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Extramural Papers of the Month

By Jerry Phelps
January 2009

Microglial Cell Enzyme Involved in Neuronal Cell Death

An international research team funded by NIEHS reported the discovery of the involvement of microglial cell IκB kinase in excitotoxin-induced neurodegeration. This discovery identifies a target for preventing mass cell death due to traumatic brain injury, stroke or neurodegenerative diseases.

The team employed a special strain of knock-out mice that have no gene for the IκB kinase enzyme in specific cells of myeloid lineage including microglia - cells that act as the first and main form of active immune defense in the central nervous system. The gene deletion reduced the IκB kinase activity in cultured microglia by up to 40 percent compared to microglia from normal mice.

Kainic acid-induced hippocampal neuronal cell death was reduced by 30 percent in the knock-out microglia. The reduction in neuronal cell death was followed by decreases in kainic acid-induced glial cell activation and expression of proinflammatory genes such as tumor necrosis factor and interleukin. Additional studies utilizing brain tissue slices in culture showed decreased susceptibility to kainic acid-induced excitotoxicity in knock-out mice brain tissue.

The discovery identifies IκB kinase as a possible target for therapeutic interventions to ameliorate or prevent additional cell death following serious brain injuries or as a result of neurodegenerative disease.

Citation: Cho IH, Hong J, Suh EC, Kim JH, Lee H, Lee JE, Lee S, Kim CH, Kim DW, Jo EK, Lee KE, Karin M, Lee SJ (http://www.ncbi.nlm.nih.gov/pubmed/18819987?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2008. Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death. Brain 131(Pt 11):3019-3033.

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Discovery of Gene Variant for Cleft Lip

About one-fifth of isolated cleft lip may be due to a single nucleotide difference in the DNA sequence of a gene involved in facial development, according to new research findings from an international research team funded in part by NIEHS. Isolated cleft lip is one of the most common birth defects. The research team said this discovery could lead to DNA tests to help couples better understand their risk of having a child with a cleft lip.

This research finding has its origin in research conducted six years ago when the team discovered that a gene called IRF6 is involved with a rare condition called Van der Woude syndrome. About 15 percent of people with the syndrome have malformations that are clinically indistinguishable from isolated cleft lip, which suggested that the gene might be involved in both conditions. Through studying the gene's sequence, they discovered a single sequence variant in a section of DNA that is almost identical across twelve different animals.

The team determined that the substitution of a single adenine molecule in place of a guanine in the IRF6 gene alters the binding site for a protein called AP-2alpha. The protein is known to be involved in craniofacial development and, when altered, causes a syndrome that involves clefts. These findings may not only lead to improvements in predicting clefts but, possibly, also to better interventions to prevent them.

Citation: Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, Domann FE, Govil M, Christensen K, Bille C, Melbye M, Jugessur A, Lie RT, Wilcox AJ, Fitzpatrick DR, Green ED, Mossey PA, Little J, Steegers-Theunissen RP, Pennacchio LA, Schutte BC, Murray JC (http://www.ncbi.nlm.nih.gov/pubmed/18836445?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Exit NIEHS. 2008. Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nat Genet 40(11):1341-1347.

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Antioxidant Administration Reduces Lung Injury from Chlorine Exposure

Dosages of vitamin C and other low molecular weight antioxidants may help prevent chlorine-induced lung injury that occurs after railroad tanker spills or that could occur as a result of terrorist attacks, according to NIEHS-supported researchers. The levels of chlorine exposure used in the research study mimic those seen during accidental exposures.

The research team exposed laboratory rats to chlorine gas at either 184 or 400 parts per million for 30 minutes in controlled environmental chambers. These levels are similar to those measured near chlorine tanker spills. Just one hour after exposure, the rats showed evidence of decreased arterial blood oxygen, increased blood carbon dioxide and acidosis, and increased markers of inflammation in respiratory fluid samples. In a subsequent experiment, administration of a mixture of antioxidants, which included ascorbic acid (vitamin C), deferoxamine and N-acetyl-L-cysteine, prior to exposure to 184 parts per million chlorine dramatically reduced the respiratory effects seen in the previous experiment.

These experiments suggest that antioxidant administration may be useful for preventing the serious lung injury and death that can occur as a result of chlorine gas exposure. Additional studies will be necessary to confirm these findings, but these results suggest that hazardous materials responders and rescue crews may benefit from prophylactic antioxidant administration prior to responding to a chlorine spill.

Citation: Leustik M, Doran S, Bracher A, Williams S, Squadrito GL, Schoeb TR, Postlethwait E, Matalon S (http://www.ncbi.nlm.nih.gov/pubmed/18708632?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2008. Mitigation of chlorine-induced lung injury by low-molecular-weight antioxidants. Am J Physiol Lung Cell Mol Physiol 295(5):L733-L743.

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Consumption of Foods with High Soy Content is Associated with Lower Sperm Concentrations in Men

New research reports that men who eat a high amount of soy-based food products have lower total sperm counts. Soy is rich in estrogenic compounds known as isoflavones including genistein, daidzein and glyciten.

The medical literature is replete with reports of steep drops in sperm count over the last 60 years in the U.S. and Europe. Possible explanations implicate increased exposure to endocrine disruptors and natural and synthetic estrogens.

In the current study, the 99 research subjects, who were the male partners of couples being evaluated at a fertility center, were asked to complete a questionnaire on the foods they eat regularly, which included 15 common soy-based foods such as tofu, soy milk, tempeh, tofu burgers, miso soup and drinks containing soy protein. Men who were in the highest category of soy intake ate one half of a serving each day of a soy-based food. Their sperm counts were on average 41 million sperm per milliliter of semen lower than men who ate no soy foods. Normal sperm counts range from 80 to 120 million per milliliter.

This study suggests that soy foods could have a deleterious effect on sperm production and might need to be avoided by men who have low sperm counts if they are trying to conceive children.

Citation: Chavarro JE, Toth TL, Sadio SM, Hauser R (http://www.ncbi.nlm.nih.gov/pubmed/18650557?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2008. Soy food and isoflavone intake in relation to semen quality parameters among men from an infertility clinic. Hum Reprod 23(11):2584-2590.



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