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DIR Papers of the Month

By Eddy Ball
November 2006

High BMI and Male Infertility

In what may be the first study of its kind, scientists in the NIEHS Epidemiology Branch have found a significant correlation between reduced couple fertility and male obesity or overweight status. Previous studies have found diminished semen quality and hormone alterations among men with high body mass index (BMI), and overweight men may be at a greater risk of erectile dysfunction - all contributors to reduced fertility. However, to the researchers' knowledge until this NIEHS-sponsored study, which appeared in the September issue of Epidemiology, no researchers had presented data regarding the effect of male obesity and overweight on couple fertility.

This analysis of fertility data from the Agricultural Health Study on 2,111 couples supports the hypothesis that the obesity epidemic is associated with the personal and societal costs of male infertility and its treatment. If confirmed in subsequent studies, these results may offer an added incentive for men to make efforts to reduce weight.

Citation: Sallmen M, Sandler DP, Hoppin JA, Blair A, Baird DD. 2006. Reduced fertility among overweight and obese men. Epidemiology 17(5):520-523.

Transcription Factor for Lung Inflammation

Investigators in the NIEHS Laboratory of Respiratory Biology, in collaboration with researchers from Duke University and the Durham Veterans Administration Medical Center, have identified a type II transcription factor, interferon-gamma (IFN-γ), that plays a critical role in the lung's response to inhaled endoxin. The research team evaluated wild type and IFN-γ-deficient mice exposed to the endoxin lipopolysaccharide (LPS), which is known to result in predictable inflammation of the lower respiratory tract. Appearing in the October issue of the American Journal of Physiology-Lung Cellular and Molecular Physiology, the study determined that complex transcriptional response to LPS, involving expression of many genes, is modified and regulated by other molecules, such as IFN-γ.

By identifying the role of the critical signaling molecule IFN-γ. in LPS-induced inflammatory lung disease, this study has identified potential targets for pharmacological intervention to modify the progression and severity of such diseases as asthma, atherosclerosis and diabetes, which are associated with dysregulation of Nuclear Factor Kappa Beta and other transcription factors.

Citation: Burch LH, Yang IV, Whitehead GS, Chao FG, Berman KG, Schwartz DA. 2006. The transcriptional response to lipopolysaccharide reveals a role for interferon-. in lung neutrophil recruitment. Am J Physiol Lung Cell Mol Physiol 291(4):L677-682.

Soluble Epoxide Hydrolase and Cardiac Function

In a study published in the August issue of Circulation Research, a DIR-funded research team investigated the role of the enzyme soluble epoxide hydrolase (sEH) in recovery of heart contractile function following ischemia, which occurs during a heart attack. The investigators examined hearts of sEH knockout mice and wild type controls at baseline and following ischemia. They measured the abilty of hearts to contract and determined that hearts from sEH knockout mice recovered better function than hearts from control mice after ischemia. Moreover, the study found that disruption of the sEH gene resulted in increased availability of epoxyeicosatrienoic acids (EETs), endogenous fatty acids that are potent vasodilators and cardioprotective factors, by interrupting their conversion to less active downstream metabolites. Researchers also demonstrated that treatment with an EET-antagonist abolished the improved functional recovery following ischemia in sEH knockout hearts, indicating that the cardioprotective effects were mediated by EETs in this model.

The study's results suggest the possibility that sEH inhibition may represent a novel approach for the treatment of cardiac dysfunction associated with heart attacks.

Citation: Seubert JM, Sinal CJ, Graves J, DeGraff LM, Bradbury JA, Lee CR, Goralski K, Carey MA, Luria A, Newman JW, Hammock BD, Falck JR, Roberts H, Rockman HA, Murphy E, Zeldin DC. 2006. Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circ Res 99(4):442-450.

BMP Signaling and Embryonic Development

In a collaborative study involving DIR investigators from the Laboratory of Reproductive and Developmental Toxicology and the Duke University Medical Center Department of Cell Biology, researchers examined the mechanism of bone morphogenetic protein (BMP) signaling in the development of mouse embryonic tissues (or organs) known as somites, which will form the vertebral column and segmented musculature of the developing organism. Published in the August issue of Development, the study reports on experiments with genetically altered mice that have modified expression of the gene Bmpr1a, demonstrating the critical role of BMP signaling, as well as its antagonistic relationship with fibroblast growth factor signaling in recruiting prospective cells correctly and directing normal somite development.

This research into mouse embryonic development may ultimately provide insight into the prevention of birth defects and failed embryonic development in humans.

Citation: Miura S, Davis S, Klingensmith J, Mishina Y. 2006. BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites. Development 133(19):3767-3775.

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