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Intramural Papers of the Month

By Robin Arnette
October 2008

DEPs Involved in a Novel Blood-Brain Barrier Signaling Pathway

Scientists from NIEHS, the University of Minnesota and Virginia Commonwealth University Medical Campus demonstrated that diesel exhaust particles (DEPs) alter blood-brain barrier function through oxidative stress and proinflammatory cytokine production. It is the first study to show this interaction and an important finding since DEPs are the main particulate component of urban air pollution worldwide.

DEPs have a carbon core with heavy hydrocarbons and hydrated sulfuric acid. Polycyclic aromatic hydrocarbons are adsorbed to the particles. Researchers knew that once DEPs enter the body through inhalation they could travel to all tissues. This research team wanted to understand the specific effects in the central nervous system (CNS).

When brain capillaries isolated from rats were exposed to DEPs, a signaling pathway involving NADPH oxidase and tumor necrosis factor alpha was activated. This pathway signaled increased expression of P-glycoprotein, a major blood-brain barrier drug efflux transporter for therapeutic drugs.

The results reveal a novel blood-brain barrier signaling pathway turned on by urban air pollutants that could affect pharmacotherapy for a number of CNS diseases.

Citation: Hartz AM, Bauer B, Block ML, Hong JS, Miller DS. ( Exit NIEHS 2008. Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier. FASEB J 22(8): 2723-2733.

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Loss of Estrogen Receptor-Alpha Affects Bone

An interdisciplinary team of researchers from NIEHS and several other institutions determined that a homozygous disruption of the estrogen receptor-alpha (ER-α) affected bone growth, mineral content and structure. Interestingly, this loss did not affect periosteal circumference. The periosteum is a dense membrane composed of fibrous connective tissue that lines the surface of bone. The study attempted to provide insight into the roles of androgen and estrogen on male and female subjects and was a follow-up analysis of the first individual described to have a germ line loss of function mutation of the ER-α gene.

The team wanted to determine the impact of a loss of function mutation in the ER-α gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER-α heterozygosity on spine density and adult height in an extended pedigree. The researchers evaluated the kindred of the mutant patient for the study and measured vital signs, height and weight. In addition to giving blood for ER-α carrier status, subjects had areal spine bone mineral density (aBMD) measurements using x-ray absorptiometry (DXA).

The data suggested that a disruption of ER-α resulted in a host of physical skeletal abnormalities, including increased osteopenia and periosteal expansion and decreased epiphyseal closure. ER-α heterozygosity did not appear to impair the skeleton. The team also found that both estrogen and androgen can contribute to bone growth, mineral content and skeletal structural integrity.

Citation: Smith EP, Specker B, Bachrach BE, Kimbro KS, Li XJ, Young MF, Fedarko NS, Abuzzahab MJ, Frank GR, Cohen RM, Lubahn DB, Korach KS. ( Exit NIEHS 2008. Impact on bone of an estrogen receptor-alpha gene loss of function mutation. J Clin Endocrinol Metab 93(8): 3088-3096.

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NELF Enhances Gene Expression

The transcription regulatory complex, Negative Elongation Factor (NELF), affects many rapidly inducible genes involved in cellular responses to stimuli, according to scientists at NIEHS and Pennsylvania State University. NELF induces RNA polymerase II (Pol II) to stall during early transcription elongation and represses expression of several genes, including Drosophila Hsp 70, mammalian proto-oncogene junB and HIV RNA. This research identifies a novel role for stalled Pol II in regulating gene expression.

The researchers wanted to determine all of the genes that NELF targeted in Drosophila and used microarray analysis of S2 cells depleted of NELF in their studies. NELF RNAi indicated that the majority of target genes exhibited decreased expression levels while far fewer genes were, like Hsp 70, up-regulated by NELF-depletion.

The presence of a stalled Pol II at down-regulated genes enhanced gene expression by maintaining a permissive chromatin architecture near the promoter-proximal region. In addition, a loss of Pol II stalling resulted in an increase in nucleosome occupancy and a decrease in histone H3 lysine 4 trimethylation, an epigenetic mark of transcription activity.

Future studies will examine how stalled Pol II affects local nucleosome architecture and promoter accessibility.

Citation: Gilchrist DA, Nechaev S, Lee C, Ghosh SK, Collins JB, Li L, Gilmour DS, Adelman K. ( Exit NIEHS 2008. NELF-mediate stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly. Genes Dev 22(14): 1921-1933.

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The Role of Genetics in Heart Rate and Heart Rate Variability

Recent studies suggest that there is a strong genetic component in the regulation of resting heart rate (HR) and heart rate variability (HRV) in quiescent mice. The investigation, performed by researchers from NIEHS and the Genomics Institute of the Novartis Research Foundation, provides the basis for investigating the precise interaction between genotype and the underlying mechanism associated with murine heart regulation.

Prior to this study, several other peer-reviewed journal articles suggested that genetics were important in HR and HRV, so the investigators examined 30 inbred strains and 29 recombinant inbred (RI) strains of mice during periods of rest using electrocardiograms (ECG) to measure HR and HRV and performed interval mapping to associate chromosomal regions with HR and HRV differences. Pulmonary function was also measured. Differences in HR and HRV were observed between strains; however, in the majority of the strains a continuous distribution of HR and HRV was observed, which implied that HR and HRV regulation is a complex trait and is influenced by multiple genes.

To determine which chromosomal regions were responsible for variations in the phenotypes, a quantitative trait locus (QTL) analysis was performed. QTLs were found on chromosome 2, 4, 5, 6 and 14.

Significant differences in HR, HRV and pulmonary function were found between strains, which indicated a strong genetic component to the regulation of these phenotypes.

Citation: Howden R, Liu E, Miller-DeGraff L, Keener HL, Walker C, Clark JA, Myers PH, Rouse DS, Wiltshire T, Kleeberger SR. ( Exit NIEHS 2008. The genetic contribution to heart rate and heart rate variability in quiescent mice. Am J Physiol Heart Circ Physiol 295(1): H59-68.

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