2011 papers of the year
By Ian Thomas
National Toxicology Program
Extramural Papers of the Year
Amyloid-binding compound extends lifespan in C. elegans
NIEHS-supported researchers at the Buck Institute for Research on Aging report that a chemical dye that lights up amyloid protein clumps characteristic of Alzheimer's disease also slows aging in the nematode, C. elegans. The lifespan-boosting effects of the dye, called Thioflavin T (ThT) or Basic Yellow 1, support the idea that the buildup of misshapen proteins is one of the fundamental events in the aging process. Using roundworms, researchers found that optimum doses of ThT reversed the effects of mutations that cause muscle proteins to misfold and become paralyzed at a particular temperature. The team also found that worms that lack genes important to dealing with misshapen proteins do not live longer when fed ThT.
Citation: Alavez S, Vantipalli MC, Zucker DJ, Klang IM, Lithgow GJ. 2011. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 472(7342):226-229. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/may/science-extramural/index.cfm#two) ]
Mitochondrial, but not nuclear, ligase3 is required for cellular viability
A multi-institutional team of scientists has determined that mitochondrial DNA ligase III (Lig3), an enzyme involved in various DNA repair pathways, is necessary for cellular growth and viability, as compared to the nuclear version of the enzyme. These findings were made through a series of experiments that incorporated various forms of the gene coding for Lig3 in mouse embryonic stem cells. This approach enabled them to determine that mitochondrial Lig3, but not nuclear Lig3, is necessary for cell viability. They also found that substitution of Lig1 for Lig3 in the mitochondria maintains cellular viability.
Citation: Simsek D, Furda A, Gao Y, Artus J, Brunet E, Hadjantonakis AK, Van Houten B, Shuman S, McKinnon PJ, Jasin M. 2011. Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair. Nature 471(7337):245-248. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/may/science-extramural/index.cfm#four) ]
Rapid evolution in Hudson River tomcod
New research findings by NIEHS grantees suggest that Hudson River tomcod have undergone rapid evolution, in response to industrial contamination of the river with polychlorinated biphenyls over the last 50 years. Investigators found changes in the gene that codes for the aryl hydrocarbon receptor 2 (AHR2), which mediates toxicity in early life stages. Because the Hudson River fish is resistant to the toxic effects of PCBs, they are able to accumulate more of the chemical, which is then transferred further up the food chain through the larger fish that consume them.
Citation: Wirgin I, Roy NK, Loftus M, Chambers RC, Franks DG, Hahn ME. 2011. Mechanistic basis of resistance to PCBs in Atlantic tomcod from the Hudson River. Science 331(6022):1322-1325. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/march/science-extramural/#one) ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/april/science-pollution/index.cfm) ]
Sperm may be harmed by BPA exposure
Researchers have found that urinary concentrations of bisphenol A (BPA) may be related to decreased sperm quality and concentration. The study included 190 men and measured sperm concentration, motility, shape, and DNA damage in semen samples from the participants. BPA was detected in 89 percent of the men's urine samples. Sperm concentration was about 23 percent lower in men in the top quartile of exposure, as compared with the lowest quartile. The highest exposed men also had about 10 percent more damaged sperm than the lowest exposed group.
These findings are consistent with previous research, though investigators are continuing this study with a larger cohort to confirm their findings.
Citation: Meeker JD, Ehrlich S, Toth TL, Wright DL, Calafat AM, Trisini AT, Ye X, Hauser R. 2010. Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic. Reprod Toxicol 30(4):532-539. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/february/science-extramural/#four) ]
Less toxic and more effective carbon nanotubes for drug delivery
Investigators have found that single-walled carbon nanotubes treated with polyethylene glycol (PEG) make more effective and less toxic drug delivery vehicles than untreated nanotubes. The researchers layered carbon nanotubes with PEG, which has been shown to improve their dispersion in aqueous solutions. Both PEG-treated and untreated nanotubes were then incubated with the chemotherapeutic drug cisplatin and injected into laboratory mice. Untreated nanotubes were found to clump together in lung tissue, while PEG-treated nanotubes showed little or no accumulation.
These results give further credence to the use of drug delivery systems utilizing single-walled carbon nanotubes.
Citation: Bhirde AA, Patel S, Sousa AA, Patel V, Molinolo AA, Ji Y, Leapman RD, Gutkind JS, Rusling JF. 2010. Distribution and clearance of PEG-single-walled carbon nanotube cancer drug delivery vehicles in mice. Nanomedicine (Lond) 5(10):1535-1546. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/february/science-extramural/#three) ]
DNA damage mapped out
Using differential epistasis maps, researchers have documented how a cellular genetic network is completely reorganized in response to DNA damaging agents. To achieve this, scientists focused on 400 genes that govern signal transduction pathways in yeast. The map was created by identifying gene interactions before and after exposure to a DNA-damaging agent, similar to compounds used in chemotherapy. Surprisingly, they found that most of the interactions identified after drug exposure were not present without the exposure, leading them to believe that the genetic network was completely reprogrammed by DNA damage.
This discovery represents a new frontier in probing dynamic interactions that enable cells to survive and thrive in varying environmental and genetic contexts.
Citation: Bandyopadhyay S, Mehta M, Kuo D, Sung MK, Chuang R, Jaehnig EJ, Bodenmiller B, Licon K, Copeland W, Shales M, Fiedler D, Dutkowski J, Guenole A, van Attikum H, Shokat KM, Kolodner RD, Huh WK, Aebersold R, Keogh MC, Krogan NJ, Ideker T. 2010. Rewiring of genetic networks in response to DNA damage. Science 330(6009):1385-1389. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/february/science-extramural/#two) ]
Autism and prenatal vitamins
In a study of 566 subjects, comparing a group of autistic children to a control group of normally developed children, researchers found that mothers who didn't take prenatal vitamins were at greater risk of having an autistic child.
Researchers examined maternal intake of prenatal vitamins in the three months before conception and the first month of pregnancy, and they looked for genotypes associated with autism. In addition to finding a distinct dose/response relationship, scientists found that the odds ratio for autism risk in mothers who took prenatal vitamins was 1.8, whereas mothers who didn’t take vitamins faced a noticeably higher risk at 7.2. This suggests that the maternal-fetal environment can magnify the effects of a susceptibility gene.
Citation: Citation: Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ, Tassone F, Hertz-Picciotto I. 2011. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology 22(4):476-485.
[ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/september/science-extramural/index.cfm#two) ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/june/science-early/index.cfm) ]
Mitochondrial dysfunction in children with autism
In this study, the investigators propose that mitochondrial deficiencies in brain cells might lead to some of the cognitive impairments associated with autism. While the study does not identify an actual cause of autism, it does suggest that cumulative damage and oxidative stress in mitochondria could influence both the onset and severity of the disorder. Although the study included only 10 autistic children and 10 age-matched controls, its findings may eventually lead to new insights on early diagnosis, treatment, and prevention efforts, though larger studies are necessary moving forward.
Citation: Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, Tassone F, Pessah IN. 2010. Mitochondrial dysfunction in autism. JAMA 304(21):2389-2396. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/february/science-extramural/#one) ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/january/science-mitochondrial.cfm) ]
Intramural Papers of the Year
Mutations resulting from subtle chemical "trickery"
When Watson and Crick first described the structure of the DNA helix in 1953, they proposed that mutations might result from mismatches whose geometry mimics that of correct base pairs. This paper provides the first direct structural evidence for this idea, and reveals how the chemical complexity of genetic information can sometimes trick even a normal, healthy cell into making a mistake, for good, enabling evolution, or bad, resulting in disease. It is an example of environmental health science research that fits beautifully into Pillar 1, fundamental research, in the emerging NIEHS strategic plan. We need to understand how things work under normal circumstances if we ever hope to really understand the consequences of environment stress.
Citation: Bebenek K, Pedersen LC, Kunkel TA. 2011. Replication infidelity via a mismatch with Watson-Crick geometry. Proc Natl Acad Sci U S A 108(5):1862-1867. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/march/science-intramural/#three) ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/february/science-mismatch/) ]
Innate immunity linked to DNA damage response
This study, the first to come out of the new NIEHS Clinical Research Unit, reveals a strong link, in human subjects, between chromosome lesions that can be induced by environmental agents, the immune-induced inflammatory response, and individual susceptibility. The investigators demonstrated that most of the Toll-like receptor (TLR) family of innate immune genes, which deal with infectious agents in responsive to DNA damage, are directly regulated by the tumor suppressor p53, and they identified the first functional consequences of a SNP in the TLR8 promoter. These findings on individual differences in TLR induction by p53 activation and DNA damage should prove useful in the development of TLR-targeted vaccines and TLR-based cancer treatments.
Citation: Menendez D*, Shatz M*, Azzam K, Garantziotis S, Fessler MB, Resnick MA. 2011. The Toll-like receptor gene family is integrated into human DNA damage and p53 networks. PLoS Genet 7(3):e1001360. (*co-first authors) [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/february/science-extramural/#two) ]
NIEHS study investigates the impact of poised RNA polymerase II on neuronal gene transcription
Activity-dependent plasticity of synapses is an important process in the development of brain circuitry, a time when the brain is susceptible to environmental insults. Rapid activity-dependent induction of genes plays a critical role in consolidating synaptic changes, so an understanding of how this occurs could provide important clues into targets of environmental toxicants.
Citation: Saha RN, Wissink EM, Bailey ER, Zhao M, Fargo DC, Hwang JY, Daigle KR, Fenn JD, Adelman K, Dudek SM.. 2011. Rapid activity-induced transcription of Arc and other IEGs relies on poised RNA polymerase II. Nat Neurosci 14(7):848-856. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/august/science-intramural/index.cfm#two) ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/june/science-explains/index.cfm) ]
A novel mechanism that may underlie learning and memory
Since smoking is suspected to be protective in Alzheimer's disease through action on nicotinic acetylcholine receptors (nAChRs), and drugs acting on these receptors improve cognitive function, the scientists investigated how endogenous acetylcholine acting through nAChRs affected cellular models of learning and memory. The long-term aim of this work is to understand the brain circuits involved in environmental disease and aid in the development of therapeutics to treat these diseases.
Citation: Gu Z, Yakel JL. 2011. Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron 71(1):155-165. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/september/science-intramural/index.cfm#four) ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/august/science-investigators/index.cfm) ]
Two point mutations may influence the efficacy of breast cancer treatment
This paper describes the initial development and characterization of a mutant estrogen receptor alpha mouse model that segregates the tissue and physiological functionality of the two transcription activation functions to certain tissues. Endocrine disrupting chemicals (EDCs) activate this mutant through the AF-1 similar to Tamoxifen and will allow assessment of the EDC tissue selective mechanism of action.
Citation: Arao Y, Hamilton KJ, Ray MK, Scott G, Mishina Y, Korach KS. 2011. Estrogen receptor alpha AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators. Proc Natl Acad Sci U S A 108(36):14986-14991. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/november/science-intramural/index.cfm#one) ]
Aprataxin structure links DNA repair mechanism to neurodegenerative disease
Exposure to environmental toxicants and stressors, chronic inflammation, and cellular respiration all contribute to production of oxidative DNA damage, including DNA strand breaks and DNA base damage, that when metabolized, can give rise to cytotoxic 5'-adenylation DNA lesions. This study provides key insights into the chemistry and biology of DNA-5'-adenylation genome repair by aprataxin, and explains how mutations in the human aprataxin gene result in small, but devastating changes to the aprataxin protein shape that underlie the crippling heritable neurodegeneration disease ataxia with oculomotor apraxia 1 (AOA1).
Citation: Tumbale P, Appel CD, Kraehenbuehl R, Robertson PD, Williams JS, Krahn J, Ahel I, Williams RS. 2011. Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease. Nat Struct Mol Biol 18(11):1189-1195. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/december/science-intramural/index.cfm#three) ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/november/science-crystallography/index.cfm) ]
IL-35 production by regulatory T cells reverses allergic asthma
Some previous studies have shown that the prevalence of allergic asthma is associated with exposure to environmental endotoxin, whereas other studies have shown that endotoxin can protect against the development of asthma. The basis for this apparent paradox has been unclear. This paper shows that although endotoxin can prime T helper 2 (Th2) and Th17 responses to inhaled allergens, it also induces T regulatory (Treg) cell proliferation. The paper further identified a specific type of Treg cell that suppresses allergic responses by producing the recently identified cytokine, IL-35.
Citation: Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN. 2012. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol 129(1):207-215. [ abstract ] [ synopsis (https://www.niehs.nih.gov/news/newsletter/2011/november/science-intramural/index.cfm#two) ]
Overcoming phosphate congestion in high energy signaling molecules
Inositol pyrophosphates regulate the body’s metabolic balance, a life-sustaining process that is under constant environmental pressure. Breakdown of metabolic control processes is evident in illnesses such as diabetes, cancer and aging. The rational design of drugs to improve human health is facilitated by the molecular template that is provided by our atomic level description of the structure and reaction mechanism of an enzyme that synthesizes inositol pyrophosphates.
Citation: Wang H, Falck JR, Hall TM, Shears, SB. 2011. Structural basis for an inositol pyrophosphate kinase surmounting phosphate crowding. Nat Chem Biol 8(1):111-6. [ abstract ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/december/science-phosphate/index.cfm) ]
National Toxicology Program Papers of the Year
Global gene profiling in mice: Similarities in the molecular landscape with human liver cancer
Hepatocellular carcinoma (HCC) is an important cause of morbidity and mortality worldwide. Although the risk factors of human HCC are well known, the molecular pathogenesis of this disease is complex and, in general, treatment options remain poor.
Using global gene expression profiling in the B6C3F1 rodent model, researchers identified the dysregulation of several mediators similarly altered in human HCC, including re-expression of fetal oncogenes, upregulation of protooncogenes, downregulation of tumor suppressor genes, and abnormal expression of cell cycle mediators, growth factors, apoptosis regulators, and angiogenesis and extracellular matrix remodeling factors. These data provide further support for the use of this model in hazard identification of compounds with potential human carcinogenicity risk, and may help in better understanding the mechanisms of tumorigenesis resulting from chemical exposure in the NTP two-year carcinogenicity bioassay.
Citation: Hoenerhoff MJ, Pandiri AR, Lahousse SA, Hong HH, Ton TV, Masinde T, Auerbach SS, Gerrish K, Bushel PR, Shockley KR, Peddada SD, Sills RC. 2011. Global gene profiling of spontaneous hepatocellular carcinoma in B6C3F1 mice: similarities in the molecular landscape with human liver cancer. Toxicol Pathol 39(4):678-699.
[ abstract ]
Chemical genomics profiling of environmental chemical modulation of human nuclear receptors
In response to the growing demand for more efficient and cost-effective means of assessing environmental chemical toxicity, the U.S. Tox21 program has proposed a number of alternative strategies for toxicity testing and data screening. The goal of this study was to develop methods to evaluate the data generated from these assays, to guide future assay selection and prioritization.
By examining roughly 3,000 environmental chemicals against a panel of 10 human nuclear receptors for reproducibility, scientists determined the assays to be appropriate in terms of biological relevance. They were also able to formulate data-driven strategies for discriminating true signals from artifacts and to prioritize assays based on data quality.
Citation: Huang R, Xia M, Cho MH, Sakamuru S, Shinn P, Houck KA, Dix DJ, Judson RS, Witt KL, Kavlock RJ, Tice RR, Austin CP. 2011. Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect 119(8):1142-1148. [ abstract ]
Gene expression alterations in immune system pathways in the thymus after exposure to immunosuppressive chemicals
Dysregulation of positive and negative selection, antigen presentation, or apoptosis in the thymus can lead to immunosuppression or autoimmunity. This study hypothesized that genomic analysis of thymus after chemical-induced atrophy would yield transcriptional profiles that suggest pathways of toxicity associated with reduced function.
By exposing rodents to four immunosuppressive agents and evaluating changes in gene expression, investigators found that all four chemicals induced thymic atrophy and changes in both the relative proportion and absolute number of CD3(+), CD4(+)/CD8(-), CD4(-)/CD8(+), and CD4(+)/CD8(+) thymocytes.
Genomic analysis revealed gene expression changes in several pathways that are commonly associated with xenobiotic-induced immune system perturbations, particularly those that contribute to the development and maturation of thymic T cells.
Citation: Frawley R, White K Jr, Brown R, Musgrove D, Walker N, Germolec D. 2011. Gene expression alterations in immune system pathways in the thymus after exposure to immunosuppressive chemicals. Environ Health Perspect 119(3):371-376. [ abstract ]
Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: A targeted rtPCR array approach for defining relative potency
Male rat fetuses exposed to certain phthalate esters (PEs) during sexual differentiation display reproductive tract malformations due to reductions in testosterone (T) production and the expression of steroidogenesis- and INSL3-related genes. In the current study, researchers examined key target genes representing sexual determination and differentiation, steroidogenesis, gubernaculum development, and androgen signaling pathways to rank the relative potency of several PEs.
Despite speculation of PPAR involvement in the effects of PEs on the fetal testis, no PPAR-related genes were affected in the fetal testes by exposure to any of the tested PEs. Furthermore, the potent PPARalpha agonist, WY-14643, did not reduce fetal testicular T production following GD 14-18 exposure, suggesting that the anti-androgenic activity of PEs is not PPARalpha-mediated.
Citation: Hannas BR, Lambright CS, Furr J, Evans N, Foster PM, Gray LE, Wilson VS. 2011. Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: A targeted rtPCR array approach for defining relative potency. Toxicol Sci; doi 10.1093/toxsci/kfr315 [Online 22 November 2011]. [ abstract ]
Aloe veranon-decolorized whole leaf extract-induced tumors in rats share similar molecular pathways with human sporadic colorectal tumors
Research by NTP and the National Center for Toxicological Research has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water.
The morphological and molecular pathways of these tumors were then compared to human colorectal cancer (hCRC) literature. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels.
Citation: Pandiri AR, Sills RC, Hoenerhoff MJ, Peddada SD, Ton TV, Hong HH, Flake GP, Malarkey DE, Olson GR, Pogribny IP, Walker NJ, Boudreau MD. 2011. Aloe vera non-decolorized whole leaf extract-induced large intestinal tumors in F344 rats share similar molecular pathways with human sporadic colorectal tumors. Toxicol Pathol 39(7):1065-1074. [ abstract ]
Voluntary exercise protects hippocampal neurons from trimethyltin injury
In the periphery, exercise induces interleukin (IL)-6 to downregulate tumor necrosis factor (TNF), elevate interleukin-1 receptor antagonist (IL-1RA), decreasing inflammation. IL-6 production in the hippocampus following exercise suggests the potential of a similar protective role as in the periphery to down-regulate TNFalpha and inflammation.
Using a chemical-induced model of hippocampal dentate granule cell death dependent upon TNF receptor signaling, researchers demonstrated neuroprotection in mice with two weeks access to running wheel. In IL-6 deficient mice, exercise did not attenuate trimethyltin-induced tremor and a diminished level of neuroprotection was observed. These data suggest a contributory role for IL-6 induced by exercise for neuroprotection in the CNS similar to that seen in the periphery.
Citation: Funk JA, Gohlke J, Kraft AD, McPherson CA, Collins JB, Jean Harry G. 2011. Voluntary exercise protects hippocampal neurons from trimethyltin injury: possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity. Brain Behav Immun 1063-1077. [ abstract ] [ story (https://www.niehs.nih.gov/news/newsletter/2011/august/science-journal/) ]
Prenatal perfluorooctanoic acid exposure in CD-1 mice: low-dose developmental effects and internal dosimetry
To investigate the low-dose effects of perfluorooctanoic acid (PFOA) on offspring, timed-pregnant CD-1 mice were gavage dosed with PFOA for all or half of gestation. In both studies, the offspring of all PFOA-treated dams exhibited significantly stunted mammary epithelial growth as assessed by developmental scoring.
Evaluation of internal dosimetry in offspring revealed that PFOA concentrations remained elevated in liver and serum for up to six weeks and that brain concentrations were low and undetectable after four weeks. Also, PFOA-induced effects on mammary tissue occurred at lower doses than effects on liver weight in CD-1 mice and persisted until 12 weeks of age following full-gestational exposure.
Citation: Macon MB, Villanueva LR, Tatum-Gibbs K, Zehr RD, Strynar MJ, Stanko JP, White SS, Helfant L, Fenton SE. 2011. Prenatal perfluorooctanoic acid exposure in CD-1 mice: low-dose developmental effects and internal dosimetry. Toxicol Sci 122(1):134-145. [ abstract ]
(Ian Thomas is a public affairs specialist with the NIEHS Office of Communications and Public Liaison, and a regular contributor to the Environmental Factor.)