found to have amyloid plaques, but the lead-exposed group's plaques were more numerous and more dense. Expression of Alzheimer's specific genes (APP and BACE1) was elevated in the lead-exposed monkeys. These effects were accompanied by higher levels of DNA oxidation and decreased DNA methyl-transferase activity, suggesting epigenetic influences on the expression of the Alzheimer's disease-related genes.

Citation: Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH. ( NIEHS Website. 2008. Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 28(1):3-9.

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Oxidative Stress Marker Identified in Stroke Victims

New research supported in part by NIEHS has revealed a possible biomarker that may be useful in determining the effectiveness of antioxidant therapies used to treat stroke victims. Laboratory studies show that oxidative stress is a major contributing factor to brain injuries resulting from the restriction of blood flow caused by stroke. To date, however, a useful biomarker has not been available.

The group hypothesized that F2-isoprostanes, which are products of neuronal cell arachidonic acid peroxidation during stroke, might be good candidates for a marker. They performed a case control study of 52 stroke patients and 27 controls. Twenty-five of the stroke patients had received the clot busting drug tissue plasminogen activator (tPA). The researchers measured antioxidant dietary intake by a questionnaire.

The study showed that F2-isoprostanes were indeed elevated in the plasma of stroke victims within the first 8 hours of the appearance of symptoms but not at 24 hours or later time points. They also found a correlation between F2-isoprostanes and matrix metalloproteinase 9 (MMP9) in tPA-treated stroke patients - confirming earlier findings that oxidative stress may be an early stimulus for MMP activation and blood-brain barrier injury. While the findings need to be confirmed in large studies, they do offer a new research opportunity in the treatment of stroke.

Citation: Kelly PJ, Morrow JD, Ning M, Koroshetz W, Lo EH, Terry E, Milne GL, Hubbard J, Lee H, Stevenson E, Lederer M, Furie KL. Exit NIEHS Website( 2008. Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study. Stroke 39(1):100-104.

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Lipoic Acid Supplementation Inhibits Lesion Development in Mice

NIEHS-supported research has determined that dietary supplementation with alpha-lipoic acid (ALA) reduces the formation of fatty plaques in two mouse models of atherosclerosis.

Atherosclerosis and its associated vascular complications are the principal cause of cardiovascular and cerebrovascular diseases (CVDs) leading to heart attacks and stroke. These diseases represent the principal cause of death in Western civilizations, accounting for more than 40% of all deaths. According to the American Heart Association, almost 62 million Americans suffer from CVDs, which have been the number one killer in the U.S. for more than nine decades.

ALA is a naturally occurring compound that appears to be useful in treating conditions associated with oxidative stress. It has been safely used for more than 30 years in Europe to prevent and treat complications associated with diabetes and cataracts.

Mice were fed diets containing either normal or high amounts of fat and cholesterol with or without 0.2 percent ALA. The animals receiving the supplementation had significantly reduced numbers of aortic lesions, 40 percent less body weight gain, and lower serum triglyceride levels. The supplementation also reduced the expression of aortic adhesion molecules and proinflammatory cytokines. The authors conclude that ALA "may be a useful adjunct in the prevention and treatment of atherosclerotic vascular diseases."

Citation: Zhang WJ, Bird KE, McMillen TS, LeBoeuf RC, Hagen TM, Frei B. ( NIEHS Website. 2008. Dietary alpha-lipoic acid supplementation inhibits atherosclerotic lesion development in apolipoprotein E-deficient and apolipoprotein E/low-density lipoprotein receptor-deficient mice. Circulation 117(3):421-428.

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