Environmental Factor, February 2008, National Institute of Environmental Health Sciences
NIEHS Papers of the Year 2007
By Jerry Phelps and Robin Arnette
- IL-6 and Gender Differences in Liver Cancer Rates
- Polymerase Stalling and Transcriptional Regulation
- S-nitrosothiols: Possibilities in Fighting Asthma and Heart Disease
- Breast Enlargement in Prepubertal Boys
- Mutant Astrocytes Play a Role in the Degeneration of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)
- Unique Substrate Specificity of DNA Polymerase Mu
- Predictive Gene Also Maintains Differentiation of Mammary Ductal Cells
- Genes in Blood Can Predict Harmful Levels of Acetaminophen
- Inhibition of RelB Synthesis by ERα Signalling Controls the Shift in Breast Cancer Cell Phenotypes
- RNA Direct Transfer of Gene Information
- Supplementation Counteracts Bisphenol A-Induced Epigenetics Changes
- DNA Polymerase Epsilon and Leading-Strand DNA Replication
- Study Links Gene Expression Changes in Babies to Arsenic Exposure
- Identification of a New Base Excision Repair Cofactor
- Parkinson-like Degenerative Changes Linked to Reduced Dopamine Storage
NIEHS investigators and grantees published nearly 2,800 peer-reviewed scientific studies in 2007. Fifteen studies are highlighted here with findings that range from new insights into basic mechanisms to the demonstration of potentially useful applications of research in the clinical setting:
IL-6 and Gender Differences in Liver Cancer Rates
A study by NIEHS grantees may shed light on why the most common form of liver cancer, hepatocellular carcinoma, strikes men with three to five times the frequency as women.
The research team treated mice with the potent liver carcinogen diethyl nitrosamine, which produced liver tumors in all the males, but in only 10-20 percent of the female mice. The researchers discovered that the male mice produced much more of the inflammatory protein interleukin-6 (IL6) than the females. When IL6 was eliminated in the male mice by treating with estrogen, the liver cancer rate dropped by about 90 percent bringing it in line with the rate in the female mice.
Citation: Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M. 2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317(5834):121-124. [Abstract] (http://www.ncbi.nlm.nih.gov/pubmed/17615358?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) [Synopsis](http://www.niehs.nih.gov/news/newsletter/2007/september/extramuralpapers.cfm#il6)
Supported by grants P42ES010337, R37ES004151 and R01ES006376. Michael Karin, Ph.D., University of California San Diego.
Polymerase Stalling and Transcriptional Regulation
Gene expression begins with the assembly of a multi-protein complex at the gene promoter followed by RNA synthesis. Recruitment of RNA polymerase II to a promoter is necessary for the activation of many genes, but sometimes polymerase activity is inhibited by regulated stalling of polymerase elongation. Using a genome-wide search for genes with RNA polymerase II stalled within the promoter-proximal region, NIEHS scientists demonstrated that stalling is widespread, and occurs at hundreds of genes that respond to stimuli and developmental signals. Thus, polymerase stalling is an important mechanism for transcriptional regulation and may play a role in the control of transcriptional responses to dynamic environmental and developmental cues.
Citation: Muse GW, Gilchrist DA, Nechaev S, Shah R, Parker JS, Grissom SF, Zeitlinger J, Adelman K. 2007. RNA polymerase is poised for activation across the genome. Nat Genet 39(12):1507-1511. [Abstract] (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17994021&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum)
S-nitrosothiols: Possibilities in Fighting Asthma and Heart Disease
NIEHS-funded research suggests the endogenous compound S-nitrosothiol may have clinical implications for a variety of diseases including asthma and heart failure. Researchers found that S-nitrosothiol, a specialized form of nitric oxide, inhibits a key regulatory system that ordinarily decreases the number of beta adrenergic receptors on the surface of cells once they have been stimulated.
Administration of S-nitrosothiols to mice prevented the receptors from being turned off. If these findings are confirmed in humans, they may lead to the development of new non-sensitizing therapeutic agents for many conditions such as heart disease, asthma, high blood pressure, chronic pain, diabetes and others.
Citation: Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, Nelson CD, Benhar M, Keys JR, Rockman HA, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler JS. 2007. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 129(3):511-522. [Abstract] (http://www.ncbi.nlm.nih.gov/pubmed/17482545?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum)
Supported by grant U19ES012496. Jonathan S. Stamler, M.D., Howard Hughes Medical Institute and Duke University Medical Center.
Breast Enlargement in Prepubertal Boys
The authors investigated possible causes of gynecomastia—development of prominent breast tissue in the male—in three healthy prepubertal boys with normal serum concentrations of endogenous steroids. The boys’ gynecomastia coincided with the topical application of products that contained lavender and tea tree oils, but was resolved shortly after discontinuing the use of products containing these oils. Furthermore, studies in human cell lines indicated that the two oils had estrogenic and anti-androgenic activities. Repeated topical exposure to lavender and tea tree oils probably caused the condition.
Citation: Henley DV, Lipson N, Korach KS, Bloch CA. 2007. Prepubertal gynecomstia linker to lavender and tea tree oils. N Engl J Med 356(5):479-485. [Abstract] (http://www.ncbi.nlm.nih.gov/pubmed/17267908?dopt=Abstract) [News Release] (http://www.niehs.nih.gov/news/releases/2007/01312007oils.cfm)
Mutant Astrocytes Play a Role in the Degeneration of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)
Mutations in the gene for superoxide dismutase (SOD1) are known to cause ALS, also known as Lou Gehrig’s disease, in which progressive degeneration of motor neurons leads to paralysis and certain death. In an NIEHS-funded study, researchers expressed this mutant protein in a variety of single cell types in culture. Motor neurons degenerated and died when they were co-cultured with astrocytes expressing mutant SOD1, while mutant SOD1 in neurons, fibroblasts or microglia did not cause neuronal death.
The findings suggest that stem cell therapy focused on replacing damaged neurons may not be feasible in ALS because mutant astrocytes would most likely kill the replacement neurons.
Citation: Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. 2007. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615-622. [Abstract] (http://www.ncbi.nlm.nih.gov/pubmed/17435755?ordinalpos=37&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum)
Supported by grant R21ES013177. Serge Przedborski, Ph.D., Columbia University.
Unique Substrate Specificity of DNA Polymerase Mu
NIEHS scientists, in collaboration with investigators at the University of North Carolina, published this study describing the crystal structure of DNA polymerase mu, an important player in the repair of double-strand breaks (DSB). The results revealed the structural basis of the substrate specificity of this polymerase, which is unique among all DNA polymerases studied to date. The data provided new insights into the repair of potentially cytotoxic DSBs that can be induced by chemotherapeutic agents and by physical and chemical agents in the environment.
Citation: Moon AF, Garcia-Diaz M, Bebenek K, Davis BJ, Zhong X, Ramsden DA, Kunkel TA, Pedersen LC. 2007. Structural insight into the substrate specificity of DNA polymerase mu. Nat Struct Mol Biol 14(1):45-53. [Abstract] (http://www.ncbi.nlm.nih.gov/pubmed/17159995?dopt=Abstract)
Predictive Gene Also Maintains Differentiation of Mammary Ductal Cells
A gene known as GATA-3 is in a family of genes responsible for driving the processes that take stem cells down the path of differentiation that lead to mature cells regardless of their ultimate fate. NIEHS-supported researchers have now determined that GATA-3 is also required for the maintenance of differentiation in ductal cells of the mammary gland. Using laboratory mice genetically altered so that they lack GATA-3, the research team found that mature cells reverted to the less specialized undifferentiated state, which is a characteristic of aggressive cancer cells. The new finding suggests that the gene may play a key role in the development of breast cancer and possibly other malignancies.
Citation: Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. 2006. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127(5):1041-1055. [Abstract] (http://www.ncbi.nlm.nih.gov/pubmed/17129787?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum)
Supported by grant U01ES012801. Zena Werb, Ph.D., University of California, San Francisco.
Genes in Blood Can Predict Harmful Levels of Acetaminophen
NIEHS scientists found that gene expression patterns derived from blood cells can provide useful indicators of acute acetaminophen exposure in rats. Prediction accuracy ranged from 88.9 to 95.8 percent, outperforming predictions based on traditional clinical parameters. Using blood expression levels of human versions of the rat discriminatory genes, the team was able to separate acetaminophen-intoxicated patients from control individuals with inflammation being the major biological signal in the genes. This study suggests that gene expression changes in peripheral blood cells are sensitive indicators of exposures to liver-damaging levels of acetaminophen and may be useful in the clinic.
Citation: Bushel PR, Heinloth AN, Li J, Huang L, Chou JW, Boorman GA, Malarkey DE, Houle CD, Ward SM, Wilson RE, Fannin RD, Russo MW, Watkins PB, Tennant RW, Paules RS. 2007. Blood gene expression signatures predict exposure levels. Proc Natl Acad Sci USA 104(46):18211-18216. [Abstract] (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17984051&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) [Synopsis] (http://www.niehs.nih.gov/news/newsletter/2008/january/intramuralpapers.cfm#gen) [News Release] (http://www.niehs.nih.gov/news/releases/2007/pattern.cfm)
Inhibition of RelB Synthesis by ERα Signalling Controls the Shift in Breast Cancer Cell Phenotypes
NIEHS-funded research findings connect RelB protein with the estrogen receptor alpha (ERα) — and raise the possibility the protein may be useful as a marker for the detection and treatment of metastatic breast cancer. In invasive ERα-negative breast cancer cells, the team found active synthesis of RelB; however, ERα signaling led to an inhibition of RelB synthesis, leading to an inverse correlation between RelB and ERα gene expression in human breast cancer tissues and cell lines.
This work provides further understanding of the role of RelB in human breast cancer and indicates that inhibition of RelB synthesis represents a mechanism by which ERα can control the shift of epithelial cells to a more invasive phenotype.
Citation: Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, Galtier F, Chalbos D, Sonenshein GE. 2007. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol 9(4):470-478. [Abstract]
Supported by grant P01ES011624. Gail E. Sonenshein, Ph.D., Boston University School of Medicine.
RNA Direct Transfer of Genetic Information
In an important twist on DNA targeted double-strand break (DSB) repair, NIEHS researchers established that RNA could play a direct role in the repair of a DSB by serving as a template at the break site. The study greatly expanded previous research findings that had demonstrated mediation of recombination by RNA, but only indirectly through a complementary DNA intermediate. Because RNA can be amplified at any time within cells, the findings could lead to new directions in gene targeting.
Citation: Storici F, Bebenek K, Kunkel TA, Gordenin DA, Resnick MA. 2007. RNA-templated DNA repair. Nature 447(7142):338-341. [Abstract] (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17429354&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) (http://www.niehs.nih.gov/news/newsletter/2007/2007jul.pdf)
Supplementation Counteracts Bisphenol A-Induced Epigenetics Changes
Recent NIEHS-funded research shows that epigenetic patterning induced by bisphenol A during early stem cell development leads to problems with fertility and breast and prostate cancer in rat pups whose mothers were fed the compound in their diets. A new study reports that maternal dietary supplementation with either of the methyl donors folic acid or genestein reversed the epigenetic effects in the offspring by stopping the hypomethylating effect of bisphenol A.
The authors conclude that the results support the inclusion of epigenetic effects of chemicals into risk assessments and support further investigation into possible dietary supplements that might counteract the adverse effects of environmental agents on the epigenome.
Citation: Dolinoy DC, Huang D, Jirtle RL. 2007. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A 104(32):13056-13061. [Abstract] (http://www.ncbi.nlm.nih.gov/pubmed/17670942?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) [Synopsis] (http://www.niehs.nih.gov/news/newsletter/2007/october/extramuralpapers.cfm#counteracts)
Supported by grants R01ES015165, R21ES013053, and T32ES007031. Dana C. Dolinoy, Ph.D. and Randy L. Jirtle, Ph.D., University Program in Genetics and Genomics, Duke University.
DNA Polymerase Epsilon and Leading-Strand DNA Replication
The identity of the “leading strand” polymerase in higher organisms remained uncertain for several decades until investigators at Umeå University in Sweden and NIEHS published a study indicating that among many possibilities, it is specifically DNA polymerase epsilon that participates in replicating the leading strand of the nuclear genome in budding yeast. DNA polymerase epsilon is conserved among higher organisms, including humans. This fundamental discovery of how the genome is replicated places us one step closer to understanding the origins of genome instability that underlie diseases in humans whose occurrence is influenced by the environment.
Citation: Pursell ZF, Isoz I, Lundström EB, Johansson E, Kunkel TA. 2007. Yeast DNA polymerase epsilon participates in leading-strand DNA replication. Science 317(5834):127-130. [Abstract] [Synopsis] [News Release]
Study Links Gene Expression Changes in Babies to Arsenic Exposure
MIT researchers and scientists with Thailand’s Chulabhorn Research Institute report that the children of mothers whose water supplies were contaminated with arsenic during their pregnancies harbored gene expression changes that may lead to cancer and other diseases later in life — even if the children never experience any direct exposure to the pollutant. In addition to establishing the potential harmful effects of these prenatal exposures, the new study also provides a possible method for screening populations to detect signs of arsenic contamination.
This is the first time evidence of such genome-wide changes resulting from prenatal exposure has ever been documented from any environmental contaminant.
Citation: Fry RC, Navasumrit P, Valiathan C, Svensson JP, Hogan BJ, Luo M, Bhattacharya S, Kandjanapa K, Soontararuks S, Nookabkaew S, Mahidol C, Ruchirawat M, Samson LD. 2007. Activation of Inflammation/NF-kappaB Signaling in Infants Born to Arsenic-Exposed Mothers. PLoS Genet 3(11) [Abstract] [Story]
Supported by grants R01ES011399 and P30ES002109. Leona Samson, Ph.D. and Rebecca Fry, Ph.D. Massachusetts Institute of Technology
Identification of a New Base Excision Repair Cofactor
Base excision repair, an important DNA repair pathway for maintenance of the genome, corrects DNA strand breaks and single base DNA damage. This study found that the high-mobility group box 1 (HMGB1) protein specifically interacts and accumulates at sites of oxidative DNA damage in living cells. The results suggest that the chromosomal architectural protein HMGB1 is a base excision repair cofactor capable of modulating base excision repair capacity.
Citation: Prasad R, Liu Y, Deterding LJ, Poltoratsky VP, Kedar PS, Horton JK, Kanno S, Asagoshi K, Hou EW, Khodyreva SN, Lavrik OI, Tomer KB, Yasui A, Wilson SH. 2007. HMGB1 is a cofactor in mammalian base excision repair. Mol Cell 27(5):829-841. [Abstract] [Synopsis]
Parkinson-like Degenerative Changes Linked to Reduced Dopamine Storage
Genetically altered VMAT2 LO mice with a decreased ability to package and store dopamine undergo a degenerative process that mimics Parkinson’s disease, report NIEHS-supported neuroscientists. The mice were carefully bred to be deficient only in the VMAT2 gene, which is responsible for packaging dopamine for future release by neurons.
Previous research found that this mouse strain included a chromosomal deletion spanning the a-synuclein gene locus. The mice were screened to verify the presence of a-synuclein; this study represents the first data on VMAT2 LO mice with normal a-synuclein expression, a quality that could make them useful for testing compounds to slow the course of the Parkinson symptoms.
Citation: Caudle WM, Richardson JR, Wang MZ, Taylor TN, Guillot TS, McCormack AL, Colebrooke RE, Di Monte DA, Emson PC, Miller GW. 2007. Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J Neurosci 27(30):8138-8148. [Abstract] [Synopsis]
Supported by grants T32ES12870, F32ES013457, R21ES013828, U54ES012068, R01ES010806 and U54ES012077. W. Michael Caudle, Jason R. Richardson, Ph.D., Gary W. Miller, Ph.D., Emory University, and Donato DiMonte, M.D., The Parkinson’s Institute