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Environmental Factor, January 2012

Intramural papers of the month

By Raluca Dumitru, Anshul Pandya, and Sonika Patial

Caffeine strengthens connections between neurons in a little-known area of the brain

A recent study published by NIEHS scientists suggests how and where caffeine might act in the brain to increase cognitive function. Previous research shows that caffeine acts by blocking the inhibitory effects of adenosine on cyclic adenosine monophosphate (AMP) production in the brain. This study represents the first demonstration of long-lasting synaptic plasticity induced by in vivo exposure to caffeine, as reported in the journal Nature Neuroscience.

As a widely consumed stimulant, caffeine’s effects on synaptic transmission in the CA2 area of the hippocampus, where adenosine A1 receptors are highly enriched, were not known. Rats were divided into three groups and given doses equivalent to two large cups of coffee, a highly caffeinated energy drink, or a dose that exceeded most people’s daily consumption. All doses of caffeine strengthened the connections between neurons of CA2, but not in other areas of the hippocampus, a brain structure important for learning and memory.

These results provide a pleasingly simple explanation for the common daily human experience. Adenosine levels increase in the brain during the day, inhibiting the production of cyclic AMP. Although these effects recover during sleep, caffeine accelerates recovery by blocking any residual adenosine action and strengthens the activity of CA2 synapses of the hippocampus. This discovery also raises exciting new questions about the role of CA2 neurons in brain function.

CitationSimons SB, Caruana DA, Zhao M, Dudek SM. (http://www.ncbi.nlm.nih.gov/pubmed/22101644)  2011. Caffeine-induced synaptic potentiation in hippocampal CA2 neurons. Nat Neurosci; doi:10.1038/nn.2962 [Online 20 November 2011].

Exposures to certain early-life factors may contribute to an early onset of uterine fibroids

Researchers involved in the NIEHS Sister Study found associations between exposure to several early-life factors and the development of early-onset uterine fibroids in black women. These findings, which replicate many of the team’s previously published associations among white women, add support to some hypotheses regarding the etiology of fibroids in women.

Uterine fibroids are highly prevalent benign tumors, with an estimated clinical prevalence as high as 50 percent for black women compared to 25 percent for white women. Blacks not only have an increased risk of developing fibroids, but also suffer more severe symptoms than whites.

The scientists examined early-life exposure to several factors in black women aged 35-59 years of age enrolled in the Sister Study cohort. The researchers found an elevated risk of early-onset uterine fibroids in association with in utero diethylstilbestrol (DES) exposure, in utero exposure to maternal diabetes or maternal hypertensive disorder, having been born preterm, having a monozygotic twin, being the firstborn child of a teenage mother, and consumption of soy formula.

Although the associations with multiple birth and maternal hypertensive disorder were not seen for white women, the general consistency of early-life findings for blacks and whites supports a possible role of early-life factors in fibroid development.

CitationD’Aloisio AA, Baird DD, DeRoo LA, Sandler DP. (http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1103620) 2011. Early-life exposures and early onset uterine leiomyomata in black women in the Sister Study. Environ Health Perspect; doi:10.1289/ehp.1103620 [Online 2 November 2011].

Snail and Slug activate TGF-beta in breast cancer

For the first time, scientists at NIEHS and SRA International, Inc. have determined the transcriptional consequences of exogenous expression of Snail and Slug in breast cancer. Snail and Slug are transcriptional repressors that have been proposed to mediate epithelial to mesenchymal transition, which has been implicated in tumor metastasis.

Researchers followed Snail and Slug expression by performing microarray analysis in a MCF-7 breast cancer cell line that did not express detectable levels of Snail and Slug. Adenovirus-infected cells served as the control. Microarray analysis showed that genes involved in the TGF-beta signaling pathway were upregulated, while genes responsible for a differentiated morphology were downregulated following Snail or Slug expression. Importantly, the overexpression of Snail and Slug changed the transcriptional signature from luminal to a more basal breast cancer that is commonly associated with highly invasive cancers.

This study suggests that the cell migration induced by Snail or Slug expression could be blocked by the addition of TGF-beta inhibitors, as inhibition of TGF-beta did not appear to affect the gene repression induced by Snail. However, the ability of cells to migrate was affected. Therefore, the sequential treatments with estrogenic agonists that control tumor growth and TGF-beta inhibitors to prevent cell migration may have therapeutic benefits.

CitationDhasarathy A, Phadke D, Mav D, Shah RR, Wade PA. (http://www.ncbi.nlm.nih.gov/pubmed/22028892)  2011. The transcription factors Snail and Slug activate the transforming growth factor-beta signaling pathway in breast cancer. PLoS One 6(10):e26514.

Pregnane X receptor regulates liver metabolism

NIEHS researchers have uncovered the mechanism for the repression of the estrogen sulfotransferase (SULT1E1) gene by rifampicin (RIF), an antibacterial and antifungal agent. This work makes the SULT1E1 gene the first gene that is repressed by pregnane X receptor (PXR) to be understood at the chromatin structure level. These findings have important public health implications as they suggest that PXR and constitutive active/androstane receptor (CAR) may cooperate in regulating hepatic levels of active estrogens, thereby affecting the physiology and pathophysiology of human liver.

The same group of NIEHS scientists previously published a study demonstrating that the activation of the SULT1E1 gene by xenobiotics is mediated by CAR, and that PXR activation by RIF repressed the SULT1E1 gene in human primary hepatocytes and hepatocellular carcinoma cells. The current study builds upon the earlier study.

Using chromatin immunoprecipitation and chromatin conformation capture assays, the research team identified the hepatocyte nuclear factor 4alpha (HNF4alpha) as the target of PXR to repress the SULT1E1 gene in human primary hepatocytes and hepatocellular carcinoma cells. In doing so, these investigators have determined how PXR cross-talks with HNF4alpha, disrupting an active chromatin structure and repressing the transcription of SULT1E1 gene. This PXR and CAR cooperation in regulating estrogen levels in the human liver may affect the physiology of the liver.

CitationKodama S, Hosseinpour F, Goldstein JA, Negishi M. (http://www.ncbi.nlm.nih.gov/pubmed/21764778)  2011. Liganded pregnane X receptor represses the human sulfotransferase SULT1E1 promoter through disrupting its chromatin structure. Nucleic Acids Res 39(19):8392-8403.

(Raluca Dumitru, M.D., Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Laboratory of Molecular Carcinogenesis Stem Cell Biology Group. Anshul Pandya, Ph.D., is an IRTA fellow in the Laboratory of Neurobiology Ion Channel Physiology Group. Sonika Patial, D.V.M., Ph.D., is a visiting fellow in the Laboratory of Signal Transduction Polypeptide Hormone Action Group.)



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