Papers of the Year
- Stimulus-Responsive Genes are Marked for Activation
- Arsenic and Type 2 Diabetes
- How Double Helical DNA Is Replicated
- The Ah Receptor Is Essential for Mediating an Anti-Inflammatory Effect
- RNA Recognition Properties of PUF Proteins Can be Adapted by Simple Substitutions
- Epigenetic Markers Change Over a Lifetime
- Structures of DNA Polymerase β Provide the First Glimpse of Pre-Mutagenic DNA Synthesis
- New Findings Contradict Aging/Mitochondrial DNA Mutation Theory
- Diabetes Risk Associated with Pesticide Use
- p53 Inhibits Cell Growth As Well As Cell Proliferation
- An Expanded Biological Repertoire for Inositol(3,4,5,6)-tetraphosphate Through Its Modulation of ClC-3 Function
- Maternal Smoking and Receptor Gene Variant Combine To Increase Risk for Childhood Asthma
- DEPs Involved in a Novel Blood-Brain Barrier Signaling Pathway
- Enzyme Variant Identified as a Susceptibility Factor for Heart Failure
- Neuronal Activity Reshapes Brain Circuitry
- Particulate Air Pollution Can Alter the Electrical Functioning In the Heart
- The Human ERG1 Channel Polymorphism, K897T, Creates a Phosphorylation Site That Inhibits Channel Activity
- Antioxidant Administration Reduces Lung Injury from Chlorine Exposure
- Effect of Prenatal Exposure to the Endocrine Disruptor Bisphenol A on Mammary Gland Morphology and Gene Expression Signature
- NOS and Nitroglycerin-Mediated Vasodilation
Out of the approximately 2,800 peer-reviewed journal articles published by NIEHS researchers and grantees in 2008, 20 studies were chosen as Papers of the Year.
Stimulus-Responsive Genes are Marked for Activation
NIEHS investigators found that many genes involved in the Drosophila innate immune response and other stimulus-response pathways are poised for activation. These genes recruit the RNA polymerase to the promoter before activation, but the progress of the RNA polymerase into the gene is blocked prior to receipt of an activating signal. In addition to the kinetic advantage afforded by pre-loading the RNA polymerase enzyme onto a given gene, a novel function for the RNA polymerase stalled near these gene promoters was uncovered: to block the assembly of repressive chromatin structures. Therefore, the presence of a poised RNA polymerase near the promoters of inactive stimulus-responsive genes maintains them in an "activate-able" state, by which the promoter is kept free of nucleosomes and accessible to upstream activators and additional RNA polymerase molecules. These results explain how rapid up-regulation of gene expression occurs in response to specific signals from the environment (e.g., stress and/or immune challenge).
Citation: Gilchrist DA, Nechaev S, Lee C, Gosh SKB, Collins J, Li L, Gilmour DS, Adelman K. 2008. NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly. Genes Dev 22:1921-1933. [Abstract] [Synopsis]
Arsenic and Type 2 Diabetes
New research findings from the National Health and Nutrition Examination Survey suggest that exposure to levels of arsenic commonly found in drinking water may be a risk factor for type 2 diabetes. The findings suggest that millions of Americans may be at increased risk for type 2 diabetes based on the level of arsenic in their drinking water.
Data on the nearly 800 participants in the study for which urinary arsenic concentrations were available, indicated that urine levels of arsenic were significantly associated with the prevalence of type 2 diabetes. After splitting the subjects into 5 groups based on the level of arsenic in their urine, the researchers determined that those in the highest category were more than three and one-half times more likely to have diabetes. The strength of arsenic as a risk factor for diabetes is similar to other factors such as obesity.
Inorganic arsenic in drinking water at concentrations higher than 100 parts per million has been linked to type 2 diabetes in studies that took place in Taiwan, Mexico, and Bangladesh where drinking water is commonly contaminated with high levels of arsenic. The US drinking water standard is currently 10 parts per million, but most people on private wells have not had their water tested and aren’t required to. The researchers estimate that about 13 million Americans live in areas where public water systems exceed the EPA standard for arsenic and this number does not included private wells and water systems.
Animal studies have shown that arsenic affects the production of glucose, insulin secretion and can cause insulin resistance. The current findings reinforce the need to evaluate the role of arsenic in diabetes development in prospective epidemiologic studies conducted in populations exposed to a wide range of arsenic levels.
Citation: Navas-Acien A, Silbergeld EK, Pastor-Barriuso R, Guallar E. 2008. Arsenic exposure and prevalence of type 2 diabetes in US adults. JAMA 300(7):814-22. [Abstract]
Supported by grant P30ES003819. Ana Navas-Acien, M.D., Ph.D., and Ellen K. Silbergeld, Ph.D., Johns Hopkins Bloomberg School of Public Health.
How Double Helical DNA Is Replicated
The two DNA strands are oriented anti-parallel to each other, yet DNA replication only proceeds in one direction. These two facts require that one DNA strand of the double helix be replicated first by a so-called "leading strand" polymerase, followed slightly thereafter by replication of the other strand by a "lagging strand" polymerase.
Fifty-four years after Watson and Crick’s description of the DNA double helix, the identity of the polymerases in higher organisms that replicated the leading and lagging strands was unknown. That situation recently changed when, in collaboration with investigators at Washington University in St. Louis, NIEHS scientists published a study indicating that, in the model eukaryote budding yeast, the lagging strand was replicated by DNA polymerase delta. The knowledge that DNA polymerase delta replicates the lagging strand advances the fundamental understanding of how the genome replicates and brings researchers one step closer to understanding the origins of genome instability that underlie environmentally-influenced diseases in humans.
The Ah Receptor Is Essential for Mediating an Anti-Inflammatory Effect
A research team made up of NIEHS Grantees from the University of Rochester and the University of California at Davis has discovered a potentially new role for the Ah receptor in treating inflammatory or immunologic disorders. This research adds new information on the diverse functions of the receptor including xenobiotic metabolism, involvement in proper blood vessel formation, and now immune responses.
The team happened upon this discovery while investigating a low-molecular with compound with potent anti-inflammatory activity known as VAF347. The compound is a drug candidate which inhibits allergic lung inflammation. The team demonstrated that VAF347 interacts with the Ah receptor resulting in stimulation of its signaling pathway. Additional experiments in Ah receptor-deficient mice confirmed the connection. These mice are resistant to the compound’s ability to block allergic lung inflammation. The data indicate the Ah receptor protein is an important target of VAF347 and its importance in mediating the anti-inflammatory effects of the compound.
Although the importance of the Ah receptor in mediating the toxicity of various organic compounds is well known, this finding suggests that harnessing the biological activity of the receptor for therapeutic purposes is possible and suggests a new tool for the treatment of inflammatory and immunologic disorders.
Citation: Lawrence BP, Denison MS, Novak H, Vorderstrasse BA, Harrer N, Neruda W, Reichel C, Woisetschläger M. 2008. Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound. Blood 112(4):1158-65. [Abstract]
Supported by grants R01ES0010619, K02ES012409 and R01ES012498. B. Paige Lawrence, Ph.D., and Michael S. Denison, Ph.D., University of Rochester and University of California, Davis.
RNA Recognition Properties of PUF Proteins Can be Adapted by Simple Substitutions
Researchers at the NIEHS determined the three-dimensional atomic structures of a yeast protein, Puf4p, which regulates target messenger RNA stability. These structural studies, along with biochemical experiments, revealed that the protein bound to its target RNAs with a required "spacer" nucleotide that flipped away from the RNA binding surface. Introduction of two amino acid residue changes reversed the RNA recognition specificity, so that the spacer nucleotide was no longer required. Appropriate regulation of target mRNA expression by PUF proteins is critical for maintenance of stem cell maintenance and embryonic development stem cells in humans and other organisms.
Structural and biochemical studies of yeast PUF4 protein revealed how this family of proteins is adapted to recognize specific, diverse mRNA sequences. This knowledge may be exploited to design PUF proteins for therapeutic or experimental purposes, such as the development of artificial splicing factors to modulate disease-related defects in pre-mRNA splicing.
Citation: Miller MT, Higgin JJ, Hall TMT. 2008. Basis of altered RNA-binding specificity by PUF proteins revealed by crystal structures of yeast Puf4p. Nat Struct Mol Biol 14:397-402. [Abstract] [Synopsis]
Epigenetic Markers Change Over a Lifetime
New findings about the epigenetic markers on an individual’s DNA may explain why some people become more susceptible to disease as they age and why individual disease risk is similar within families. NIEHS-funded researchers at the Bloomberg School of Public Health of Johns Hopkins University found that certain DNA methylation patterns or epigenetic markers change during a person’s lifetime and the amount of change is similar among related people.
The research team analyzed DNA methylation in over 200 individuals from two cohorts of subjects; an Icelandic cohort and a group of people from Salt Lake City. Two samples of DNA, taken 11 years apart, were analyzed from the Icelandic population. One third of them had significant changes in their DNA methylation; some higher, some lower. This change over time represents a proof-of-principle than an individual’s epigenetics does change with age.
The Salt Lake City cohort is made up of two and three generation families whose DNA was sampled 16 years apart. The results show that DNA methylation changes tended to be similar among family members—if one member’s level dropped or increased over time, a similar change occurred in other family members.
The study authors conclude that "the implications of these results are potentially profound for population-based studies of human disease." The epigenetic changes seen over time might directly influence the onset or progression of disease. The epigenetic changes might also reflect age-related or environmental exposures.
Citation: Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekström TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP. 2008. Intra-individual change over time in DNA methylation with familial clustering. JAMA 299(24):2877-83. [Abstract]
Supported by grant R01ES015211. M. Daniele Fallin, Ph.D., Johns Hopkins Bloomberg School of Public Health.
Structures of DNA Polymerase β Provide the First Glimpse of Pre-Mutagenic DNA Synthesis
Researchers at NIEHS used crystallographic structures of DNA polymerase β (Pol β) with right (matched) and wrong (mismatched) nucleotide substrates to gain insight into how mutations were averted during the enzymatic process of DNA synthesis. The team created G-A and C-A mismatches in the Pol β active site by employing a stable nucleotide analog, dAMPCPP, which could bind to the polymerase but not be inserted. The structures revealed that both types of substrates — matched and mismatched — produced the same polymerase conformation. However, the mismatched substrate induced a shift in the template strand that produced an abasic site-like pre-synthesis intermediate.
The structures were consistent with mutagenesis studies and provided a strategy to avert misinsertion of the wrong nucleotide. This study shed light on the specific structural changes necessary during high fidelity DNA synthesis, a process central to DNA repair and replication and, ultimately, the protection against mutations due to environmental exposures.
Citation: Batra VK, Beard WA, Shock DD, Pedersen LC, Wilson SH. 2008. Structures of DNA polymerase beta with active site mismatches suggest a transient abasic site intermediate during misincorporation. Mol Cell 30:315-324. [Abstract] [Synopsis]
New Findings Contradict Aging/Mitochondrial DNA Mutation Theory
Point mutations in mitochondrial DNA do not cause aging in mice according to NIEHS-supported research published in the April issue of Nature Genetics. The data contradict a widely-believed theory that mitochondrial mutation drive the aging process. In the study, mice with mitochondrial mutations 500 times higher than normal levels do not show signs of premature aging.
Previous research has led to the development of the theory that accumulated mitochondrial mutations throughout life eventually cause the decline in tissue functioning associated with aging. The study authors used a new technique to measure the accumulation of mitochondrial DNA mutations. They found that mutation frequency in mouse mitochondria is more than 10 times lower than has been previously reported, suggesting the earlier work overestimated the mutation frequency. The investigators say that the new technique is much more sensitive than previous assays.
The authors used wild-type mice and "mutator" mice with abnormally high levels of mitochondrial mutations. Mice homozygous for the mutator gene have 2,500 times higher numbers of mitochondrial mutations than the wild-type mice and also have a reduced lifespan. However, heterozygotes have about 500 times the numbers of mitochondrial mutations, but show no signs of premature aging or reductions in life-span.
These data suggest that wild-type mice could never accumulate enough mutations to cause aging symptoms. However, since the researchers only counted point mutations, it is possible that large mitochondrial DNA deletions could still be an underlying cause of aging.
Citation: Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS, Prolla TA, Loeb LA. 2008. DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40(4):392-4. [Abstract]
Supported by grant U01ES011045. Lawrence A. Loeb, M.D., Ph.D., University of Washington.
Diabetes Risk Associated with Pesticide Use
NIEHS investigators studied the incidence of diabetes in the Agricultural Health Study, a prospective study of 31,787 licensed pesticide applicators, and found that pesticide applicators that used chlorinated pesticides for more than 100 days in their lifetimes were found to be at greater risk of developing diabetes.
Since enrollment, 1,171 applicators reported a new diagnosis of diabetes, and among the 50 different pesticides studied, seven specific pesticides — aldrin, chlordane, heptachlor, dichlorvos, trichlorfon, alachlor and cyanazine — increased the risk of diabetes in those who had ever used them and those who had increasing days of use. The strongest relationship was found for trichlorfon, with an 85 percent increase in risk for frequent and infrequent users and nearly a 250 percent increase for those who used it more than 10 times. The results suggest that pesticides may be a contributing factor for diabetes along with known risk factors such as obesity, lack of exercise and having a family history of diabetes.
Although the amount of diabetes explained by pesticides is small, these new findings may extend beyond the pesticide applicators in the study. Some of the pesticides used by these workers are used by the general population, though the strength and formulation may vary. Other insecticides in this study are no longer available on the market; however, these chemicals persist in the environment and measurable levels may still be detectable in the general population and in food products.
Citation: Montgomery MP, Kamel F, Saldana TM, Alavanja MCR, Sandler DP. 2008. Incident diabetes and pesticide exposure among licensed pesticide applicators: Agricultural Health Study 1993 – 2003. Am J Epidemiol 167:1235-1246. [Abstract] [Synopsis]
p53 Inhibits Cell Growth As Well As Cell Proliferation
New research findings by NIEHS Grantees at the University of California at San Diego that the tumor suppressor gene p53 is involved in regulating the growth of cells as well as the proliferation of cells. p53 target genes that inhibit cell proliferation had long been known, but its targets for inhibiting cellular growth were unknown.
Abnormal cell proliferation and growth of cells are characteristics of cancer. The p53 protein acts in the cell nucleus to control the expression of other genes whose products can inhibit cell proliferation and growth. The researchers discovered that two p53 target genes, known as Sestrin1 and Sestrin2, provide an important link between p53 and a protein kinase called mTOR, a central regulator of cell size. Incidentally, mTOR is the target for the immunosuppressive drug rapamycin, which was recently shown to have anti-cancer activity.
The major tumor suppressor p53 can either inhibit cell proliferation and cell growth or induce cell death. Its different functions are mediated through numerous target genes and depend on the extent of damage to the cell. More than half of all human cancers are either missing p53 expression or express a defective version of the protein. Understanding the mechanisms by which p53 suppresses tumors may lead to the development of new cancer preventives and chemotherapeutic agents.
Citation: Budanov AV, Karin M. 2008. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134(3):451-60. [Abstract]
Supported by grants R01ES006376, R37ES004151 and P42ES010337. Michael Karin, Ph.D., University of California, San Diego.
An Expanded Biological Repertoire for Inositol(3,4,5,6)-tetraphosphate Through Its Modulation of ClC-3 Function
Inositol phosphates are "second messengers" that can play key roles in helping cells adapt to environmental insults, toxins, infections or genetic defects. Inositol(3,4,5,6)-tetraphosphate [Ins(3,4,5,6)P(4)] inhibits plasma membrane chloride ion flux in secretory epithelia. However, in most other mammalian cells, receptor-dependent elevation of Ins(3,4,5,6)P(4) levels is an "orphan" response that lacks biological significance. NIEHS scientists have shown that the chloride ion channel, ClC-3, is inhibited by Ins(3,4,5,6)P4, thus defining a signal transduction pathway involving Ins(3,4,5,6)P4.
They have also expanded the range of cell types that respond to Ins(3,4,5,6)P4 by showing that Ins(3,4,5,6)P(4) inhibits the ClC-3 conductance in postsynaptic membranes of neonatal hippocampal neurons. This signal transduction pathway could be involved in other cellular processes in which ClC-3 function may be regulated by Ins(3,4,5,6)P4, including tumor cell migration, apoptosis and inflammatory responses. The data suggest that Ins(3,4,5,6)P4 is a ubiquitous cellular signal with diverse biological actions.
Citation: Mitchell J, Wang X, Zhang G, Gentzsch M, Nelson DJ, Shears SB. 2008. An expanded biological repertoire for Ins(3,4,5,6)P4 through its modulation of ClC-3 function. Curr Biol 18:1600-1605. [Abstract]
Maternal Smoking and Receptor Gene Variant Combine To Increase Risk for Childhood Asthma
Exposure to in utero maternal smoking and childhood second hand smoke are associated with wheezing, a common symptom of asthma, according to a new study from NIEHS-funded investigators at the University of Southern California. However, children who were homozygous for a single nucleotide polymorphism in the beta2-adrenergic receptor and who were exposed to maternal smoking in utero were three-times more likely to develop asthma symptoms compared to unexposed children without the altered gene. Similar effects were evident for exposure to second hand smoke during childhood.
Additionally, as the number of smokers increased in the home, the risk for symptoms increased for children with the gene polymorphism. The researchers examined two cohorts of children recruited in 1993 and 1996 and found similar results. The 3,128 non-Hispanic and Hispanic white children were participants in the Children’s Health Study.
These results suggest that because of the high prevalence of asthma in children, intervention strategies are critically needed to reduce smoke exposures to children in general and especially those who are genetically susceptible to the adverse effects of exposure to second hand smoke.
Citation: Wang C, Salam MT, Islam T, Wenten M, Gauderman WJ, Gilliland FD. 2008. Effects of in utero and childhood tobacco smoke exposure and beta2-adrenergic receptor genotype on childhood asthma and wheezing. Pediatrics 122(1):e107-14. [Abstract]
Supported by grants P01ES009581, P01ES011627 and P30ES007048. Frank Gilliland, M.D., Ph.D., University of Southern California.
DEPs Involved in a Novel Blood-Brain Barrier Signaling Pathway
Diesel exhaust particles are the main particulate component of urban air pollution worldwide, and scientists from NIEHS have shown that diesel exhaust particles alter blood-brain barrier function through oxidative stress and proinflammatory cytokine production. When brain capillaries isolated from rats were exposed to diesel exhaust particles, a signaling pathway involving NADPH oxidase and tumor necrosis factor alpha was activated, resulting in increased expression of P-glycoprotein, a major blood-brain barrier transporter. The results revealed a novel blood-brain barrier signaling pathway activated 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. 2008. Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier. FASEB J 22: 2723-2733. [Abstract] [Synopsis]
Enzyme Variant Identified as a Susceptibility Factor for Heart Failure
Researchers from Germany and the U.S. have identified variations in a gene that contributes to heart failure in people with hypertension. Ephx2, codes for the enzyme soluble epoxide hydrolase, which normally degrades specific epoxides. In this case, the epoxides can be cardioprotective in the setting of heart failure but not necessarily relevant for healthy individuals. In persons with heart failure, low Ephx2 activity would not break down the epoxides and as a result, the heart could be protected from further damage. However, in persons with both heart failure and an altered gene resulting in a hyperactive soluble epoxide hydrolase, the epoxides would be degraded and put the person at increased risk for heart failure conditions.
The Centers for Disease Control and Prevention list heart disease as the leading cause of death in the U.S. Heart failure is the third most common cause of death in Western countries, after coronary heart disease and stroke. Heart failure commonly results from coronary disease and hypertension. It usually develops over a long period of time and is therefore commonly seen in older individuals. When the heart is no longer able to pump enough blood to meet the body’s requirements, the heart muscle enlarges in an effort to compensate. However, often the heart does not overcome the increased burden and becomes weakened further, especially in cases of pre-existing hypertension.
Using two strains of laboratory rats, one susceptible to hypertension and stroke and the other susceptible to hypertension and heart failure, the researchers observed that the heart failure rats possessed a single nucleotide polymorphism in the Ephx2 gene that is not present in the stroke prone rats. They conclude the demonstrated role of Ephx2 in the initial stages of heart disease in laboratory animals and humans, suggests "a potential avenue for developing new heart failure treatments."
Citation: Monti J, Fischer J, Paskas S, Heinig M, Schulz H, Gösele C, Heuser A, Fischer R, Schmidt C, Schirdewan A, Gross V, Hummel O, Maatz H, Patone G, Saar K, Vingron M, Weldon SM, Lindpaintner K, Hammock BD, Rohde K, Dietz R, Cook SA, Schunck WH, Luft FC, Hubner N. 2008. Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nat Genet 40(5):529-37. [Abstract]
Supported by grant R37ES002710. Bruce D. Hammock, Ph.D., University of California, Davis.
Neuronal Activity Reshapes Brain Circuitry
During postnatal development, connections between neurons, or synapses, are formed in abundance and then eliminated to shape the brain circuitry according to experience. NIEHS researchers discovered that continued weakening of synapses, induced with prolonged low-frequency stimulation, can lead to loss of synapses. Small synapses were found to be most susceptible to loss. This result represented the first step in uncovering the mechanisms responsible for such activity-dependent synapse elimination, which likely plays an important role in developmental disorders such as schizophrenia and autism.
Citation: Bastrikova N, Gardner GA, Reece JM, Jeromin A, Dudek SM. 2008. Synapse elimination accompanies functional plasticity in hippocampal neurons. Proc Natl Acad Sci USA 105:3123-3127. [Abstract] [Synopsis]
Particulate Air Pollution Can Alter the Electrical Functioning In the Heart
New research findings from $NIEHS Grantees at the Harvard University Department of Environmental Health suggests that exposure to fine particulate air pollution and black carbon particles can adversely affect the heart’s ability to conduct electrical signals in people with pre-existing coronary artery disease. The study conducted with 48 Boston-area heart patients, found changes in the ST-segment of the patient’s electrocardiograms, possibly indicating inadequate blood flow to the heart or inflamed heart muscle.
The average 24-hour levels for all pollutants measured in the study were below accepted National Air Quality standards indicating the patients were breathing air considered healthy. Fine particulate matter and black carbon are combustion by-products and are generated in areas of heavy traffic. The heart effects were highest within the first month after hospitalization, and for heart attack patients or those with diabetes. Previous studies have shown an association between exposure to road traffic and heart problems. %% All the patients had undergone in-hospital procedures to examine or open blocked coronary arteries. The ST-segment changes observed in the study were asymptomatic, but the findings expand the evidence that air pollution can affect heart health, either through inflaming the heart muscle or through reducing blood flow to the heart.
The American Heart Association and the American College of Cardiology recommend that some heart patients, particularly those who have had a heart attack, avoid driving for two to three weeks after leaving the hospital because of the stress heavy traffic can create. This study provides additional rationale to avoid or reduce heavy traffic exposure for people with heart conditions because of the potential exposure to elevated levels of air pollution particles. The study authors suggest additional research is necessary to determine whether the pollution-related ST-segment changes are due to increased heart inflammation, reduced blood flow, oxidative stress, or increased risk of arrhythmias.
Citation: Chuang KJ, Coull BA, Zanobetti A, Suh H, Schwartz J, Stone PH, Litonjua A, Speizer FE, Gold DR. 2008. Particulate air pollution as a risk factor for ST-segment depression in patients with coronary artery disease. Circulation 118(13):1314-20. [Abstract]
Supported by grants P01ES009825 and P30ES000002. Frank E. Speizer, M.D., and Diane R. Gold, M.D., M.P.H., Harvard Medical School.
The Human ERG1 Channel Polymorphism, K897T, Creates a Phosphorylation Site That Inhibits Channel Activity
Polymorphisms in the human ether-a-go-go-related gene 1, hERG1, are associated with cardiac arrhythmias. The Kv11.1 channels encoded by hERG1 are also essential for rhythmic excitability of the pituitary, where they are regulated by thyroid hormone through a signal transduction cascade involving the phosphatidyl¬inositol 3-kinase (PI3K) and the Ser/Thr-directed protein phosphatase, PP5. NIEHS investigators showed that the hERG1 polymorphism at codon 897, which is read as a Thr instead of a Lys, created a new phosphorylation site for the Akt protein kinase on the Kv11.1 channel protein. Consequently, hormonal signaling through the PI3K signaling cascade, which normally stimulates the Lys897 channels through PP5-mediated dephosphorylation, inhibited the Thr897 channels through Akt-mediated phosphorylation.
As a result, hormonal regulation of Kv11.1 in humans with the Lys897Thr polymorphism is predicted to prolong the QT interval of cardiac myocytes. A systematic bioinformatics search for single nucleotide polymorphisms in human ion channel genes identified fifteen additional candidates for such "phosphorylopathies," which are predicted to create or destroy putative phosphorylation sites. Changes in protein phosphorylation may represent a general mechanism for the effects of genetic variation on human health and its interaction with the environment.
Citation: Gentile S, Martin N, Scappini E, Williams J, Erxleben C, Armstrong DL. 2008. The human ERG1 channel polymorphism, K897T, creates a phosphorylation site that inhibits channel activity. Proc Natl Acad Sci USA 105:14704-14708. [Abstract] [Synopsis]
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 as a result of terrorist attacks according to NIEHS-supported research from the University of Alabama Birmingham. The levels of chlorine exposure used in the research study mimic those seen during accidental exposures.
Chlorine is a powerful oxidant that is used in bleaches, disinfectants and in a wide variety of industrial processes. Under normal conditions, it is a pale green gas that is denser than air. Thousands of tons of chlorine gas are transported by rail in the U.S. each year. Recently chlorine rail cars have been suggested as targets for terrorist attacks. Media reports suggest that as many as 100,000 people could be killed or seriously harmed from the explosion of a single railroad tank car traveling through a major city.
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 decrease 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: Postlethwait E, Matalon S. 2008. Mitigation of chlorine-induced lung injury by low-molecular-weight antioxidants. Am J Physiol Lung Cell Mol Physiol 295(5):L733-43. [Abstract]
Supported by grant U01ES015676. Edward Postlethwait, Ph.D., and Sadis Matalon, Ph.D., University of Alabama, Birmingham.
Effect of Prenatal Exposure to the Endocrine Disruptor Bisphenol A on Mammary Gland Morphology and Gene Expression Signature
Bisphenol A (BPA), known as an environmental endocrine disruptor, is widely used as a plasticizer. This study investigated whether exposure to BPA in utero alters the architecture, proliferative index and genomic signature of the rat mammary gland during critical stages of development.
Genomic profiles were obtained by microarray analysis, and some genes were validated by real-time RT-PCR. BPA exposure induced changes in the mammary gland that were time and dose specific. High-dose exposure resulted in architectural modifications, mainly in the number of undifferentiated epithelial structures of the breast tissue. The proliferative index did not show remarkable differences in the effect of BPA.
However, low and high doses of BPA changed the gene expression signature of the mammary gland following a different fashion: low dose had the highest effect by 50 days, while high dose had a highest influence on gene expression by 100 days. Both doses presented a significant cluster of up-modulated genes related to the immune system at the age of maximal changes.
In addition, high-dose exposure induced changes in genes related to differentiation suggesting alterations in the normal development of the gland. The increase of undifferentiated structures and the changes in the gene expression profile at different ages suggested that prenatal exposure to BPA can affect the susceptibility of the mammary gland to transformation.
Citation: Moral R, Wang R, Russo IH, Lamartiniere CA, Pereira J, Russo J. 2008. Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature. J Endocrinol 196(1):101-12. [Abstract]
Supported by grant U01ES012771. Raquel Moral, Richard Wang, Irma H Russo, Coral A Lamartiniere, Julia Pereira and Jose Russo, Fox Chase Cancer Center.
NOS and Nitroglycerin-Mediated Vasodilation
Nitroglycerin helps patients with angina and a past history of heart attacks by relaxing the smooth muscles around blood vessels, which allows more blood to reach cardiac muscles. However, the exact mechanism involved in nitric oxide synthase (NOS) activation was unknown. Researchers at NIEHS and the University of Sao Paulo School of Medicine have found evidence that nitroglycerin triggered constitutive NOS activation using cell cultures, isolated vessels and whole animals. The work may offer insight into the molecular mechanisms involved in nitrate resistance.
The team's studies indicated that endothelial NOS was phosphorylated at Ser1177 on the endothelial isoform and Ser852 on the neuronal isoform in the aorta of mice and rats treated with nitroglycerin. The finding confirmed that NOS isoforms were involved in vasorelaxation. Aortic ring studies determined that high doses of nitroglycerin produced vasodilation that was independent of the endothelium and could not be annulled by NOS inhibitors. At higher doses nitroglycerin is known to be bioactivated to nitric oxide.
Citation: Bonini MG, Stadler K, Silva Sde O, Corbett J, Dore M, Petranka J, Fernandes DC, Tanaka LY, Duma D, Laurindo FR, Mason RP. 2008. Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation. Proc Natl Acad Sci USA 105:8569-8574. [Abstract] [Synopsis]