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Environmental Factor, January 2013

2012 papers of the year

Research funded by grants (click title for abstract)

In-house research (click title for abstract)

National Toxicology Program research (click title for abstract)

 

Research funded by grants 

Non-coding DNA variants may link early exposures with later health problems

Researchers, supported in part by NIEHS, report that genetic differences linked to a variety of diseases are activated during fetal development. These findings could help explain why some early environmental exposures increase disease risk years or even decades later.

The researchers investigated whether variants in noncoding regions of DNA regulate gene expression, by looking at thousands of these variants identified in genome-wide association studies (GWAS). The researchers also identified the genes regulated by hundreds of GWAS variants, including genes associated with several diseases. Almost 80 percent of GWAS variants in regulatory DNA were connected to genes that were not the closest ones to the variant, which is probably why previous attempts to link GWAS variants with target genes have been so difficult.

Citation: Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA. (http://www.ncbi.nlm.nih.gov/pubmed/22955828)  2012. Systematic localization of common disease-associated variation in regulatory DNA. Science 337(6099):1190-1195. [synopsis]

 

Reversible epigenetic changes associated with bee behavior

Researchers studying honeybees report what could be the first evidence of reversible epigenetic changes associated with behavior. The research may shed light on problems that people have with learning, memory, stress response, and mood disorders, which all involve interactions between genetic and epigenetic components. The work was supported by an NIH Director’s Pioneer Award.

The researchers found no differences in DNA methylation between worker and queen bees, roles that are irreversible. However, they saw substantial differences between nurses and forager bees. Reverting foragers back to nurses reestablished methylation levels for a majority of genes, providing evidence of reversible epigenetic changes that are associated with behavior.

Citation: Herb BR, Wolschin F, Hansen KD, Aryee MJ, Langmead B, Irizarry R, Amdam GV, Feinberg AP. (http://www.ncbi.nlm.nih.gov/pubmed/22983211)  2012. Reversible switching between epigenetic states in honeybee behavioral subcastes. Nat Neurosci 15(10):1371-1373. [synopsis]

 

Triclosan impairs heart and skeletal muscle contractility

NIEHS grantees report that triclosan hinders muscle contractions at a cellular level and also causes muscle problems in fish and mice. Triclosan is an antibacterial agent widely used in personal-care products such as hand soap and toothpaste, and it has been detected in waterways and fish. This new study provides evidence of the chemical’s potentially negative effects on human and environmental health and also reveals a mechanism for these effects.

Mice given a single dose of triclosan showed an 18-percent reduction in grip strength for up to 60 minutes. Minnows exposed to triclosan in the water for seven days showed significantly reduced swimming activity compared to controls.

Citation: Cherednichenko G, Zhang R, Bannister RA, Timofeyev V, Li N, Fritsch EB, Feng W, Barrientos GC, Schebb NH, Hammock BD, Beam KG, Chiamvimonvat N, Pessah IN. (http://www.ncbi.nlm.nih.gov/pubmed/22891308)  2012. Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle. Proc Natl Acad Sci U S A 109(35):14158-14163. [synopsis]

 

Whole genome sequencing reveals genetic basis for diversity and evolution

In one of the first population genomics studies to use high-coverage whole-genome sequencing, NIEHS-supported researchers analyzed the genomes of 15 Africans from three different hunter-gatherer groups. The work reveals new insight into human diversity and evolution and also shows the potential of new genome sequencing technology for uncovering the genetic basis of normal variations in humans and for identifying the genetic basis of disease risk.

The results from the genome analysis provide evidence that the direct ancestors of modern humans might have interbred with members of an unknown ancestral group of hominins and that different groups evolved distinctly. The work also identifies new candidate genes that are likely involved in making Pygmies short in stature.

Citation: Lachance J, Vernot B, Elbers CC, Ferwerda B, Froment A, Bodo JM, Lema G, Fu W, Nyambo TB, Rebbeck TR, Zhang K, Akey JM, Tishkoff SA. (http://www.ncbi.nlm.nih.gov/pubmed/22840920)  2012. Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers. Cell 150(3):457-469. [synopsis]

 

Gene variants linked with faster Parkinson’s disease progression

NIEHS grantees report that Parkinson's disease patients with two specific variants of the alpha-synuclein gene progressed toward motor decline significantly faster than patients without these variants. This work could lead to new therapies and help identify those who would benefit most from early intervention.

Although the findings need replication in other well-characterized Parkinson’s disease populations, the researchers say that their work shows that these gene variants could be used to identify patients who will likely experience faster disease progression. The work also points to the alpha-synuclein pathway as a promising potential therapeutic target.

Citation: Ritz B, Rhodes SL, Bordelon Y, Bronstein J. (http://www.ncbi.nlm.nih.gov/pubmed/22615757)  2012. Alpha-synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease. PLoS One 7(5):e36199. [synopsis

 

Cardiovascular effects of Beijing Olympics air pollution reduction

The Chinese government shut down factories and limited automobile traffic during the Beijing Olympics, to lessen air pollution. These temporary changes in air pollution levels were associated with acute changes in cardiovascular biomarkers in healthy young people, according to a study from NIEHS grantees. The research adds evidence that higher levels of air pollution are linked with an increased risk of cardiovascular problems.

During the Olympics, the study participants showed significant reductions in von Willebrand factor and soluble CD62P levels, which are both associated with blood coagulation. Soluble CD62P and systolic blood pressure levels increased significantly once the pollution controls were lifted after the Olympics.

Citation: Rich DQ, Kipen HM, Huang W, Wang G, Wang Y, Zhu P, Ohman-Strickland P, Hu M, Philipp C, Diehl SR, Lu SE, Tong J, Gong J, Thomas D, Zhu T, Zhang JJ. (http://www.ncbi.nlm.nih.gov/pubmed/22665106)  2012. Association between changes in air pollution levels during the Beijing Olympics and biomarkers of inflammation and thrombosis in healthy young adults. JAMA 307(19):2068-2078. [synopsis] [story]

 

Environmental exposures influence behavior of later generations

A new NIEHS-funded study shows that animals whose ancestors were exposed to a fungicide have a more profound reaction to stress than the offspring of unexposed animals. The work demonstrates that an ancestor’s exposure can influence the stress response of future generations.

The authors of the study used a systems biology approach by examining genetic and molecular changes in the brain as well as behavior. They exposed gestating female rats to the fungicide vinclozolin and later performed testing on the third generation of offspring. When exposed to stress during adolescence, the offspring of exposed rats had greater anxiety, sensitivity to stress, and more activity in stress-related regions of the brain.

Citation: Crews D, Gillette R, Scarpino SV, Manikkam M, Savenkova MI, Skinner MK. (http://www.ncbi.nlm.nih.gov/pubmed/22615374)  2012. Epigenetic transgenerational inheritance of altered stress responses. Proc Natl Acad Sci U S A 109(23):9143-9148. [synopsis]

 

Autism risk linked to maternal diabetes and obesity

Findings from the NIEHS-funded Childhood Autism Risks from Genetics and the Environment (CHARGE) study provide evidence that maternal metabolic conditions can increase the risk for autism, as well as developmental delay without autistic symptoms. The findings suggest that fetal exposure to elevated levels of glucose and maternal inflammation adversely affect fetal development.

The metabolic conditions studied included obesity or hypertension at the start of pregnancy, or diabetes during pregnancy, which were linked with significantly increased risk for having a child with autism or other developmental disorders. In addition, children with autism spectrum disorder and diabetic mothers had greater deficits in adaptive communication, language comprehension, and language production than children with autism spectrum disorder born to healthy mothers.

Citation: Krakowiak P, Walker CK, Bremer AA, Baker AS, Ozonoff S, Hansen RL, Hertz-Picciotto I. (http://www.ncbi.nlm.nih.gov/pubmed/22492772)  2012. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics 129(5):e1121-1128. [synopsis

 

Health implications of temperature variability

Climate change is expected to bring increasing variability in summer temperatures, which could shorten life expectancy for older people with chronic medical conditions, according to an NIEHS-funded study. Although other studies have looked at the short-term effects of heat waves, this study examined the long-term effects of climate change on life expectancy.

The researchers used Medicare data from 1985 to 2006 to follow the health of 3.7 million chronically ill people over age 65. They studied whether mortality related to variability in summer temperature in 125 cities and took into account other factors, such as winter temperature variance, ozone levels, and individual risk factors. They compiled results for 125 individual cities and then pooled the results.

Citation: Zanobetti A, O'Neill MS, Gronlund CJ, Schwartz JD. (http://www.ncbi.nlm.nih.gov/pubmed/22493259)  Summer temperature variability and long-term survival among elderly people with chronic disease. Proc Natl Acad Sci U S A 109(17):6608-6613. [synopsis] [story]

 

Air pollution linked to cognitive decline

In one of the first studies of its kind, NIEHS grantees report that a significantly faster decline in the cognitive function of older women is associated with long-term exposure to particulate matter (PM) air pollution at levels typical of many areas of the U.S.

The researchers estimate that a 10-microgram per cubic meter increase in long-term PM exposure was cognitively equivalent to aging by approximately two years. If the findings are confirmed in other studies, reducing air pollution could offer a way to lessen age-related cognitive decline and, because cognitive decline often precedes the development of dementia, a way to reduce the future population burden of dementia.

Citation: Weuve J, Puett RC, Schwartz J, Yanosky JD, Laden F, Grodstein F. (http://www.ncbi.nlm.nih.gov/pubmed/22332151)  2012. Exposure to particulate air pollution and cognitive decline in older women. Arch Intern Med 172(3):219-227. [synopsis]

 

The cost of asthma from traffic-related air pollution

NIEHS-funded researchers have estimated that childhood asthma associated with air pollution in Long Beach and Riverside, Calif., costs $18 million each year.

Using a new method that researchers say more accurately estimates the overall burden of asthma and the costs associated with air pollution, they calculated the total annual cost for a typical asthma case to be $3,819 in Long Beach and $4,063 in Riverside. The largest portion of this cost came from asthma-related school absences, which often require that parents or caregivers miss work. The investigators say that their new method takes into account the full impact of traffic-related pollution and can be applied to other urban areas.

Citation: Brandt SJ, Perez L, Künzli N, Lurmann F, McConnell R. (http://www.ncbi.nlm.nih.gov/pubmed/22267764)  2012. Costs of childhood asthma due to traffic-related pollution in two California communities. Eur Respir J 40(2):363-70. [synopsis] [story]

 

Menthol lessens irritation from cigarette smoke

An NIEHS-supported study has shown that menthol, the cooling agent in peppermint, counteracts the irritating effects of cigarette smoke constituents. The researchers studied acrolein, acetic acid, and cyclohexanone, which are irritating components of cigarette smoke that vary widely in their chemical structure and biological properties. The experiments demonstrated that menthol’s counterirritant effects resulted from activation of the chemical receptor TRPM8.

By suppressing reactions such as coughing, menthol could increase the amount of smoke inhaled and thus promote addiction to nicotine. The 2009 Family Smoking Prevention and Tobacco Control Act banned flavored tobacco additives but exempted menthol while the U.S. Food and Drug Administration evaluated scientific data.

Citation: Willis DN, Liu B, Ha MA, Jordt SE, Morris JB. (http://www.ncbi.nlm.nih.gov/pubmed/21903934)  2011. Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants. FASEB J 25(12):4434-4444. [synopsis] [story]

 

Perfluorinated compounds and immune response in children

Research funded by NIEHS has shown that elevated exposure to perfluorinated compounds was associated with reduced immune responses in children.

The prospective study found that children with elevated exposure to perfluorinated compounds had lower antibody responses to childhood immunizations. The antibody response to childhood immunization reflects how well the immune system is functioning. The researchers report that this study is one of the first to link childhood exposure to perfluorinated compounds with immune system deficiency. The results point to the importance of assessing the immunotoxic potential of these compounds, which are highly persistent and can contaminate drinking water, as well as food.

Citation: Grandjean P, Anderson EW, Budtz-Jorgensen E, Nielsen F, Molbak K, Weihe P, Heilmann C. (http://www.ncbi.nlm.nih.gov/pubmed/22274686)  2012. Serum vaccine antibody concentrations in children exposed to perfluorinated compounds. JAMA 307(4):391-397. [synopsis] [story]

 

Rice consumption and arsenic exposure in pregnant women

NIEHS grantees report that urinary arsenic concentrations were higher for pregnant women who had recently consumed rice than for those who had not. The findings highlight the need to monitor arsenic levels in food.

The researchers tested for arsenic in the urine of 229 pregnant women in New Hampshire, 73 of whom reported eating rice during the two days before urine collection. The arsenic concentration of the tap water in the women’s homes was also tested to identify any exposure from drinking water. The women who reported eating rice during the two days prior to urine collection had a median total urinary arsenic concentration of 5.27 micrograms per liter, which was significantly different from the 3.38 micrograms per liter median concentration for those who did not consume rice.

The researchers note the need for more research to determine any health impacts of this source of exposure. Any identified health risks will also need to be weighed against the nutritional benefits of eating rice.

Citation: Gilbert-Diamond D, Cottingham KL, Gruber JF, Punshon T, Sayarath V, Gandolfi AJ, Baker ER, Jackson BP, Folt CL, Karagas MR. (http://www.ncbi.nlm.nih.gov/pubmed/22143778)  2011. Rice consumption contributes to arsenic exposure in US women. Proc Natl Acad Sci U S A 108(51): 20656-20660. [synopsis] [story]

 

Consuming canned soup linked to higher BPA levels

Researchers funded by NIEHS found that a group of volunteers who consumed a serving of canned soup every day for five days had more than a 1,000 percent increase in urinary bisphenol A (BPA) concentrations than when the same individuals consumed fresh soup daily for five days.

Eating a serving of canned soup daily was associated with a 1,221 percent increase in BPA concentration compared to levels in urine collected after consumption of fresh soup. Even though the elevation in urinary BPA concentrations might be temporary, the researchers comment that their findings could be important, especially as more and improved alternatives to epoxy linings are developed.

Citation: Carwile JL, Ye X, Zhou X, Calafat AM, Michels KB. (http://www.ncbi.nlm.nih.gov/pubmed/22110104)  2011. Canned soup consumption and urinary bisphenol A: a randomized crossover trial. JAMA 306(20):2218-2220. [synopsis]

 

 

In-house research

EET research may help in the fight against cancer

A collaborative team of NIEHS-funded scientists has found that the removal of small molecules produced in the body called epoxyeicosatrienoic acids (EETs) may prevent the formation of blood vessels that feed tumor cells.

High levels of EETs are beneficial in patients with diseases, such as hypertension, heart attack, and stroke, because the molecules cause blood vessels to dilate. However, the team determined for the first time that EETs in the healthy tissue surrounding the tumors also work with a protein known to induce blood vessel growth, called vascular endothelial growth factor, to activate blood vessel formation that feeds tumors. Mice in the experiments with higher EETs produced more metastatic tumors than mice with lower EETs.

Citation: Panigrahy D, Edin ML, Lee CR, Huang S, Bielenberg DR, Butterfield CE, Barnés CM, Mammoto A, Mammoto T, Luria A, Benny O, Chaponis DM, Dudley AC, Greene ER, Vergilio JA, Pietramaggiori G, Scherer-Pietramaggiori SS, Short SM, Seth M, Lih FB, Tomer KB, Yang J, Schwendener RA, Hammock BD, Falck JR, Manthati VL, Ingber DE, Kaipainen A, D'Amore PA, Kieran MW, Zeldin DC. (http://www.ncbi.nlm.nih.gov/pubmed/22182838)  2012. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest 122(1):178-191. [synopsis] [story]

 

Calcium influx is a critical component of embryonic development

Upon fertilization by the sperm, repetitive calcium oscillations occur as a result of the movement of calcium from egg storage or outside the cell, into the egg cytoplasm, and then back into storage or out of the egg. These calcium oscillations are essential for mammalian egg activation and the early stages of embryonic development.

NIEHS scientists determined that some of the signaling pathways induced by calcium movements take place directly under the egg's plasma membrane, rather than entirely inside of the egg. The research has far-reaching implications for clinically assisted reproduction and fertility preservation technologies, since defects in calcium signaling at fertilization can result in a failure of the embryo to implant or develop to term.

Citation: Miao YL, Stein P, Jefferson WN, Padilla-Banks E, Williams CJ. (http://www.ncbi.nlm.nih.gov/pubmed/22371584)  2012. Calcium influx-mediated signaling is required for complete mouse egg activation. Proc Natl Acad Sci U S A 109(11):4169-4174. [synopsis] [story]

 

Pol II pausing modulates basal gene expression in signal transduction cascades

NIEHS scientists have revealed that RNA polymerase II (Pol II) pausing does not necessarily lead to higher gene expression upon induction of stimulus-responsive networks. Rather, it is important in modulating basal gene expression. The research offers a new model for understanding how paused Pol II impacts gene expression in resting cells.

The researchers found that many downstream target genes were rapidly induced, despite not harboring paused Pol II at their promoters prior to pathogenic challenge. Their findings indicate that, although the regulatory components are more modestly expressed in response to immune challenge, their basal expression in resting cells is more tightly regulated so that these cells are better poised to rapidly initiate the immune response cascade as needed.

Citation: Gilchrist DA, Fromm G, dos Santos G, Pham LN, McDaniel IE, Burkholder A, Fargo DC, Adelman K. (http://www.ncbi.nlm.nih.gov/pubmed/22549956)  2012. Regulating the regulators: the pervasive effects of Pol II pausing on stimulus-responsive gene networks. Genes Dev 26(9):933-944. [synopsis]

 

Clustered mutations attributed to body’s natural defenses

A team of NIEHS-funded scientists has identified DNA regions with a high number of nonrandom mutations in yeast and some human cancers. Contrary to the traditionally held view that mutations occur randomly, these mutations were not caused by environmental damage, but by a specific set of proteins known as APOBEC cytosine-deaminases, which are part of the human immune system’s response to viruses that enter the body.

The research team developed bioinformatics tools to determine if human cancers contained similar mutation clusters similar to those found in yeast and, surprisingly, nearly half of them did. The results of this study suggest that several antiviral drugs, capable of stimulating APOBEC genes, should be considered potential mutagens.

Citation: Roberts SA, Sterling J, Thompson C, Harris S, Mav D, Shah R, Klimczak LJ, Kryukov GV, Malc E, Mieczkowski PA, Resnick MA, Gordenin DA. (http://www.ncbi.nlm.nih.gov/pubmed/22607975)  2012. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell 46(4):424-435. [synopsis] [story]

 

Fertility drugs and young-onset breast cancer

Among participants in the NIEHS Two Sister Study, funded in part by Susan G. Komen for the Cure, women who had used ovary-stimulating fertility drugs, clomiphene citrate or follicle-stimulating hormone, without getting pregnant, had reduced risk of young-onset breast cancer.

Participants were pairs of sisters, one of whom had been diagnosed with breast cancer before the age of 50. They were categorized based on whether they had used ovulation-stimulating fertility drugs and whether pregnancy had resulted. Unlike previous studies, the Two Sister Study distinguished between fertility treatments that produced pregnancy versus those that did not. Moreover, use of sisters who are well-matched for many factors allows for a fair comparison.

Citation: Fei C, DeRoo LA, Sandler DP, Weinberg CR. (http://www.ncbi.nlm.nih.gov/pubmed/22773825)  2012. Fertility drugs and young-onset breast cancer: Results from the Two Sister Study. J Natl Cancer Inst 104(13):1021-1027. [synopsis]

 

Cerium dioxide nanoparticles may lead to human immune cell death

A new study by NIEHS researchers using human peripheral blood monocytes from healthy donors shows that cerium dioxide (CeO2) nanoparticles at environmentally relevant exposure levels causes cell death via apoptosis and autophagy. It is the first report on the effects of CeO2 nanoparticles in primary human cells. Given the fact that CeO2 emissions from diesel fuel are estimated to reach 22 million pounds per year in Europe, it is vital to understand their potential impact on human health.

The apoptotic mechanism was independent of caspase activation, but dependent on mitochondrial damage and induction of apoptosis-inducing factor. Cell death was also mediated through autophagy, which increased if the p53 tumor suppressor protein was inhibited.

Citation: Hussain S, Al-Nsour F, Rice AB, Marshburn J, Yingling B, Ji Z, Zink JI, Walker NJ, Garantziotis S. (http://www.ncbi.nlm.nih.gov/pubmed/22717232)  2012. Cerium dioxide nanoparticles induce apoptosis and autophagy in human peripheral blood monocytes. ACS Nano 6(7):5820-5829. [synopsis]

 

New treatment allows medicines to cross blood-brain barrier

A study by NIEHS researchers identified a signaling pathway that reduces the transport activity of P-glycoprotein, an ATP-driven drug efflux pump in rat brain capillaries known to be a major obstacle to delivering medicines to the brain. The work may lead to new treatments for brain and spinal cord injury, brain cancer, and epilepsy in humans.

The research team used a confocal microscopy-based assay to identify a signaling pathway that abolished P-glycoprotein transport activity without changing transporter protein expression. These findings were validated in vivo and led the researchers to conclude that reducing P-glycoprotein activity can allow small molecule pharmaceuticals to safely cross the blood-brain barrier.

Citation: Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS. (http://www.ncbi.nlm.nih.gov/pubmed/22949658)  2012. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proc Natl Acad Sci U S A 109(39):15930-15935. [synopsis] [story]

 

Glucocorticoid signaling could lead to better therapeutics

NIEHS scientists have determined that glucocorticoids modulate the signaling profile of G protein-coupled receptors (GPCRs) through alterations in arrestin gene expression. Since GPCRs are targeted by nearly half of all prescription drugs, the work could result in the development of specific treatments that will reduce side effects and boost efficacy.

The activity of GPCRs is governed by a group of adaptor proteins called arrestins. Using several different cell types, the research team discovered that glucocorticoids directly regulate arrestin gene expression. The fluctuation in arrestin expression can modify the effect GPCRs can have on human cells by biasing their signaling profile to favor G protein-dependent or beta-arrestin-dependent responses.

Citation: Oakley RH, Revollo J, Cidlowski JA. (http://www.ncbi.nlm.nih.gov/pubmed/23045642)  2012. Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors. Proc Natl Acad Sci U S A 109(43):17591-17596. [synopsis] [story]

 

Bacteria in house dust worsens asthma

NIEHS scientists found that flagellin (FLA), a bacterial protein found in house dust, exacerbates asthma by inducing allergic responses to allergens. The findings, which were confirmed in a human study, reinforce the connection between asthma and the environment.

Inhalation of FLA or house dust extracts containing FLA together with chicken ovalbumin (OVA) caused mice in the study to develop allergic pulmonary inflammation following OVA challenge. The research team also found that the mammalian receptor for FLA, toll-like receptor 5 (TLR5), was required for priming of strong allergic responses in mice by some house dust extracts. The study concluded that household FLA promotes the development of allergic asthma by TLR5-dependent priming.

Citation: Wilson RH, Maruoka S, Whitehead GS, Foley JF, Flake GP, Sever ML, Zeldin DC, Kraft M, Garantziotis S, Nakano H, Cook DN. (http://www.ncbi.nlm.nih.gov/pubmed/23064463)  2012. The Toll-like receptor 5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens. Nat Med 18(11):1705-1710. [synopsis] [story]

 

Mechanisms of anticancer drug resistance

NIEHS scientists described the molecular mechanisms by which topoisomerase II (topo II)-DNA adducts are repaired by the mammalian tyrosyl-DNA phosphodiesterase 2 (Tdp2) enzyme. Since some of the most successful cancer chemotherapeutics work by inducing topo II-DNA adducts that promote cancer cell death, this study determines how Tdp2, in turn, contributes to anticancer drug resistance through its topo II-DNA adduct repair functions.

By defining the protein-DNA conjugate processing mechanism at the atomic level, the team determined that Tdp2 dictates a repair pathway by recognizing and removing these topo II-DNA adducts. These findings have future implications in devising strategies to prevent anticancer drug resistance by targeting Tdp2 and developing Tdp2 inhibitors.

Citation: Schellenberg MJ, Appel CD, Adhikari S, Robertson PD, Ramsden DA, Williams RS. (http://www.ncbi.nlm.nih.gov/pubmed/23104055)  2012. Mechanism of repair of 5’-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2. Nat Struct Mol Biol 19(12):1363-1371. [synopsis] [story]

 

 

National Toxicology Program research

Arsenic-transformed malignant prostate epithelia can convert noncontiguous normal stem cells into an oncogenic phenotype

Researchers explored the hypothesis that the repeated demonstrations of arsenic-induced cancer stem cell (CSC) overabundance in tumors and multiplicity of primary tumors may be explained by an ability of arsenic transformed cells to recruit normal stem cells (NSCs) into CSCs.

The scientists placed arsenic-induced malignant epithelial cells (MECs) in noncontact co-culture by using inserts with normal stem cells (NSC) and assessed the NSCs for malignant transformation. The NSCs rapidly acquired physical (invasion, colony formation, matrix metalloproteinase secretion) and molecular characteristics of CSCs. The results showed that arsenic-transformed MECs recruited NSCs into CSCs at a significant distance (50-100 cell wide) and had an impact on cancer growth, dissemination, and field canceration.

Citation: Xu Y, Tokar EJ, Sun Y, Waalkes MP. (http://www.ncbi.nlm.nih.gov/pubmed/22472196)  Arsenic-Transformed Malignant Prostate Epithelia Can Convert Noncontiguous Normal Stem Cells into an Oncogenic Phenotype. Environ Health Perspect 20(6):865-871. [story]

 

Testing an aflatoxin B1 gene signature in rat archival tissues

Formalin-fixed and paraffin-embedded (FFPE) tissues from toxicology studies are a valuable resource for linking histopathological diagnosis to gene expression profiles for insights into molecular mechanisms of chemical pathologies and disease. 

Fourteen genes that represent cell cycle progression, response to DNA damage, xenosensor and detoxication systems were evaluated by quantitative PCR in FFPE tissues and corresponding fresh frozen liver samples from male rats treated for 90 days with aflatoxin B1, a liver carcinogen, and concurrent control animals. The resulting data demonstrate that it is now possible to conduct retrospective evaluations of gene signatures in archival tissues. Archival toxicogenomics will reduce animal use by allowing for prior toxicology studies to be interrogated for critical molecular events in chemically induced disease.

Citation: Merrick BA, Auerbach SS, Stockton PS, Foley JF, Malarkey DE, Sills RC, Irwin RD, Tice RR. (http://www.ncbi.nlm.nih.gov/pubmed/22545673)  2012. Testing an aflatoxin B1 gene signature in rat archival tissues. Chem Res Toxicol 25(5):1132-1144.

 

Hepatocellular carcinomas in B6C3F1 mice treated with Ginkgo biloba extract for two years differ from spontaneous liver tumors in cancer gene mutations and genomic pathways

This study provides a molecular context for the genetic changes associated with hepatocarcinogenesis in Ginkgo biloba leaf extract (GBE)-exposed mice and illustrates the marked differences between these tumors and those arising spontaneously in the B6C3F1 mouse.

The molecular changes observed in hepatocellular carcinoma (HCC) from GBE-treated animals may be of relevance to those seen in human HCC and other types of cancer. Although a significant amount of data is present in the scientific literature pertaining to the reported health benefits of GBE use, these findings suggest that with long term use of high doses of GBE there may be potential health risks, and it is therefore important that the health status of individuals on chronic GBE therapy is monitored.

Citation: Hoenerhoff MJ, Pandiri AR, Snyder SA, Hong HH, Ton T-V, Peddada S, Shockley KR, Witt K, Chan P, Rider C, Kooistra L, Nyska A, Sills RC. (http://www.ncbi.nlm.nih.gov/pubmed/23262642)  2012. Hepatocellular carcinomas in B6C3F1 mice treated with Ginkgo biloba extract for two-years differ from spontaneous liver tumors in cancer gene mutations and genomic pathways. Toxicol Pathol; doi:10.1177/0192623312467520 [Online 21 December 2012].

 

An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents

Black cohosh extract (BCE) is used as a remedy for pain and gynecological ailments, and modern preparations are commonly sold as ethanolic extracts available as dietary supplements. In this first study of its kind, researchers used rodent models to characterize the general toxicity of BCE and address suspected estrogenic and anti-estrogenic activity.

BCE induced dose-dependent hematological changes consistent with a non-regenerative macrocytic anemia and increased frequencies of peripheral micronucleated red blood cells. Effects were more severe in mice — seen at all exposure dose levels — than rats. Dose-dependent thymus and liver toxicity was also observed in rats. Apparent effects on puberty were observed, but were not associated with alteration in estrogenic and anti-estrogenic activity.

Citation: Mercado-Feliciano M, Cora MC, Witt KL, Granville CA, Hejtmancik MR, Fomby L, Knostman KA, Ryan MJ, Newbold R, Smith C, Foster PM, Vallant MK, Stout MD. (http://www.ncbi.nlm.nih.gov/pubmed/22687605)  2012. An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents. Toxicol Appl Pharmacol 263(2):138-147.

 

The genome architecture of the Collaborative Cross mouse genetic reference population

The Collaborative Cross Consortium, which includes NTP scientist Jef French, Ph.D., reports on the development of a unique genetic resource population, the Collaborative Cross (CC), a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains using mice from The Jackson Laboratory, involved the University of North Carolina, Tel Aviv University, and Geniad in Australia.

The report includes information on access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.

Collaborative Cross Consortium. (http://www.ncbi.nlm.nih.gov/pubmed/22345608)  2012. The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics190(2):389-401.

(The contributing writer for Extramural summaries was Nancy D. Lamontagne a science writer with MDB, Inc., a contractor for the NIEHS Division of Extramural Research and Training, Superfund Research Program, and Worker Education and Training Program.

Intramural summaries were written by Mamta Behl, Ph.D., a contract neurotoxicologist in the NTP Toxicology Branch; Nisha Cavanaugh, Ph.D., a former Intramural Research Training Award (IRTA) postdoctoral fellow in the NIEHS Laboratory of Structural Biology DNA Repair and Nucleic Acid Enzymology Group; Raluca Dumitru, M.D., Ph.D., a former Intramural Research Training Award fellow in the NIEHS Laboratory of Molecular Carcinogenesis Stem Cell Biology Group; Brant Hamel Ph.D., a former IRTA fellow in the NIEHS Laboratory of Signal Transduction Molecular Endocrinology Group; Melissa Kerr, a chemistry student at North Carolina Central University and intern in the NIEHS Office of Communications and Public Liaison; Anshul Pandya, Ph.D., a former IRTA fellow in the Laboratory of Neurobiology Ion Channel Physiology Group; Sonika Patial, D.V.M., Ph.D., a visiting fellow in the Laboratory of Signal Transduction Polypeptide Hormone Action Group; Bhargavi Rao, Ph.D., an IRTA fellow in the NIEHS Laboratory of Molecular Carcinogenesis Chromatin and Gene Expression Group; Jeffrey Stumpf, Ph.D., a former IRTA Fellow in the NIEHS Laboratory of Molecular Genetics Mitochondrial DNA Replication Group; Sheetal Thakur, Ph.D., an IRTA fellow in the NIEHS/NTP Toxicology Branch; Ian Thomas, a public affairs specialist with the NIEHS Office of Communications and Public Liaison, and a regular contributor to the Environmental Factor; Darshini Trivedi, Ph.D., an IRTA fellow in the NIEH Laboratory of Toxicology and Pharmacology Metabolism and Molecular Mechanisms Group; Sheila Yong, Ph.D., a visiting fellow in the NIEHS Laboratory of Signal Transduction Inositol Signaling Group; and Emily Zhou, Ph.D., a former research fellow in the NIEHS Laboratory of Signal Transduction Inositol Signaling Group.

Authors of the NTP Papers of the Year contributed their summaries, which were submitted by their NTP branch chiefs.)




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