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Extramural papers of the month

By Jerry Phelps
October 2010

Amplifying stem cells

The success of hematopoietic stem cell transplantation into human patients for treating blood diseases depends on the number of stem cells in the graft. Culturing stem cells with a cocktail of growth factors before transplantation can induce proliferation, but the increase in cell number is rapidly followed by differentiation, which is accompanied by loss of the cell surface markers CD34 and CD133.

NIEHS grantees recently identified the purine derivative StemRegenin 1 (SR1) in a screen for small molecules that could stimulate stem cell growth without hastening differentiation. Culturing human stem cells collected from peripheral blood with a cytokine cocktail plus SR1 increased the number of CD34+ and CD133+ cell populations as compared to control cells treated with the growth factors alone and also increased the number of multilineage colonies formed by stem cells. SR1treatment increased both short- and long-term engraftment of human umbilical cord blood CD34+ cells into mice as compared to uncultured or control stem cells cultured with cytokines alone.

SR1 inhibited the aryl hydrocarbon (Ah) receptor, a nuclear receptor that has been implicated in pathways that regulate hematopoiesis. The authors conclude that modulating Ah receptor activity may be a useful strategy for improving clinical outcome of stem cell transplantation.

Citation: Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20688981) Exit NIEHS 2010. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329(5997):1345-1348.

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Low dose BPA alters gene expression in the fetal mouse ovary

A research team led by NIEHS grantee Patricia Hunt, Ph.D., at Washington State University reports that gene expression changes in fetal mouse ovaries occur as soon as 12 hours after the mother has been exposed to bisphenol A. These changes may produce adverse reproductive outcomes as the mice grow and develop.

Bisphenol A is a ubiquitous chemical found in many forms of plastic that humans come in contact with daily. A growing body of evidence demonstrates that it is an endocrine disruptor at all stages of life.

The research shows that bisphenol A affects the earliest stages of egg production in the ovaries of developing mice fetuses, suggesting that their offspring may suffer genetic defects in biological processes such as mitosis and DNA replication. This is an example of a transgenerational effect, in that the grandchildren of the exposed animals will be at risk for adverse health effects.

The research team also reports finding down-regulation of mitotic or cell cycle genes raising the possibility that bisphenol A exposure might act to shorten the reproductive lifespan by reducing the pool of fetal oocytes that later mature into eggs. If this effect is true in humans, it could result in premature menopause in women.

Citation: Lawson C, Gieske M, Murdoch B, Ye P, Li Y, Hassold T, Hunt PA. (http://www.ncbi.nlm.nih.gov/pubmed/20739668) Exit NIEHS 2010. Gene Expression in the Fetal Mouse Ovary Is Altered by Exposure to Low Doses of Bisphenol A. Biol Reprod. Epub ahead of print. DOI: 10.1095/biolreprod.110.084814

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Common genetic variants associated with blood lipids

A genome-wide association study partially supported by NIEHS reports genetic variants associated with levels of four blood lipids - total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. The paper is a worldwide multi-institute collaborative effort based on data from more than 100,000 individuals of European descent.

Additional analyses were undertaken in populations of East Asian, South Asian, and African American ancestry using a different cohort of Europeans as a control group. The single nucleotide polymorphisms found in this control European cohort were largely replicated in the non-European populations, albeit to a lesser extent in the African American population.

In order to assess the clinical relevance of these loci, associations with coronary artery disease were assessed in 25,000 cases and 66,000 controls of European descent. Thirteen loci showed association, with most of them also being associated with low-density lipoprotein, showing a causal risk factor. A second clinical phenotype, hyperlipidaemia, was also assessed in a smaller study, where individuals with greater numbers of risk loci showed higher lipid levels.

The study identifies a large number of loci associated with blood lipids in both European and non-European populations, as well as provides clinical and biological evidence that increases the strength of these associations.

Citation: Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20686565) Exit NIEHS 2010. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466(7307):707-713.

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Charlotte, NC light rail transit use reduces obesity risk

New research findings supported solely by NIEHS as part of its built environment grant portfolio demonstrate that increasing the availability of light rail systems and improving neighborhood environments is associated with a reduction in body mass index.

Researchers conducted two surveys in Charlotte, NC, before and after the completion of a light rail system serving downtown locations. The surveys assessed levels of physical activity, body mass index, perception of neighborhood environments, and the use of public transit systems. They found that construction of the light rail system led to increases in walking and subsequent weight loss. These findings were also associated with having a positive impression of one's neighborhood. The use of the light-rail system to commute to work resulted in an average reduction in body mass index of 1.18 kilogram per meter squared and an 81 percent decreased risk of becoming obese.

Citation: MacDonald JM, Stokes RJ, Cohen DA, Kofner A, Ridgeway GK. (http://www.ncbi.nlm.nih.gov/pubmed/20621257) Exit NIEHS 2010. The effect of light rail transit on body mass index and physical activity. Am J Prev Med 39(2):105-112.

(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training.)



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