Research funded by grants
- Cadmium exposure linked to shorter telomeres
- Triclosan associated with liver damage in mice
- U.S.-wide study links autism with prenatal exposure to fine particulate air pollution
- Causes of hospitalization during heat waves
- Roadmap epigenomics program maps more than 100 types of cells
- Children’s lungs grew stronger as pollution declined in California
- How alpha-synuclein causes Parkinson’s-associated neural damage
- Th17 cells convert into regulatory T cells during immune response
- Epigenomic mapping of human tissues
- Researchers pinpoint how mutation increases autism risk
- Recombinase enzymes recognize matching DNA three bases at a time
- Newly discovered cells regenerate liver tissue without forming tumors
- Intestinal microbes protect the liver and prevent liver fibrosis
- Discontinuation of tamoxifen may lessen benefit of breast cancer prevention
- Time-lapse crystallography reveals link between oxidative stress and disease
- Genetic and environmental factors interact to affect the severity of infant RSV bronchiolitis
- Ctp1 acts as a bridge over troubled DNA
- Sensitive tool to track replication enzymology
- The origins of the ovarian theca cells
- Mammalian milk secretion uses novel mechanism
- Heart rate variability in relation to Parkinson’s disease risk
- Bidirectional transcription facilitates gene responsiveness
- Enzyme responsible for majority of mutations in certain cancers identified
- Ambient air pollution increases the risk of asthma and wheeze in adult women
- Lack of cross-reactivity between GST allergens could lead to new diagnostic tools
National Toxicology Program research
Research funded by grants
Cadmium exposure linked to shorter telomeres
A study, supported in part by NIEHS, found an association between cadmium exposure and shorter leukocyte telomere length, a marker of cellular aging. Findings from the study also indicate that cadmium might be harmful at levels well below current safety standards set by environmental and occupational safety agencies.
The researchers examined leukocyte telomere length, as well as blood and urine samples, from more than 6,700 adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002. Since other studies have shown an association between shorter leukocyte telomere lengths and diseases of aging, including cardiovascular disease, type 2 diabetes, dementia, and cancer, the findings provide insight into the biological mechanisms underlying cadmium exposure and chronic disease risks.
Citation: Zota AR, Needham BL, Blackburn EH, Lin J, Park SK, Rehkopf DH, Epel ES. 2015. Associations of cadmium and lead exposure with leukocyte telomere length: findings from National Health and Nutrition Examination Survey, 1999-2002. Am J Epidemiol 181(2):127-136. (Synopsis)
Triclosan associated with liver damage in mice
NIEHS grantees report that mice with long-term exposure to the antibacterial agent triclosan experienced fibrosis and acceleration of cancer development in the liver. These findings add to earlier reports that this widely used antimicrobial agent can disrupt hormones and impair muscle contraction.
The researchers exposed mice to triclosan for six months, which equates to approximately 18 human years. Triclosan-treated mice exhibited cell proliferation, liver fibrosis, and proinflammatory responses that together form the type of environment within which human liver cancer forms. The researchers also chemically-induced liver tumors in the mice and found that the mice exposed to triclosan had a large increase in tumor multiplicity, size, and incidence compared to unexposed mice. Findings from the study suggest that triclosan’s negative effects on the liver may result from interference with the constitutive androstane receptor, which plays a role in clearing foreign chemicals from the body.
Citation: Yueh MF, Taniguchi K, Chen S, Evans RM, Hammock BD, Karin M, Tukey RH. 2014. The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci U S A 111(48):17200-17205. (Synopsis) (Story)
U.S.-wide study links autism with prenatal exposure to fine particulate air pollution
NIEHS grantees report that women exposed to high levels of fine particulate matter during pregnancy, particularly in the third trimester, may have up to twice the risk of having a child with autism than mothers exposed to low levels of particulate matter.
The study examined the children of people living in all 50 states who were part of the Nurses' Health Study II, a cohort of more than 116,000 U.S. female nurses. From this group, the researchers identified 245 children with autism and a control group of 1,522 children without autism. They collected data on where participants lived during pregnancy and then predicted their exposure to airborne particulate matter. The analysis showed that exposure during pregnancy to particulate matter with diameters less than or equal to 2.5 microns was significantly associated with an increased risk for autism.
Citation: Raz R, Roberts AL, Lyall K, Hart JE, Just AC, Laden F, Weisskopf MG. 2015. Autism spectrum disorder and particulate matter air pollution before, during, and after pregnancy: a nested case-control analysis within the Nurses' Health Study II cohort. Environ Health Perspect 123(3):264-270. (Synopsis)
Causes of hospitalization during heat waves
Researchers partially funded by NIEHS report that, among older adults, heat waves were associated with increased risk of hospitalization for fluid and electrolyte disorders, renal failure, urinary tract infection, sepsis, and heat stroke. Extreme heat is the most common cause of deaths tied to severe weather in the U.S.
The researchers found that older Americans were 2 1/2 times more likely to be hospitalized from heat stroke during heat wave periods than on nonheat wave days. Extreme heat also put the elderly at 18 percent greater risk of being hospitalized for fluid and electrolyte disorders; 14 percent greater risk for renal failure; 10 percent greater risk for urinary tract infections; and 6 percent greater risk for sepsis. The researchers said that sepsis had not been previously considered a possible outcome of extreme heat.
Roadmap epigenomics program maps more than 100 types of cells
Researchers supported by the National Institutes of Health (NIH) Common Fund Roadmap Epigenomics Program, which is co-led by NIEHS, have mapped the epigenomes of more than 100 types of human cells and tissues. This information can help scientists find out how changes to the genome and epigenome can lead to conditions such as Alzheimer’s disease, cancer, asthma, and fetal growth abnormalities.
The researchers integrated information about histone marks, DNA methylation, DNA accessibility, and RNA expression to produce high-resolution maps of gene regulatory elements across 127 reference epigenomes from a diverse group of cell and tissue types — 111 from the Roadmap Epigenomics Program and 16 from the Encyclopedia of DNA Elements project. The resulting comprehensive catalog of epigenomic data provides a first-of-its kind resource for researchers to make direct comparisons across cell types and tissues.
Citation: Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M. 2015. Integrative analysis of 111 reference human epigenomes. Nature 518(7539):317-330. (Synopsis) (Story)
Children’s lungs grew stronger as pollution declined in California
New research from NIEHS grantees found that as air quality improved in the Los Angeles basin, children’s lung health also improved. Improving lung function during developmental years could lead to greater lung function in adulthood, potentially reducing risks for adverse health outcomes.
As part of the Children's Health Study, the researchers annually measured lung function in three cohorts of children who lived in the same five communities while they were 11-15 years old, but during different calendar periods — 1994-1998, 1997-2001, and 2007-2011. More than 2,000 children were included in the study.
After adjusting for age, gender, ethnicity, height, respiratory illness, and other variations, the researchers found large improvements in lung development for children studied in 2007-2011, compared to children studied in 1994-1998 or 1997-2001. The lung function gains strongly correlated with lower levels of particulate pollution (PM2.5 and PM10) and nitrogen dioxide in the communities studied.
Citation: Gauderman WJ, Urman R, Avol E, Berhane K, McConnell R, Rappaport E, Chang R, Lurmann F, Gilliland F. 2015. Association of improved air quality with lung development in children. N Engl J Med 372(10):905-913. (Synopsis) (Story)
How alpha-synuclein causes Parkinson’s-associated neural damage
New research, funded in part by NIEHS, has revealed key insights into how alpha-synuclein aggregates cause damage to neurons in diseases such as Parkinson’s disease (PD). The research also revealed a possible new therapeutic strategy that might prevent the progressive neuron loss of PD.
In PD, alpha-synuclein aggregates released from neurons activate immune cells known as microglia, leading to chronic neuroinflammation that damages neurons. Using cultured rat cells, the researchers conducted experiments to find out more about how alpha-synuclein affects microglial activity. The experiments showed that neuron-derived alpha-synuclein aggregates act as chemoattractants that direct microglial migration by acting on NADPH oxidase and several downstream proteins. Blocking the targets involved in alpha-synuclein–mediated microglial directional migration could protect against progressive neuronal loss, representing a potential therapeutic strategy for PD and other diseases involving alpha-synuclein aggregates.
Citation: Wang S, Chu CH, Stewart T, Ginghina C, Wang Y, Nie H, Guo M, Wilson B, Hong JS, Zhang J. 2015. Alpha-synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc Natl Acad Sci U S A 112(15):E1926- E1935. (Synopsis)
Th17 cells convert into regulatory T cells during immune response
New research, funded in part by NIEHS, shows that the Th17 lineage of T helper cells, which can cause severe human inflammatory diseases, can also differentiate into regulatory T cells to help resolve inflammation. The instability and plasticity of Th17 might offer a new therapeutic target for inflammatory diseases.
By developing new fate-mapping mouse models to track Th17 cells during immune responses, the researchers found that CD4+ T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. During an immune response, the TH17 cells showed a change in their signature transcriptional profile and acquired a strong regulatory capacity. The transcriptional profiles of Th17 cells before and after conversion into regulatory T cells also revealed a role for transforming growth factor-beta signaling and the aryl hydrocarbon receptor in conversion.
Citation: Gagliani N, Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limon P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA. 2015. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523(7559):221-225. (Synopsis)
Epigenomic mapping of human tissues
As part of the NIH Roadmap Epigenomics Program, an NIEHS grantee and colleagues produced a new atlas of human tissue epigenomes and found that DNA methylation varies greatly among human tissues.
The researchers created a baseline assessment of the epigenome by conducting DNA sequencing of 18 tissue types from four people, and examining DNA methylation. They found widespread differences in the methylation between tissues. Organs extensively differed in the degree of genome-wide methylation. For example, the pancreas had an unusually low level of methylation, while the thymus had high levels of methylation.
As expected, methylation levels tended to be lower around areas of DNA that coded for genes expressed by the type of tissue analyzed. In other words, a cell from muscle tissue had less methylation close to muscle-related genes.
Citation: Schultz MD, He Y, Whitaker JW, Hariharan M, Mukamel EA, Leung D, Rajagopal N, Nery JR, Urich MA, Chen H, Lin S, Lin Y, Jung I, Schmitt AD, Selvaraj S, Ren B, Sejnowski TJ, Wang W, Ecker JR. 2015. Human body epigenome maps reveal noncanonical DNA methylation variation. Nature 523(7559):212-216. (Synopsis)
Researchers pinpoint how mutation increases autism risk
Scientists have identified more than 1,000 gene mutations related to autism, but understanding exactly how they work is elusive. An NIEHS grantee and colleagues report how one of these mutations affects a biochemical pathway that leads to changes in the brain.
The researchers used cell and mouse experiments to study a gene mutation tied to overexpression of the UBE3A enzyme, which studies have suggested must be tightly regulated for normal brain development. They discovered that protein kinase A (PKA) normally phosphorylates UBE3A, acting as a master switch to disengage UBE3A from substrates to block its activity. In cells derived from an autism patient, the researchers observed that an autism-linked mutation disrupted this phosphorylation site, leading to enhanced UBE3A activity and excessive development of small protrusions called dendritic spines on neurons in the brain. A higher than normal density of dendritic spines has been linked with autism.
Citation: Yi JJ, Berrios J, Newbern JM, Snider WD, Philpot BD, Hahn KM, Zylka MJ. 2015. An autism-linked mutation disables phosphorylation control of UBE3A. Cell 162(4):795-807.(Synopsis)
Recombinase enzymes recognize matching DNA three bases at a time
The exchange of genetic information between DNA strands, known as DNA recombination, is important for DNA repair and also drives evolution. New research, funded in part by NIEHS, has revealed the physical basis for these DNA strand exchange reactions.
The researchers studied four different recombinases: Escherichia coli RecA, human Rad51, eukaryotic forms of RecA, and Saccharomyces cerevisiae Dmc1. Imaging studies showed that bacterial RecA, Rad51, and Dmc1 all stabilize strand exchange intermediates in precise three-nucleotide steps, a finding that was confirmed using molecular dynamics simulation.
Additionally, the researchers found that while Rad51, RecA, and Dmc1 can all step over DNA mismatches, only Dmc1, which is specialized for recombination during meiosis, can stabilize a mismatching triplet. This discovery provides insight into why eukaryotes evolved a recombinase that is specialized for meiosis.
Citation: Lee JY, Terakawa T, Qi Z, Steinfeld JB, Redding S, Kwon Y, Gaines WA, Zhao W, Sung P, Greene EC. 2015. Base triplet stepping by the Rad51/RecA family of recombinases. Science 349(6251):977-981. (Synopsis)
Newly discovered cells regenerate liver tissue without forming tumors
Researchers at the University of California, San Diego Superfund Research Program Center, have discovered a population of liver cells that are better at regenerating liver tissue than ordinary liver cells, or hepatocytes. The study is the first to identify these so-called hybrid hepatocytes and show that they are able to regenerate liver tissue without giving rise to cancer. While most of the work described in the study was done in mouse models, the researchers found similar cells in human livers.
They isolated hybrid hepatocytes, conventional hepatocytes, and bile duct cells, and analyzed the differences in their transcriptome, the set of all RNA molecules in the cell. From the analysis, they saw that hybrid hepatocytes were very similar to conventional hepatocytes, but diverge in a few ways that may help explain how they repair liver tissue without leading to tumor cells.
Citation: Font-Burgada J, Shalapour S, Ramasamy S, Hsueh B, Rossell D, Umemura A, Taniguchi K, Nakagawa H, Valasek MA, Ye L, Kopp JL, Sander M, Carter H, Deisseroth K, Verma IM, Karin M. 2015. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162(4):766-779. (Story)
Intestinal microbes protect the liver and prevent liver fibrosis
Bacteria and other microbes in the intestines prevent liver fibrosis, or scarring in mice, according to a study at the University of California, San Diego, funded in part by the NIEHS Superfund Research Program. It is the first study to show a beneficial role of intestinal microbiota in maintaining liver homeostasis and preventing liver fibrosis resulting from chronic damage to the liver.
Researchers compared the onset of liver fibrosis in conventional mice, which have typical intestinal microbiota, to germ-free mice. They induced liver injury in both sets of mice and measured the changes to their livers.
They found increased liver fibrosis in the germ-free mice compared to the conventional mice. Hepatocytes, which make up more than 70 percent of the liver, also showed more oxidative stress and cell death in the germ-free mice.
Citation: Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y, Eckmann L, Dhungana S, Pathmasiri W, Sumner S, Westwater C, Brenner DA, Schnabl B. 2015. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 29(3):1043-1055. (Story)
Discontinuation of tamoxifen may lessen benefit of breast cancer prevention
Although many women who are at higher risk for breast cancer may benefit from taking tamoxifen, a medication approved to prevent and treat breast cancer, high levels of discontinuation of use before five years may lessen potential gains, according to NIEHS epidemiologists.
The researchers identified 788 tamoxifen users among 50,884 women in the Sister Study, a cohort of women who were breast-cancer free at enrollment and had a sister who had been diagnosed with breast cancer. Using a National Cancer Institute risk-benefit index, these women were classified as having no, moderate, or strong evidence that the chemopreventive benefits of tamoxifen outweighed the risk of side effects.
The majority of tamoxifen users had moderate or strong evidence that benefits exceeded risks, but nearly half stopped taking tamoxifen before the recommended five years. Women with a sister diagnosed with breast cancer before tamoxifen initiation or who reported genetic testing appeared more likely to discontinue use.
Time-lapse crystallography reveals link between oxidative stress and disease
NIEHS researchers and colleagues discovered how oxidative stress can lead to blocked DNA repair, which is implicated in many human diseases. They were able to visualize how oxidized DNA nucleotides are incorporated during replication, and how a cell discriminates between damaged and undamaged substrates. These findings could lead to a better understanding of how DNA damage stemming from environmental exposures leads to diseases such as cancer.
Utilizing time-lapse crystallography, a method that allows the visualization of DNA synthesis over time, the team found that incorporation of oxidized DNA substrates confounds later stages of DNA repair, which ultimately may lead to breaks in DNA and cell death. Interestingly, cancerous cells are able to escape cell death in an environment with more oxidative stress by removing oxidized DNA substrates. Targeting the way cancer cells handle oxidative stress may lead to more effective treatments
Citation: Freudenthal BD, Beard WA, Perera L, Shock DD, Kim T, Schlick T, Wilson SH. 2015. Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide. Nature 517(7536):635-639. (Synopsis) (Story)
Genetic and environmental factors interact to affect the severity of infant RSV bronchiolitis
NIEHS scientists and an international team of collaborators determined that living conditions and toll-like receptor 4 (TLR4) genotypes interact in infants to determine the consequence of respiratory syncytial virus (RSV) infection. The findings open new avenues for interventions.
Severe RSV infection is the leading cause of infant hospitalization worldwide. Activation of TLR4, an endotoxin lipopolysaccharide (LPS)-sensing receptor, has been implicated in RSV progression. The researchers studied hospitalized babies with RSV bronchiolitis in rural and urban regions of Argentina. They found that among rural children with high LPS exposure, TLR4 mutations correlating with reduced response to LPS are found more frequently in mild cases, but in urban children with low LPS exposure, the mutations are found more frequently in severe cases.
Citation: Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L, Salim M, Rodriguez A, Reynaldi A, Garcia A, Bado D, Buchholz UJ, Hijano DR, Coviello S, Newcomb D, Bellabarba M, Ferolla FM, Libster R, Berenstein A, Siniawaski S, Blumetti V, Echavarria M, Pinto L, Lawrence A, Ossorio MF, Grosman A, Mateu CG, Bayle C, Dericco A, Pellegrini M, Igarza I, Repetto HA, Grimaldi LA, Gudapati P, Polack NR, Althabe F, Shi M, Ferrero F, Bergel E, Stein RT, Peebles RS, Boothby M, Kleeberger SR, Polack FP.2015. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. J Clin Invest 125(2):571-582. (Synopsis) (Story)
Ctp1 acts as a bridge over troubled DNA
Using X-ray crystallography, biophysical techniques, and yeast genetics, NIEHS scientists revealed that Ctp1/CtIP/Sae2, a critical protein involved in the eukaryotic DNA damage response, binds and bridges DNA. The discovery illuminates a new function for the protein. Ctp1 family proteins coordinate with the Mre11/Rad50/Nbs1 nuclease complex, a central component of DNA double-strand break (DSB) repair machinery.
In describing Ctp1 molecular architecture, the authors identified three key regions with interconnected functionality. First, they determined the crystal structure of a conserved N-terminal tetrameric helical dimer-of-dimers domain (THDD) that enables Ctp1 to form a functional tetramer. Next, they demonstrated that both the THDD and a conserved C-terminal CxxC-RHR motif (RHR) possess DNA binding properties with preference for forked DNA, and that Ctp1 can bind two separate DNA molecules simultaneously. Finally, a flexible, intrinsically disordered region containing multiple DSB-responding protein-binding motifs separates the THDD and RHR.
Citation: Andres SN, Appel CD, Westmoreland JW, Williams JS, NguyenY, Robertson PD, Resnick MA, Williams RS. 2015. Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair. Nat Struct Mol Biol 22(2):158-166. (Synopsis) (Story)
Sensitive tool to track replication enzymology
NIEHS researchers and colleagues demonstrated a novel high-resolution method for tracking in vivo replication enzymology. Taking advantage of ribonucleotide inclusion in eukaryotic DNA as markers of replication, they devised a new 5’ DNA end-mapping method, called hydrolytic end sequencing (HydEn-seq).
The HydEn-seq technique could be applicable to enzymatic DNA hydrolysis or other lesions in DNA. The authors also project the usefulness of this technique for sensing polymerization changes due to endogenous or exogenous environmental stress. Moreover, with the availability of engineered replicases favoring ribonucleotide inclusion, HydEn-seq could also be made applicable to identifying replication origins, termination zones, and polymerase usage in organisms besides yeast.
Citation: Clausen AR, Lujan SA, Burkholder AB, Orebaugh CD, Williams JS, Clausen MF, Malc EP, Mieczkowski PA, Fargo DC, Smith DJ, Kunkel TA. 2015. Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation. Nat Struct Mol Biol 22(3):185-191. (Synopsis)
The origins of the ovarian theca cells
NIEHS scientists and their research partners discovered the origins of the steroid-producing theca cells in the ovary, and the signaling pathways involved in cell fate specification and differentiation of theca cells. During development, the ovary establishes follicles, consisting of the oocyte surrounded by granulosa and theca cells. This unit represents the foundation of mammalian reproduction, and dysfunction in any of these cell types may result in infertility.
Using an inducible lineage-tracing model, the authors showed that adult theca cells stem from two distinct progenitor populations — fetal ovary and early embryonic tissue, called mesonephros. Ovary-derived theca cells exhibit higher expression of genes implicated in cell growth and proliferation, while those derived from the mesonephros are enriched for genes that regulate steroidogenesis. Regardless of their origin or adult function, the same signaling pathway is responsible for theca cell differentiation from the two populations.
Citation: Liu C, Peng J, Matzuk MM, Yao HH. 2015. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells. Nat Commun 6:6934. (Synopsis) (Story)
Mammalian milk secretion uses novel mechanism
According to NIEHS scientists and their co-authors, Orai1, a calcium channel subunit, is responsible for delivering 50 percent of the calcium ions present in mammalian milk, and for signaling milk secretion through mammary cell contractility. The finding that Orai1 is required for milk ejection redefines how the process is thought to occur. The paper described this important mechanism behind the process of lactation.
Using genetically modified mice, the researchers found that mice lacking Orai1 produced milk containing low concentrations of calcium. They also captured the pulsating contractions of the mammary alveoli and quantified the dependency of alveoli cells on Orai1, using state-of-the-art 3-D imaging technology. Alveoli from mice without Orai1 exhibited infrequent contractions, were less responsive to oxytocin, and were less coordinated. These data demonstrate that calcium ions play a role in cellular signaling greater than being simply a nutritional component.
Citation: Davis FM, Janoshazi A, Janardhan KS, Steinckwich N, D’Agostin DM, Petranka JG, Desai PN, Roberts-Thomson SJ, Bird GS, Tucker DK, Fenton SE, Feske S, Monteith GR, Putney JW Jr. 2015. Essential role of Orai1 store-operated calcium channels in lactation. Proc Natl Acad Sci U S A 112(18):5827-5832. (Synopsis)
Heart rate variability in relation to Parkinson’s disease risk
Using data from the 20-year Atherosclerosis Risk in Communities (ARIC) study, NIEHS scientists provided the first epidemiological evidence that decreased heart rate variability (HRV) is associated with an increased risk of neurodegeneration in Parkinson’s disease (PD), years prior to the manifestation of detectable motor symptoms. HRV is a marker of alterations in the cardiac autonomic system.
In addition to cardinal motor dysfunctions, such as tremor, patients often suffer from a range of nonmotor symptoms. These symptoms may include sleep disturbances, smell and taste dysfunction, constipation, and changes in HRV. Research on this pathology and other nonmotor symptoms in the prodromal stage of PD may lead to methods for identifying individuals with higher risk of PD and to a better understanding of disease etiology.
Citation: Alonso A, Huang X, Mosley TH, Heiss G, Chen H. 2015. Heart rate variability and the risk of Parkinson disease: the Atherosclerosis Risk in Communities study. Ann Neurol 77(5):877-883. (Synopsis)
Bidirectional transcription facilitates gene responsiveness
NIEHS researchers shed new light on the regulatory landscape surrounding mammalian protein-coding genes, enhancing the understanding of the basic mechanisms of how cells respond to stresses from their environment. The scientists reported that bidirectional promoters contributed to an optimized environment for recruitment of transcription factors and the transcription machinery.
Using bone marrow-derived macrophages from C57BL/6 mice, high-throughput sequencing of transcription start site (TSS)-associated RNAs was performed to precisely annotate both sense and anti-sense TSSs near mouse mRNA genes. Bidirectional promoter architecture was found to be widespread, as anti-sense TSSs were observed at more than 75 percent of active promoters. The study revealed two previously unappreciated features of promoter architecture that affect both resting and stimulus-responsive transcription, as seen during immune challenge.
Citation: Scruggs BS, Gilchrist DA, Nechaev S, Muse GW, Burkholder A, Fargo DC, Adelman K. 2015. Bidirectional transcription arises from two distinct hubs of transcription factor binding and active chromatin. Mol Cell 58(6):1101-1112. (Synopsis)
Enzyme responsible for majority of mutations in certain cancers identified
Scientists were aware that the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) cytidine deaminases were capable of inducing DNA damage and mutations, but a team led by NIEHS researchers determined that mutations made by APOBEC3A were more frequently found in certain cancers. Other researchers previously named APOBEC3B as the deaminase primarily responsible for a majority of DNA mutations in cancerous cells.
APOBEC3A and APOBEC3B prefer distinct DNA motifs, which allowed the researchers to follow their signatures in The Cancer Genome Atlas, a cancer sequence database. They mined 15 published cohorts of cancer whole-genome mutations and found that five cancer types — bladder, breast, head and neck, lung adenocarcinoma, and lung squamous cell carcinoma — had a significant presence of APOBEC signatures. In these cancers, APOBEC3A caused 10 times more DNA sequence changes than APOBEC3B.
Citation: Chan K, Roberts SA, Klimczak LJ, Sterling JF, Saini N, Malc EP, Kim J, Kwiatkowski DJ, Fargo DC, Mieczkowski PA, Getz G, Gordenin DA. 2015. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet 47(9):1067-1072. (Synopsis) (Story)
Ambient air pollution increases the risk of asthma and wheeze in adult women
Long-term exposure to particulate matter less than 2.5 micrometers in diameter (PM 2.5) increases the risk of developing asthma and wheeze in adult women, according to NIEHS researchers and collaborators. These results suggest that respiratory effects are apparent at levels well below current national standards.
Using PM 2.5 and nitrogen dioxide (NO2) concentrations estimated in the Sister Study, a nationwide cohort study of more than 50,000 U.S. women, researchers examined how ambient air pollution was related to follow-up self-reports of wheeze, chronic cough, and doctor diagnosed asthma in women without baseline symptoms. PM 2.5 and NO2 concentrations were estimated at participants’ primary addresses at the time of study enrollment, and annual averages were then derived from a national network of air pollution monitoring stations. In addition to the associations with PM2.5, there was evidence for an association of NO2 with wheeze.
Citation: Young MT, Sandler DP, DeRoo LA, Vedal S, Kaufman JD, London SJ. 2014. Ambient air pollution exposure and incident adult asthma in a nationwide cohort of U.S. women. Am J Respir Crit Care Med 190(8):914-921. (Synopsis)
Lack of cross-reactivity between GST allergens could lead to new diagnostic tools
NIEHS scientists and colleagues determined that glutathione S-transferase (GST) allergens from cockroach, roundworm, and two dust mite species did not contain cross-reactive sites. Since the finding contradicts previous studies that suggested these GST allergens were cross-reactive, allergists can use the information to offer a more accurate diagnosis of the sensitizing organism and suggest the appropriate treatment. The discovery was the result of IgE reactivity assays and crystal structure data of allergen GSTs generated by the NIEHS members of the team.
The researchers investigated the IgE reactivity of U.S. patients allergic to cockroach and mite GSTs from four species, by comparing the common solvent-accessible areas in the crystal structures that could be responsible for cross-reactivity. They also tested IgE antibodies from patients who are normally exposed to cockroach and mite allergens, but not to roundworm allergen or the tropical species of mite.
Citation: Mueller GA, Pedersen LC, Glesner J, Edwards LL, Zakzuk J, London RE, Arruda LK, Chapman MD, Caraballo L, Pomes A. 2015. Analysis of glutathione S-transferase allergen cross-reactivity in a North American population: relevance for molecular diagnosis. J Allergy Clin Immunol 136(5):1369-1377. (Synopsis)
NTP contributes to the 1000 Genomes High-Throughput Screening Study
NTP scientists and their research partners conducted the 1000 Genomes High-Throughput Screening Study, a population-wide in vitro cytotoxicity screening method that provides rapid estimates of human toxicodynamic variability and data on mechanisms that contribute to variation between individuals.
The researchers assessed variation in response to 179 chemicals by testing 1,086 lymphoblastoid cell lines (LCLs) from the 1000 Genomes Project, which represented nine populations from five continents, with diverse geographical and ancestral origins. Various concentrations for each chemical were applied to LCLs, and approximately half of the chemicals produced a cytotoxic response. Several of these toxic chemicals were shown to associate with a single nucleotide polymorphism, called rs13120371, in the solute carrier transporter gene SLC7A11. The gene had previously been implicated in chemoresistance, and the findings suggest a major role for membrane proteins and solute carrier transporters in an individual’s susceptibility to environmental chemicals.
Citation: Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA. 2015. Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect 123(5):458-466. (Synopsis)
NTP finds toxicity associated with organophosphorus flame retardants
Manufacturers are turning away from using brominated flame retardants (BFRs) because of their toxicity and environmental persistence, but a team led by NTP researchers found that many organophosphorus flame retardants (OPFRs), the chemicals used to replace BFRs, may pose similar health hazards.
Utilizing cell-based in vitro assays and in vivo model systems using lower organisms, such as zebrafish and C. elegans, team members evaluated the potential for developmental toxicity and neurotoxicity among eight OPFRs. They covered a wide range of structures, and compared their activities with two well-characterized BFRs, tetrabromobisphenol A and tetrabromodiphenyl ether.
Assays revealed that exposure to many OPFRs caused adverse effects at equal or greater potency than BFRs. However, not all OPFRs were active in assays used to test these chemicals. These findings suggest that OPFRs differ in their health effects and lay the groundwork for further evaluation.
Citation: Behl M, Hsieh JH, Shafer TJ, Mundy WR, Rice JR, Boyd WA, Freedman JH, Hunter ES 3rd, Jarema K, Padilla S, Tice RR. 2015. Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity. Neurotoxicol Terato 52(Pt B):181-193. (Synopsis)
NTP finds molecular differences between hepatoblastomas and hepatocellular carcinomas
NTP researchers demonstrated that mouse hepatoblastoma (HB) is molecularly distinct from a hepatocellular carcinoma (HCC). They also determined that mouse HB is similar to human HB at the genomic level. The work suggests that mouse HB is a suitable model for evaluating human cancer.
The scientists used HB, HCC, and normal liver samples from B6C3F1 mice to determine relationships in global gene expression and mutation spectra of Ctnnb1 and Hras, two common hepatic cancer genes. They found that mouse and human HB share similarities, including embryonic development pathway dysregulation, stem cell pluripotency pathways, and genomic imprinting. In contrast, HB and HCC had strikingly different global gene expression and mutation spectra, although both may arise from a common hepatic progenitor cell. They suggest that exome sequencing at high read depths and cell lineage tracing experiments may further define the cellular origin of HB.
Citation: Bhusari S, Pandiri AR, Nagai H, Wang Y, Foley J, Hong HL, Ton TV, DeVito M, Shockley KR, Peddada SD, Gerrish KE, Malarkey DE, Hooth MJ, Sills RC, Hoenerhoff MJ. 2015. Genomic profiling reveals unique molecular alterations in hepatoblastomas and adjacent hepatocellular carcinomas in B6C3F1 mice. Toxicol Pathol 43(8):1114-1126. (Synopsis)