Implementation Highlights and Accomplishments
Identify and understand fundamental shared mechanisms or common biological pathways, e.g., inflammation, epigenetic changes, oxidative stress, mutagenesis, etc., underlying a broad range of complex diseases, in order to enable the development of applicable prevention and intervention strategies.
- Investigate the effects of the environment on genome structure and function.
- Investigate the effects of the environment on the epigenetic regulation of biological and pathological processes.
- Understand the role of key biological mechanisms and their regulation in determining resistance and susceptibility to environmental stressors.
- Understand the normal processes of human development, maturation, and aging, and identify environmental factors that contribute to altered function.
- Develop a pipeline to integrate high-throughput screening, cell systems, and model organisms, to identify fundamental mechanisms underlying responses to existing and emerging environmental toxicants, and to better predict their relationship to disease.
Population-Based Model Organism Research for GxE Exploration in Complex Disease Outcomes (R01)
This Funding Opportunity Announcement (FOA) will support research using population-based model organism resources for environmental health science and toxicology questions. This FOA is particularly interested in the interplay between environment, genetics, and epigenetics and the identification and understanding of host susceptibility to environmental exposures, relevant to human disease outcomes. RFA-ES-17-009
Immuno-Oncology Translation Network (IOTN): Cancer Immunoprevention Research Projects (U01)
The purpose of this specific FOA is to establish Cancer Immunoprevention Research Projects that will function as components of a Cancer Immunotherapy Consortium (CIC), which will also include Cancer Immunotherapy Research Projects. The CIC will form an integrated network of multi-disciplinary, collaborative teams with the overarching goals of accelerating translational research of innate and adaptive immune mechanisms that contribute to tumor initiation and progression, and evaluating new or improved immunopreventive and immunotherapeutic strategies (including combinations with standard or other therapies). Studies should be largely pre-clinical involving clinically-relevant models and endpoints, and have the potential for rapid translation into early-phase clinical applications. RFA-CA-17-046
Tobacco Regulatory Science (R01)
The purpose of this Funding Opportunity Announcement (FOA) is to invite R01 applications to support biomedical and behavioral research that will provide scientific data to inform regulation of tobacco products to protect public health. Research Projects must address the research priorities related to the regulatory authority of the Food and Drug Administration (FDA) Center for Tobacco Products (CTP). The awards under this FOA will be administered by NIH using funds that have been made available through FDA CTP and the Family Smoking Prevention and Tobacco Control Act (P.L. 111-31). Research results from this FOA are expected to generate findings and data that are directly relevant in informing the FDA's regulation of the manufacture, distribution, and marketing of tobacco products to protect public health. RFA-OD-18-002
Computational Analyses Exploiting Reference Epigenomic Maps (R01)
Part of the NIH Common Fund program in Epigenomics, this FOA targeted investigators proposing computational analyses that will take advantage of the publicly available reference epigenomic maps generated as part of the Roadmap Epigenomics Program. Eleven grants awarded August 2014. RM-14-001
Nanomaterials Health Implications Research (NHIR): Comprehensive Evaluation of Interactions between Engineered Nanomaterials and Biological System (U01)
These research projects will investigate interactions between Engineered Nanomaterials (ENMs) and biological systems to generate comprehensive biological response profiles for ENMs that will be provided by Engineered nanomaterials Resource and Coordination Core (ERCC) being solicited through a companion FOA (RFA-ES-15-012). ES-15-013
Novel Assays for Screening the Effects of Chemical Toxicants on Cell Differentiation (R43/R44)
This Funding Opportunity Announcement (FOA) solicits Small Business Innovative Research (SBIR) grant applications from small business concerns (SBCs) to develop medium- to high-throughput assays to evaluate the effects of toxicants on pluripotent or induced pluripotent cells with respect to cell differentiation and the resulting differentiated cell populations. The ability to incorporate genetic diversity in these assays would be useful. These assays will provide information on mechanisms of chemically-induced biological activity, help to prioritize chemicals for more extensive toxicological evaluation, support more predictive models of in vivo biological response, and potentially inform on the role of genetic diversity in toxicological effects. ES-15-006
Novel Assays for Screening the Effects of Chemical Toxicants on Cell Differentiation (R41)
This Funding Opportunity Announcement (FOA) solicits Small Business Technology Transfer (STTR) grant applications from small business concerns (SBCs) to develop medium- to high-throughput assays to evaluate the effects of toxicants on pluripotent or induced pluripotent cells with respect to cell differentiation and the resulting differentiated cell populations. The ability to incorporate genetic diversity in these assays would be useful. These assays will provide information on mechanisms of chemically-induced biological activity, help to prioritize chemicals for more extensive toxicological evaluation, support more predictive models of in vivo biological response, and potentially inform on the role of genetic diversity in toxicological effects. ES-15-005
TaRGET II: Environmental Epigenomic Analysis in Tissue Surrogates (U01)
Environmental exposure induced perturbations of epigenomic marks are correlated with disease pathogenesis. Identifying changes in epigenomic marks (e.g., DNA methylation, histone modifications, chromatin accessibility) in affected tissues/cells is not always feasible in humans. The purpose of this Funding Opportunity Announcement (FOA) is to establish a consortium that will explore the conservation of perturbations of epigenomic marks across target tissues/cells and surrogate tissues/cells using mouse models of environmentally relevant diseases. Ultimately, these analyses will provide insights into the design and interpretation of human studies where target tissues are inaccessible. ES-15-001
Environmental Influences during Windows of Susceptibility in Breast Cancer Risk (U01)
This funding opportunity will support transdisciplinary research projects to investigate the influence of environmental exposures during specific time windows of susceptibility on breast cancer risk. Applicants must propose transdisciplinary research project that addresses one or more potential windows of susceptibility and facilitates the integration of experimental model and human studies to accelerate understanding of the contribution of environmental factors to breast cancer risk, the underlying mechanisms, and potential prevention strategies. ES-14-012
Innovative Approaches for the Identification of Mitochondria-Cell Signaling Networks in Response to Environmental Stress
This FOA uses the R21/R33 Phased Innovation Award mechanism to develop new technologies and experimental models to elucidate mitochondrial-cell signaling. Technologies developed in the R21 phase may include more sensitive reagents for detection of specific reactive oxygen or nitrogen species, enhanced approaches for metabolic flux analysis, and expanded in vitro or experimental models for identifying alterations in signaling pathways in response to environmental stressors. Fourteen grants were awarded May 2015. ES-14-006
The Role of Environmental Exposures in the Development of Autoimmune Disease (R21)
This announcement encourages exploratory research applications aimed at investigating the role environmental exposures play in the development and/or the exacerbation of autoimmune disease. Of particular interest are projects that will identify and characterize critical windows of exposure susceptibility, projects that explore mechanisms responsible for gender differences in response and development of autoimmune disease, and studies that can produce potential biomarkers for use in subsequent human surveillance studies. ES-13-011
Research Linking Environmental Exposure to Neurodegenerative Disease (R21)
The purpose of this FOA is to stimulate research on the role of environmental exposure in neurodegenerative disease (ND) by developing feasibility data for new concepts or by adapting new technologies, tools and methods of use for studies in neurodegenerative diseases. The emphasis for this FOA would be especially focused on Alzheimer’s (AD), Amyotrophic Lateral Sclerosis and Parkinson's (PD) to stimulate advancement of neurodegenerative research by better establishing the importance of environmental exposure in disease causation in accordance with the goals of the new strategic plan. ES-13-007
Research Linking Environmental Exposure to Alzheimer's Disease (R01)
The purpose of this funding opportunity announcement (FOA) is to support research establishing a link between environmental exposure and the risk for Alzheimer’s disease (AD). Research is encouraged ranging from basic mechanistic exposure studies to human-based studies. This new effort seeks to promote work to further the understanding of the combined roles of exposure and processes implicated in AD such as inflammation and genetic susceptibility. This FOA is intended to support the broad research goals of the 2012-2017 Strategic Plan for NIEHS. ES-13-006
Novel Assays for Screening the Effects of Chemical Toxicants on Cell Differentiation (SBIR [R43])
This Funding Opportunity Announcement (FOA) solicits Small Business Innovative Research (SBIR) grant applications from small business concerns (SBCs) to develop medium- to high-throughput assays to evaluate the effects of toxicants on pluripotent or induced pluripotent cells with respect to cell differentiation and the resulting differentiated cell populations. These assays will provide information on mechanisms of chemically-induced biological activity, help to prioritize chemicals for more extensive toxicological evaluation, support more predictive models of in vivo biological response, and potentially inform on the role of genetic diversity in toxicological effects. ES-13-003
Selected Programs and Awards
Molecular Miscroscopy Consortium
The Molecular Microscopy Consortium allows scientists from NIEHS, the University of North Carolina at Chapel Hill, and Duke University to use single particle cryo-electron microscopy and other tools in molecular microscopy to solve macromolecular structures at the atomic level. Cryo-EM requires smaller quantities of material than other structural methods and is especially suitable for the study of hard to crystallize large macromolecular complexes and membrane proteins.
2016 Outstanding New Environmental Scientist (ONES) Awardee Somshuvra Mukhopadhyay, M.B.B.S., Ph.D., at the University of Texas at Austin, will study the process cells use to remove the toxin manganese, which can cause a syndrome like Parkinson’s disease.
NIEHS grantee Trudy Mackay, Ph.D., geneticist at North Carolina State University, has won the prestigious Wolf Prize. Each year, Israel’s Wolf Foundation recognizes individuals in several scientific and artistic disciplines. On Jan. 13, Mackay was named the 2016 winner for agriculture.
According to an NCSU press release, the Wolf Prize is one of the world’s most prestigious awards for academic achievement, and several winners have gone on to win a Nobel Prize. The international committee that selected Mackay cited her “pioneering studies on the genetic architecture of complex traits and the discovery of fundamental principles of quantitative genetics with broad applications for agricultural improvements.”
NIEHS has funded two new environmental health science core research centers: at North Carolina State University (NC State) and the University of California, Davis (UC Davis). These new centers join the 20 others currently funded.
- The NC State Center for Human Health and the Environment will collaborate with researchers at the East Carolina University Brody School of Medicine, North Carolina Central University, North Carolina Department of Health and Human Services, and Research Triangle Institute NIH Eastern Regional Comprehensive Metabolomics Resource Core. Leveraging the technical expertise of CHHE and its partners, the center will focus on how environmental stressors interact with biomolecular signaling pathways, the genome, and the epigenome. Robert Smart, PhD will be the center’s director. NC State and UC Davis join NIEHS environmental health sciences research centers.
- The UC Davis center comprises a team of scientists from 19 departments, across four schools and colleges, and will be directed by Irva Hertz-Piccioto, PhD. The center will focus on exposures such as particles and volatile organic compounds in ambient air, pollutants in drinking water and food, and household or personal care products. NC State and UC Davis join NIEHS environmental health sciences research centers.
Workshops and Conferences
- BioMed21 – A Human Pathway-based Approach to Disease and Medicine
- Application of In Vitro-In Silico Approaches in Toxicology Safety Assessment and Regulation - OpenTox USA 2017 Conference
- Exploring Telomeres as Sentinels for Environmental and Psychosocial Stress and Susceptibility Workshop
- Advances in Andrology: The Basic Science Behind Fertility
- The Promise of Genome Editing Tools to Advance Environmental Health Research
- International Society of Exposure Science (ISES) Annual Meeting
- Enabling Inference-based Decision-making: Predicting v. Observing
- Toxic Metals: From Exposures and Model Systems to Human Populations
- Triangle Consortium for Reproductive Biology Annual Meeting
- Epigenetics, Stem Cells, and Environmental Health Symposium and Workshop
- Environment and Health: What’s the Human Microbiome Have to do with it?
- TaRGET II Consortium Meeting
- Inflammation and the Environmental: The Role of the Mitochondrion and Energy Metabolism
- Society of Toxicology (SOT) Meeting
- Aquatic Models and 21st Century Toxicology
- Elucidating Environmental Dimensions of Neurological Disorders and Diseases: Understanding New Tools from Federal Chemical Testing Programs
- Environmental Stressors in Disease and Implications for Human Health
- Health Effects and Mitigation of Arsenic: Current Research Efforts and Future Directions
- Identifying and Reducing Environmental Health Risks of Chemicals in Our Society
- International Symposium on Alternatives Assessment
- Juvenile Toxicology
- Modeling the Health Risks of Climate Change
- NIEHS Environmental Health Science FEST, December 5 – 8, 2016
- Parkinson's Disease: Understanding the Environment and Gene Connection
- The Interplay Between Environmental Exposures and Obesity
Selected Scientific Advances
Perera L (DIR), Li Y (DIR), Coons LA, Houtman R, van Beuningen R, Goodwin B, Auerbach SS (NTP), Teng CT (NTP). 2017. Binding of bisphenol A, bisphenol AF, and bisphenol S on the androgen receptor: Coregulator recruitment and stimulation of potential interaction sites. Toxicology in vitro 44:287-302. [Abstract]
This is the first report to describe the recruitment of coregulators to the BPA analogue-AR complexes and to show that the BPA analogues may have the potential to bind at multiple locations on the AR complex.
Hall JA (NTP), McElwee MK (DIR), Freedman JH. 2017. Identification of ATF-7 and the Insulin Signaling Pathway in the Regulation of Metallothionein in C. elegans Suggests Roles in Aging and Reactive Oxygen Species. Environ. Mol. Mutagen. [Abstract]
To better understand mechanisms controlling metallothionein expression, the regulatory factors and pathways that controlled cadmium-inducible transcription of the C. elegans metallothionein gene, mtl-1, were identified.
Harrill AH (NTP), McAllister KA (DERT). 2017. New rodent population models may inform human health risk assessment and identification of genetic susceptibility to environmental exposures. Environ. Health Perspect. 125(8):086002. [ePub] [Abstract]
This paper provides an introduction for environmental health scientists to emerging population-based rodent resources. Mouse reference populations provide an opportunity to model environmental exposures and gene–environment interactions in human disease and to inform human health risk assessment.
Witt KL (DNTP), Hsieh JH, Smith-Roe SL (DNTP), Xia M, Huang R, Zhao J, Auerbach SS (DNTP), Hur J, Tice RR (DNTP). 2017. Assessment of the DNA damaging potential of environmental chemicals using a quantitative high-throughput screening approach to measure p53 activation. J. Chem. Inf. Model 57(1):36-49. [Abstract]
To determine the usefulness of screening for p53 activation as part of a comprehensive toxicity profile approach, we screened the Tox21 compound library in a commercially available reporter gene assay.
Wellman AS (DIR), Metukuri MR (DIR), Kazgan N (DIR), Xu X (DIR), Xu Q (DIR), Ren NSX (DIR), Czopik A, Shanahan MT, Kang A (DIR), Chen W (DIR), Azcarate-Peril MA, Gulati AS, Fargo DC (DIR), Guarente L, Li X (DIR). 2017. Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation during Aging in Mice by Altering the Intestinal Microbiota. Gastroenterology 153(3):772-786. [Abstract]
Researchers investigated how Sirtuin 1 (SIRT1), a conserved mammalian NAD+-dependent protein deacetylase, senses environmental stress to alter intestinal integrity.
Weinberg CR (DIR), Shi M (DIR), Basso O, DeRoo LA, Harmon Q (DIR), Wilcox AJ (DIR), Skjaerven R. 2017. Season of Conception, Smoking, and Preeclampsia in Norway. Environ. Health Perspect. 125(6):067022 [ePub]. [Abstract]
This study explored the seasonal pattern of preeclampsia risk. Investigators modeled the seasonal effects and applied harmonic Cox regression to model confounder-adjusted effects in the Medical Birth Registry of Norway for deliveries between 199 and 2009. They also examined effect measure modification. The results suggest that there is a seasonal driver for preeclampsia.
Pillon MC (DIR), Sobhany M (DIR), Borgnia MJ, Williams JG (DIR), Stanley RE (DIR). 2017. Grc3 programs the essential endoribonuclease Las1 for specific RNA cleavage. Proc Natl Acad Sci 114(28):E5530-E5538. [Abstract]
To gain mechanistic insight into the endoribonuclease activity of Las1 and the polynucleotide kinase activity of Grc3, investigators reconstituted C2 cleavage in vitro and characterized the assembly of the Grc3/Las1 complex. These studies reveal functional cross talk between Las1 and Grc3; both enzymes are dependent on one another for higher-order assembly, nuclease and kinase enzymatic activities, recognition and cleavage of the C2 site, and efficient ribosome production.
Sung EJ (NTP), Ryuda M, Matsumoto H, Uryu O, Ochiai M, Cook ME (DIR), Yi NY, Wang H, Putney JW (DIR), Bird GS (DIR), Shears SB (DIR), Hayakawa Y. 2017. Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress. Proc Natl Acad Sci 114(52):13786-13791. [Abstract]
Through genetic manipulation of the GBP/Mthl10 axis in larvae and adult flies, researchers were able to demonstrate how organismal longevity is interconnected to immunological, metabolic, and stress-protective responses. The results provide a molecular basis for hypothesizing that a successful defense against environmental insults—be they pathogenic inflammation or noninfective challenges—will ultimately reduce lifespan.
Lynch C, Zhao J, Huang R, Kanaya N, Bernal L, Hsieh JH, Auerbach SS (DNTP), Witt KL (DNTP), Merrick BA (DNTP), Chen S, Teng CT (DNTP), Xia M. 2017. Identification of Estrogen-Related Receptor Alpha Agonists in the Tox21 Compound Library. Endocrinology 159(2):744-753. [Abstract]
In this study, investigators screened ∼10,000 (8311 unique) compounds, known as the Tox21 10K collection, to identify agonists of estrogen-related receptor α (ERRα). They performed this screen using two stably transfected HEK 293 cell lines, one with the ERRα-reporter alone and the other with both ERRα-reporter and PGC-1α expression vectors.
Steiner AZ, Pritchard D, Stanczyk FZ, Kesner JS, Meadows JW, Herring AH, Baird DD (DIR). Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age. 2017. JAMA 318(14):1367-1376. [Abstract]
The purpose of this study was to determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. Using a prospective time-to-pregnancy cohort study of women ages 30-44 years, researchers did not find an association between biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve and reduced fertility in women with no history of infertility.
Zhao F (DIR), Franco HL (DIR), Rodriguez KF (DIR), Brown PR (DIR), Tsai MJ, Tsai SY, Yao HH (DIR). 2017. Elimination of the male reproductive tract in the female embryo is promoted by COUP-FII in mice. Science 357(6352):717-720. [Abstract]
Researchers discovered that female mouse embryos lacking Coup-tfII (chicken ovalbumin upstream promoter transcription factor II) in the Wolffian duct mesenchyme became intersex—possessing both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced phosphorylated extracellular signal-regulated kinase signaling in Wolffian duct epithelium was responsible for the retention of male structures in an androgen-independent manner.
Schellenberg MJ (DIR), Lieberman JA, Herrero-Ruiz A, Butler LR (DIR), Williams JG (DIR), Munoz-Cabello AM, Mueller GA (DIR), London RE (DIR), Cortes-Ledesma F, Williams RS (DIR). 2017. ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links. Science 357(6358):1412-1416. [Abstract]
Topoisomerase 2 DNA-protein crosslinks are induced by widely used anticancer drugs, environmental toxicants, chemical metabolites, tobacco exposures, or DNA damage caused by ultraviolet light. This paper reports the discovery of the ZATT-TDP2 complex, a novel sensor of TOP2-DPCs that facilitates the direct resolution of these highly genotoxic lesions, and underpins cellular resistance to TOP2 targeted cancer therapy.
Shock DD (DIR), Freudenthal BD (DIR), Beard WA (DIR) and Wilson SH (DIR). 2017. Modulating the DNA polymerase beta reaction equilibrium to dissect the reverse reaction. Nature chemical biology 13(10):1074-1080. [Abstract]
This study has kinetically characterized pyrophosphorolysis and identified a PPi analog, imidodiphosphate (PNP), that alters the internal equilibrium, permitting structural characterization by time-lapse X-ray crystallography. These results impact the mechanistic understanding of DNA polymerase nucleotidyl transferase chemistry and that key enzyme structural transitions can influence function.
Cinghu S (DIR), Yang P (DIR), Kosak JP (DIR), Conway AE (DIR), Kumar D (DIR), Oldfield AJ (DIR), Adelman K (DIR), Jothi R (DIR). 2017. Intragenic Enhancers Attenuate Host Gene Expression. Mol Cell 68(1):104-117.e6. [Abstract]
The authors show that transcription at intragenic enhancers interferes with and attenuates host gene transcription during productive elongation.
Shalaby KH (DIR), Lyons-Cohen MR (DIR), Whitehead GS (DIR), Thomas SY (DIR), Prinz I, Nakano H (DIR), Cook DN (DIR). 2017. Pathogenic Th17 inflammation is sustained in the lungs by conventional dendritic cells and TLR4 signaling. J Allergy Clin Immunol. [Abstract]
This study sought to understand whether maintenance of lung TH7 inflammation requires environmental agents in addition to antigen and to identify the lung antigen-presenting cell types that sustain the self-renewal of TH7 cells.
Kang HS (DIR), Kumar D (DIR), Liao G (DIR), Lichti-Kaiser K (DIR), Gerrish K (DIR), Liao XH, Refetoff S, Jothi R (DIR), Jetten AM (DIR). 2017. GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation. The Journal of clinical investigation [ePub]. [Abstract]
In the current study, the investigators demonstrate that GLIS3 acts downstream of thyroid-stimulating hormone (TSH) and TSH receptor (TSHR) and is indispensable for TSH/TSHR-mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone. Using ChIP-Seq and promoter analysis, the investigators demonstrate that GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, both of which showed enhanced GLIS3 binding at their promoters.
Jamsen JA (DIR), Beard WA (DIR), Pedersen LC (DIR), Shock DD (DIR), Moon AF (DIR), Krahn JM (DIR), Bebenek K (DIR), Kunkel TA (DIR), Wilson SH (DIR). 2017. Time-lapse crystallography snapshots of a double-strand break repair polymerase in action. Nature communications 8(1):253. [Abstract]
The authors report time-lapse X-ray crystallography snapshots of catalytic events during gap-filling DNA synthesis by pol μ. These observations provide insight on structural attributes of this X-family double-strand break repair polymerase that impact its biological function in genome maintenance.
Whitehead GS (DIR), Thomas SY (DIR), Shalaby KH (DIR), Nakano K (DIR), Moran TP (DIR), Ward JM (DIR), Flake GP (NTP), Nakano H (DIR), Cook DN (DIR). 2017. TNF is required for TLR ligand-mediated but not protease-mediated allergic airway inflammation. The Journal of clinical investigation 127(9):3313-3326. [Abstract]
The researchers compared molecular mechanisms by which 2 different classes of adjuvants, TLR ligands and proteases, promote allergic responses to bystander proteins. They found that TNF signaling through airway epithelial cells (AECs) induced a suite of genes in those cells and was required for TLR ligand–mediated development of antigen-specific Th2 cells, but not antigen-specific Th17 cells.
Moon AF (DIR), Pryor JM, Ramsden DA, Kunkel TA (DIR), Bebenek K (DIR), Pedersen LC (DIR). 2017. Structural accommodation of ribonucleotide incorporation by the DNA repair enzyme polymerase Mu. Nucleic Acids Res 45(15):9138-9148. [Abstract]
To gain insight on how the Family X member DNA polymerase μ (Pol μ) incorporates rNTPs almost as efficiently as deoxyribonucleotides, investigators used X-ray crystallography to describe the structures of pre- and post-catalytic complexes of Pol μ with a ribonucleotide bound at the active site. These structures reveal that Pol μ binds and incorporates a rNTP with normal active site geometry and no distortion of the DNA substrate or nucleotide.
Li P (DIR), Wang L, Bennett BD (DIR), Wang J (DIR), Li J, Qin Y (DIR), Takaku M (DIR), Wade PA (DIR), Wong J, Hu G (DIR). 2017. Rif1 promotes a repressive chromatin state to safeguard against endogenous retrovirus activation. Nucleic Acids Res 45(22):12723-12738. [Abstract]
In the current study, researchers examined DNA polymerase (pol) γ and pol β as possible complementing enzymes in the case of APTX deficiency. The activities of pol β lyase and FEN1 nucleotide excision were able to remove the 5′-AMP-dRP group in mitochondrial extracts from APTX−/− cells. However, the lyase activity of purified pol γ was weak against the 5′-AMP-dRP block in a model BER substrate, and this activity was not able to complement APTX deficiency in mitochondrial extracts from APTX−/−Pol β−/− cells. FEN1 also failed to provide excision of the 5′-adenylated BER intermediate in mitochondrial extracts. These results illustrate the potential role of pol β in complementing APTX deficiency in mitochondria.
Ҫağlayan M (DIR), Prasad R (DIR), Krasich R (DIR), Longley MJ (DIR), Kadoda K, Tsuda M, Sasanuma H, Takeda S, Tano K, Copeland WC (DIR), Wilson SH (DIR). 2017. Complementation of aprataxin deficiency by base excision repair enzymes in mitochondrial extracts. Nucleic Acids Res 45(17):10079-10088. [Abstract]
Researchers questioned whether the pol β lyase is capable of serving a back up role during mitochondrial BER in APTX deficient cells, and also tested the activity of purified pol γ against a 5′-adenylated BER intermediate.
Tang S (DIR), Fang Y (DIR), Huang G, Xu X (DIR), Padilla-Banks E (DIR), Fan W (DIR), Xu Q (DIR), Sanderson SM, Foley JF (NTP), Dowdy S (NTP), McBurney MW, Fargo DC (DIR), Williams CJ (DIR), Locasale JW, Guan Z, Li X(DIR). 2017. Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. The EMBO journal 36(21):3175-3193. [Abstract]
This study explores the role of SIRT1 in modulating methionine metabolism, and how it impacts the maintenance of mouse embryonic stem cells and subsequent embryogenesis. The authors describe a novel regulatory mechanism for methionine metabolism and highlights the importance of methionine metabolism in SIRT1-mediated mouse embryonic stem cell maintenance and embryonic development.
Fessler MB (DIR), Carnes MU (DIR), Salo PM (DIR), Wilkerson J, Cohn RD, King D (NTP), Hoppin JA, Sandler DP (DIR), Travlos G (NTP), London SJ (DIR), Thorne PS, Zeldin DC (DIR). 2017. House Dust Endotoxin and Peripheral Leukocyte Counts: Results from Two Large Epidemiologic Studies. Environ Health Perspec 125(5):057010. [Abstract]
Researchers investigated the relationship between house dust endotoxin concentration and peripheral leukocyte counts in human subjects to better understand the association between environmental exposures and leukocyte count.
Gu C (DIR), Nguyen HN (DIR), Ganini D (DIR), Chen Z, Jessen HJ, Gu Z, Wang H (DIR) and Shears SB (DIR). 2017. KO of 5-InsP7 kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype. Proc Natl Acad Sci U S A 114(52):13786-13791. [Abstract]
Scientists used CRISPR to KO PPIP5Ks in the HCT116 colon cancer cell line. This procedure eliminates 1,5-InsP8 and raises 5-InsP7 levels threefold. Expression of p53 and p21 was up-regulated; proliferation and G1/S cell-cycle transition slowed. Thus, PPIP5Ks are potential targets for tumor therapy.
Montrose L, Faulk C, Francis J, Dolinoy DC. 2017. Perinatal Lead (Pb) Exposure Results in Sex and Tissue-Dependent Adult DNA Methylation Alterations in Murine IAP Transposons. Environ Mol Mutag 58(8):540-550. [Abstract]
Researchers evaluated brain and kidney DNA methylation profiles of four representative intracisternal A particle retrotransposons in adult mice exposed to human physiologically relevant levels of lead two weeks prior to mating through lactation.
Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, Vrbanac AF, Li W, Perkins A, Matsutani T, Zhong Z, Dhar D, Navas-Molina JA, Xu J, Loomba R, Downes M, Yu RT, Evans RM, Dorrestein PC, Knight R, Benner C, Anstee QM, Karin M. 2017. Inflammation-induced IgA plus cells dismantle anti-liver cancer immunity. Nature 551(7680):340–345. [Abstract]
Scientists investigated how adaptive immunity affects hepatocellular carcinoma (HCC), a leading cause of cancer deaths. This study shows that IgA+ cells, found in human and mouse NASH-afflicted livers, mediate immunosuppression that fosters HCC development by inhibiting a strongly protective, tumour-directed CTL response. Manipulations that unleash CTL activity cause regression of established HCC in mice and should be applicable to humans.
Ren NS (DIR), M Ji (DIR), EJ Tokar (NTP), EL Busch, X Xu (DIR), D Lewis (DIR), X Li, A Jin, Y Zhang, WK Wu, W Huang (DIR), L Li (DIR), DC Fargo (DIR), TO Keku, RS Sandler and X Li (DIR). 2017. Haploinsufficiency of SIRT1 Enhances Glutamin Metabolism and Promotes Cancer Development. Curr Biol 27(4):483-494. [Abstract]
Scientists demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development.
Zang Q, K Mansouri, AJ Williams, RS Judson, DG Allen, WM Casey (DNTP) and NC Kleinstreuer (DNTP). 2017. In Silico Prediction of Physicochemical Properties of Environmental Chemicals Using Molecular Fingerprints and Machine Learning. J. Chem. Inf. Model 57(1):36-49. [Abstract]
The purpose of the present study was to generate an open-source quantitative structure–property relationship (QSPR) workflow to predict a variety of physicochemical properties that would have cross-platform compatibility to integrate into existing cheminformatics workflows.
Gao L, Mutlu E (DNTP), Collins LB, Walker NJ (DNTP), Hartwell HJ, Olson JR, Sun W, Gold A, Ball LM, Swenberg JA. 2017. DNA Product Formation in Female Sprague-Dawley Rats Following Polyhalogenated Aromatic Hydrocarbon (PHAH) Exposure. Chem Res Toxicol 30(3):794-803. [Abstract]
In this study, researchers evaluated the toxic equivalency factor (TEF) from the standpoint of induced DNA oxidation products and their relationship to toxicity and carcinogenicity.
Shaw ND (DIR), H Brand, ZA Kupchinsky, H Bengani, L Plummer, TI Jones, S Erdin, KA Williamson, J Rainger, A Stortchevoi, K Samocha, BB Currall, DS Dunican, RL Collins, JR Willer, A Lek, M Lek, M Nassan, S Pereira, T Kammin, D Lucente, A Silva, CM Seabra, C Chiang, Y An, M Ansari, JK Rainger, S Joss, JC Smith, MF Lippincott, SS Singh, N Patel, JW Jing, JR Law, N Ferraro, A Verloes, A Rauch, K Steindl, M Zweier, I Scheer, D Sato, N Okamoto, C Jacobsen, J Tryggestad, S Chernausek, LA Schimmenti, B Brasseur, C Cesaretti, JE Garcia-Ortiz, TP Buitrago, OP Silva, JD Hoffman, W Muhlbauer, KW Ruprecht, BL Loeys, M Shino, AM Kaindl, CH Cho, CC Morton, RR Meehan, V van Heyningen, EC Liao, R Balasubramanian, JE Hall (DIR), SB Seminara, D Macarthur, SA Moore, KI Yoshiura, JF Gusella, JA Marsh, JM Graham, Jr., AE Lin, N Katsanis, PL Jones, WF Crowley, Jr., EE Davis, DR FitzPatrick and ME Talkowski. 2017. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat. Genet. 49(2):238-248. [Abstract]
Using a combination of whole-exome, whole-genome, and target sequencing, the authors discovered that rare missense variants in SMCHD1 represent the predominant genetic contributor to arhinia.
Caglayan M (DIR), JK Horton (DIR), DP Dai (DIR), DF Stefanick (DIR), SH Wilson (DIR). 2017. Oxidized nucleotide insertion by pol beta confounds ligation during base excision repair. Nature Communications 8:14045. [Abstract]
The authors report that the DNA ligation step of base excision repair (BER) is compromised after polymerase β (pol β) insertion of oxidized purine nucleotides into the BER intermediate in vitro. These results suggest the possibility that BER mediated toxic strand breaks are produced in cells under oxidative stress conditions.
Wallace BD (DIR), Z Berman, GA Mueller (DIR), Y Lin, T Chang (DIR), SN Andres (DIR), JL Wojtaszek (DIR), EF DeRose (DIR), CD Appel (DIR), RE London (DIR), S Yan and RS Williams (DIR). APE2 Zf-GRF facilitates 3’-5’ resection of DNA damage following oxidative stress. Proc Natl Acad Sci 114(2):304-309. [Abstract]
The authors establish the apurinic/apyrimidinic endonuclease 2 (APE2) Zf-GRF domain as a prototypical member of the Zf-GRF class of nucleic acid-binding modules, and through structural analysis reveal that the APE2 protein is composed of a compacted three-stranded β-sheet and a CHCC Zn2+-binding site, harboring structure-specific ssDNA-binding activity.
Williams CJ (DIR), A Chu, WN Jefferson (DIR), D Casero, D Sudhakar, N Khurana, CP Hogue, C Aryasomayajula, P Patel, P Sullivan, E Padilla-Banks (DIR), S Mohandessi, C Janzen and M Wadehra. 2017. Epithelial membrane protein 2 (EMP2) deficiency alters placental angiogenesis, mimicking features of human placental insufficiency. J Pathol 242(2):246-259. [Abstract]
To test the role of Epithelial membrane protein-2 (EMP2) in pregnancy, mice lacking EMP2 were generated and their fertility was examined. To determine if these results translated to human pregnancy, placentas from normal, term deliveries or those complicated by placental insufficiency resulting in intrauterine growth restriction (IUGR) were stained for EMP2.
Seok SH, W Lee, L Jiang, K Molugu, A Zheng, Y Li, S Park, CA Bradfield and Y Xing. 2017. Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex. Proc Natl Acad Sci 114(21):5431-5436. [Abstract]
This study reveals three-dimensional structural codes for specific engagement of DRE that discriminates it from the closely related hypoxia response elements; the highly intertwined dimerization and interdomain interfaces remotely control DRE-binding and ligand-induced exposure of nuclear localization signal.
Cisse YM, Russart KL, Nelson RJ. 2017. Parental Exposure to Dim Light at Night Prior to Mating Alters Offspring Adaptive Immunity. Sci Rep 7:45497. [Abstract]
This study explored the relationship between parental exposure to dim light at night and cell-mediated and humoral immunity in their offspring.
Xiao S, JR Coppeta, HB Rogers, BC Isenberg, J Zhu, SA Olalekan, KE McKinnon, D Dokic, AS Rashedi, DJ Haisenleder, SS Malpani, CA Arnold-Murray, KW Chen, MY Jiang, L Bai, CT Nguyen, JY Zhang, MM Laronda, TJ Hope, KP Maniar, ME Pavone, MJ Avram, EC Sefton, S Getsios, JE Burdette, JJ Kim, JT Borenstein and TK Woodruff. 2017. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat Commun 8:14584. [Abstract]
This study shows that a microfluidic system supports murine ovarian follicles to produce the human 28-day menstrual cycle hormone profile, which controls human female reproductive tract and peripheral tissue dynamics in single, dual and multiple unit microfluidic platforms.
Laronda MM, Rutz AL, Xiao S, Whelan KA, Duncan FE, Roth EW, Woodruff TK, Shah RN. 2017. A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nat Commun 8:15261. [Abstract]
Researchers 3D printed microporous hydrogel scaffolds to test how varying pore geometry, accomplished by manipulating the advancing angle between printed layers, affects the survival of ovarian follicles.
Ferrucio B, M Tiago, RD Fannin (DIR), L Liu (DIR), K Gerrish (DIR), SS Maria-Engler, RS Paules (NTP) and SB de Moraes Barros. 2016. Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes. Toxicol In Vitro 38:67-76. [Abstract]
This study aimed to characterize human melanocytes after individual or combined exposure to carbaryl (100 μM) and solar radiation (375 mJ/cm2).
Stanko JP (NTP), GE Kissling (DIR), VA Chappell (NTP) and SE Fenton (NTP). 2016. Differences in the Rate of in Situ Mammary Gland Development and Other Developmental Endpoints in Three Strains of Female Rat Commonly Used in Mammary Carcinogenesis Studies: Implications for Timing of Carcinogen Exposure. Toxicol. Pathol 44(7):1021-1033. [Abstract]
In this study, in situ mammary gland development was assessed in females of the Harlan Sprague-Dawley (Hsd:SD), Charles River Sprague-Dawley (Crl:SD), and Charles River Long-Evans (Crl:LE) rat strains at postnatal days 25, 33, and 45.
Behl M (DNTP), JR Rice (DNTP), MV Smith, CA Co, MF Bridge, J-H Hsieh (DNTP), JH Freedman and WA Boyd (DNTP). 2016. Comparative Toxicity of Organophosphate Flame Retardants and Polybrominated Diphenyl Ethers to Caenorhabditis elegans. Toxicol Sci 154(2):241-252. [Abstract]
In this study, the toxicological effects of 4 brominated flame retardants, including 3 polybrominated diphenyl ethers and 3,3',5,5'-tetrabromobisphenol A, were compared with 6 aromatic organophosphate flame retardants (OPFRs) and 2 aliphatic OPFRs.
Strickland J, Zang Q, Kleinstreuer N (DNTP), Paris M, Lehmann DM, Choksi N, Matheson J, Jacobs A, Lowit A, Allen D, Casey W (DNTP). 2016. Integrated decision strategies for skin sensitization hazard. J Appl Toxicol 36(9):1150–1162. [Abstract]
This study describes the process undertaken by ICCVAM to develop integrated decision strategies based on the adverse outcome pathway using in vitro, in chemico, and in silico information.
Kleinstreuer NC (DNTP), Ceger P, Watt ED, Martin M, Houck K, Browne P, Thomas RS, Casey WM (DNTP), Dix DJ, Allen D, Sakamuru S, Xia M, Huang R, Judson R. 2016. Development and Validation of a Computational Model for Androgen Receptor Activity. Chem Res Toxicol 30(4):946-964. [Abstract]
Researchers integrated 11 high-throughput in vitro screening ToxCast/Tox21 in vitro assays into a computational network model to distinguish true androgen receptor pathway activity from technology-specific assay interference.
Rubel CA, SP Wu (DIR), L Lin, T Wang (DIR), RB Lanz, X Li, R Kommagani, HL Franco, SA Camper, Q Tong, JW Jeong, JP Lydon and FJ DeMayo (DIR). 2016. A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function. Cell Reports 17(5):1414-1425. [Abstract]
This study describes the role of uterine GATA binding protein 2 (Gata2) in the regulation of a key regulatory network of gene expression for progesterone signaling at the early pregnancy stage.
Zhang J (DIR), McCann KL (DIR), Qiu C (DIR), Gonzalez LE (DIR), Baserga SJ, Hall TM (DIR). 2016. Nop9 is a PUF-like protein that prevents premature cleavage to correctly process pre-18S rRNA. Nat Commun 7:13085. [Abstract]
Researchers report a 2.1-Å crystal structure of Nop9 and a small-angle X-ray-scattering model of a Nop9:RNA complex that reveals a 'C'-shaped fold formed from 11 Pumilio repeats.
Zhang S, Zhou B (DIR), Wang L (DIR), Li P (DIR), Bennett BD (DIR), Snyder R (DIR), Garantziotis S (DIR), Fargo DC (DIR), Cox AD, Chen L, Hu G (DIR). 2016. INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer. Oncogene 36(10):1430-1439. [Abstract]
This study shows that the INO80 chromatin remodeling complex is required for oncogenic transcription and tumor growth in non-small-cell lung cancer (NSCLC).
Lai L (DIR), Azzam KM (DIR), Lin WC (DIR), Rai P (DIR), Lowe JM (DIR), Gabor KA (DIR), Madenspacher JH (DIR), Aloor JJ (DIR), Parks JS, Naar AM, Fessler MB (DIR). 2016. MicroRNA-33 regulates the innate immune response via ATP binding cassette transporter-mediated remodeling of membrane microdomains. J Biol Chem 291(37):19651−19660. [Abstract]
The authors report that multiple toll-like receptor (TLR) ligands down-regulate miR-33 in murine macrophages. In the case of lipopolysaccharide, this is a delayed, Toll/interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon-β-dependent response that also down-regulates Srebf-2, the host gene for miR-33.
Liu C (DIR), Rodriguez K (DIR), Yao HH (DIR). 2016. Mapping lineage progression of somatic progenitor cells in the mouse fetal testis. Development 143(20):3700-3710. [Abstract]
The authors construct a comprehensive map of somatic cell lineage progression in the mouse testis.
Reid NM, Proestou DA, Clark BW, Warren WC, Colbourne JK, Shaw JR, Karchner SI, Hahn ME, Nacci D, Oleksiak MF, Crawford DL, Whitehead A. 2016. The genomic landscape of rapid repeated evolutionary adaptation to toxic pollution in wild fish. Science 354(6317):1305-1308. [Abstract]
Through analysis of 384 whole killifish genome sequences and comparative transcriptomics in four pairs of sensitive and tolerant populations, the authors identify the aryl hydrocarbon receptor-based signaling pathway as a shared target of selection.
Dunaway K, Goorha S, Matelski L, Urraca N, Lein PJ, Korf I, Reiter LT, LaSalle JM. 2016. Dental Pulp Stem Cells Model Early Life and Imprinted DNA Methylation Patterns. Stem Cells. 35(4):981-988. [Abstract]
Using whole genome bisulfite sequencing, the authors show that dental pulp stem cells (DPSCs), derived from baby teeth and cultured in serum-containing media, have partially methylated domains (PMDs) and mimic the inner cell mass (ICM) and placental methylome more closely than induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs).
Fouquerel E, Lormand J, Bose A, Lee HT, Kim GS, Li J, Sobol RW, Freudenthal BD, Myong S, Opresko PL. 2016. Oxidative guanine base damage regulates human telomerase activity. Nat Struct Mol Biol 23(12):1092–1100. [Abstract]
Researchers examined how the common oxidative lesion 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG) regulates telomere elongation by human telomerase.
Ho SM, Rao RC, To S, Schoch E, Tarapore P. 2016. Bisphenol A and its analogues disrupt centrosome cycle and microtubule dynamics in prostate cancer. Endocr Relat Cancer 24(2):83-96. [Abstract]
Researchers examine whether exposure of prostate cancer cells (LNCaP, C4-2) to low-dose BPA and its structural analogues (BPS, BPF, BPAF, TBBPA, DMBPA and TMBPA) affects centrosome amplification (CA), a hallmark of cancer initiation and progression.
Schmitt AM, Garcia JT, Hung T, Flynn RA, Shen Y, Qu K, Payumo AY, Peres-da-Silva A, Broz DK, Baum R, Guo S, Chen JK, Attardi LD, Chang HY. 2016. An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet 48(11):1370-1376. [Abstract]
In this study, researchers demonstrate that lncRNAs guide the organismal DNA damage response. DNA damage activated transcription of the DINO (Damage Induced Noncoding) lncRNA via p53.
Dunaway KW, Islam MS, Coulson RL, Lopez SJ, Vogel Ciernia A, Chu RG, Yasui DH, Pessah IN, Lott P, Mordaunt C, Meguro-Horike M, Horike SI, Korf I, LaSalle JM. 2016. Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes. Cell Rep 17(11):3035-3048. [Abstract]
Using whole-genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.2-q13.3 maternal duplication, this study describes how significant global DNA hypomethylation is enriched over autism candidate genes and affects gene expression.
Bell MR, Hart BG, Gore AC. 2016. Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 2. Sex-specific neuromolecular effects in the brain. Mol Cell Endocrinol 420:125-37. [Abstract]
Reese SE (DIR), S Zhao (DIR), MC Wu, BR Joubert (DERT), CL Parr (DIR), SE Haberg, PM Ueland, RM Nilsen, O Midttun, SE Vollset, SD Peddada (DIR), W Nystad and SJ London (DIR). 2016. DNA Methylation Score as a Biomarker in Newborns for Sustained Maternal Smoking during Pregnancy. Environ Health Perspect 125(4):760-766. [Abstract]
Kang HS (DIR), Y Takeda (DIR), K Jeon (DIR) and AM Jetten (DIR). 2016. The Spatiotemporal Pattern of Glis3 Expression Indicates a Regulatory Function in Bipotent and Endocrine Progenitors during Early Pancreatic Development and in Beta, PP and Ductal Cells. PLoS One 11(6):e0157138 [Abstract]
Markunas CA (DIR), AJ Wilcox (DIR), Z Xu (DIR), BR Joubert (DIR), S Harlid (DIR), V Panduri (DIR), SE Haberg, W Nystad, SJ London (DIR), DP Sandler (DIR), RT Lie, PA Wade (DIR) and JA Taylor (DIR). 2016. Maternal Age at Delivery Is Associated with an Epigenetic Signature in Both Newborns and Adults. PLoS ONE 11(7):e0156361 [Abstract]
Kang HS (DIR), LY Chen (DIR), K Lichti-Kaiser (DIR), G Liao (DIR), K Gerrish (DIR), CD Bortner (DIR), HH Yao (DIR), EM Eddy (DIR) and AM Jetten (DIR). 2016. Transcription Factor GLIS3: a New and Critical Regulator of Postnatal Stages of Mouse Spermatogenesis. Stem Cells 34(11):2772-2783. [Abstract]
Paquette AG, Houseman EA, Green BB, Lesseur C, Armstrong DA, Lester B, Marsit CJ. 2016. Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. Epigenetics. 11(8):603-13. [Abstract]
Krakowiak P, Walker CK, Tancredi D, Hertz-Picciotto I, Van de Water J. 2016. Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism Res 10(1):89-98. [Abstract]
Ma H, O'Farrell PH. 2016. Selfish drive can trump function when animal mitochondrial genomes compete. Nat Genet. 48(7):798-802. [Abstract]
Morgan, DL (DNTP), Jokinen, MP, Johnson, CL, Price, HC, Gwinn, WM (DNTP), Bousquet, RW, Flake, GP (DNTP). 2016. Chemical reactivity and respiratory toxicity of the alpha-diketone flavoring agents: 2,3-butanedione, 2,3-pentanedione, and 2,3-hexanedione. Toxicol Pathol 44(5):763-783. [Abstract]
Nayak AP, Green BJ, Lemons AR, Marshall NB, Goldsmith WT, Kashon ML, Anderson SE, Germolec DR (DNTP), Beezhold DH. 2016. Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naive mice. Clin Exp Allergy 46(6):861-70. [Abstract]
Ryan KR (DNTP), Sirenko O, Parham F (DNTP), Hsieh JH (DNTP), Cromwell EF, Tice RR (DNTP), Behl M (DNTP). 2016. Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high-throughput screen for developmental neurotoxicity or neurotoxicity. Neurotoxicology 53:271-281. [Abstract]
Swartley, OM, Foley, JF (DNTP), Livingston, DP, 3rd, Cullen, JM, Elmore, SA (DNTP). 2016. Histology atlas of the developing mouse hepatobiliary hemolymphatic vascular system with emphasis on embryonic days 11.5-18.5 and early postnatal development. Toxicol Pathol 44(5):705-725. [Abstract]
Ribas V, BG Drew, Z Zhou, J Phun, NY Kalajian, T Soleymani, P Daraei, K Widjaja, J Wanagat, TQ de Aguiar Vallim, AH Fluitt, S Bensinger, T Le, C Radu, JP Whitelegge, SW Beaven, P Tontonoz, AJ Lusis, BW Parks, L Vergnes, K Reue, H Singh, JC Bopassa, L Toro, E Stefani, MJ Watt, S Schenk, T Akerstrom, M Kelly, BK Pedersen, SC Hewitt (DIR), KS Korach (DIR) and AL Hevener. 2016. Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci. Transl. Med. 8(334):334ra54. [Abstract]
Gassman NR (DIR), E Coskun, P Jaruga, M Dizdaroglu and SH Wilson (DIR). 2016. Combined Effects of High-Dose Bisphenol A and Oxidizing Agent (KBrO) on Cellular Microenvironment, Gene Expression, and Chromatin Structure of Ku70-deficient Mouse Embryonic Fibroblasts. Environ Health Perspect 124(8):1241-1252. [Abstract]
Schellenberg MJ (DIR), L Perera (DIR), CN Strom, CA Waters, B Monian (DIR), CD Appel (DIR), CK Vilas (DIR), JG Williams (DIR), DA Ramsden and RS Williams (DIR). 2016. Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by Tdp2. Nucleic Acids Res 44(8):3829-3844. [Abstract]
Huen K, Calafat AM, Bradman A, Yousefi P, Eskenazi B, Holland N. 2016. Maternal phthalate exposure during pregnancy is associated with DNA methylation of LINE-1 and Alu repetitive elements in Mexican-American children. Environ Res 148:55-62. [Abstract]
Maertens A, Bouhifd M, Zhao L, Odwin-DaCosta S, Kleensang A, Yager JD, Hartung T. 2016. Metabolomic network analysis of estrogen-stimulated MCF-7 cells: a comparison of overrepresentation analysis, quantitative enrichment analysis and pathway analysis versus metabolite network analysis. Arch Toxicol. 91(1):217-230. [Abstract]
Joubert BR, Felix JF, Yousefi P, Bakulski KM, Just AC, Breton C, Reese S, Markunas CA, Richmond RC, Xu C-J, Kupers LK, Oh SS, Hoyo C, Gruzieva O, Soderhall C, Salas LA, Baiz N, Zhang H, Lepeule J, Ruiz C, Ligthart S, Wang T, Taylor JA, Duijts L, Sharp GC, Jankipersadsing SA, Nilsen RM, Vaez A, Fallin MD, Hu D, Litonjua AA, Fuemmeler BF, Huen K, Kere J, Kull I, Munthe-Kaas MC, Gehring U, Bustamante M, Saurel-Coubizolles MJ, Quraishi BM, Ren J, Tost J, Gonzalez JR, Peters MJ, Haberg SE, Xu Z, van Meurs JB, Gant TR, Kerkhof M, Corpeleijn E, Feinberg AP, Eng C, Baccarelli AA, Benjamin Neelon SE, Bradman A, Merid SK, Bergstrom A, Herceg Z, Hernandez-Vargas H, Brunekreef B, Pinart M, Heude B, Ewart S, Yao J, Lemonnier N, Franco OH, Wu MC, Hofman A, McArdle W, Van der Vlies P, Falahi F, Gillman MW, Barcellos LF, Kumar A, Wickman M, Guerra S, Charles M-A, Holloway J, Auffray C, Tiemeier HW, Smith GD, Postma D, Hivert M-F, Eskenazi B, Vrijheid M, Arshad H, Anto JM, Dehghan A, Karmaus W, Annesi-Maesano I, Sunyer J, Ghantous A, Pershagen G, Holland N, Murphy SK, DeMeo DL, Burchand EG, Ladd-Acosta C, Snieder H, Nystad W, Koppelman GH, Relton CL, Jaddoe VWV, Wilcox A, Melen E, London SJ. 2016. DNA methylation in newborns and maternal smoking in pregnancy: Genome-wide consortium meta-analysis. Am J Hum Genet 98(4):680-696. [Abstract]
Researchers from 16 cohorts in the Pregnancy And Childhood Epigenetics (PACE) consortium identified more than 6,000 differentially methylated CpG sites in newborns in relation to maternal smoking during pregnancy, with nearly half of the sites not previously associated with smoking and methylation in either newborns or adults.
Behl M (DNTP), Hsieh JH, Shafer TJ, Mundy WR, Rice JR (DNTP), Boyd WA (DNTP), Freedman JH (DNTP-former), Hunter ES, Jarema K, Padilla S (DNTP), Tice RR (DNTP). 2015. Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity. Neurotoxicol Teratol 52(Pt B):181-93. [Abstract]
Bhusari, S, Pandiri, AR (DNTP), Nagai, H, Wang, Y, Foley, J (DNTP), Hong, HL (DNTP), Ton, TV (DNTP), DeVito, M (DNTP), Shockley, KR, Peddada, SD, Gerrish, KE, Malarkey, DE (DNTP), Hooth, MJ (DNTP), Sills, RC (DNTP), Hoenerhoff, MJ (DNTP). 2015. Genomic profiling reveals unique molecular alterations in hepatoblastomas and adjacent hepatocellular carcinomas in B6C3F1 mice. Toxicol Pathol 43(8):1114-1126. [Abstract]
Yang J(DIR), Bennett BD(DIR), Luo S, Inoue K(DIR), Grimm SA(DIR), Schroth GP, Bushel PR(DIR), Kinyamu HK(DIR), Archer TK (DIR). 2015. LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells. Mol Cell Biol 35(18):3225-43. [Abstract]
Freudenthal BD (DIR), Beard WA (DIR), Cuneo MJ, Dyrkheeva NS (DIR), Wilson SH (DIR). 2015. Capturing snapshots of APE1 processing DNA damage. Nat Struct Mol Biol 22(11):924-31. [Abstract]
Boyd, WA (DNTP), Smith, MV, Co, CA, Pirone, JR, Rice, JR (DNTP), Shockley, KR, Freedman, JH (DNTP-former). 2015. Developmental Effects of the ToxCast™ Phase I and II Chemicals in Caenorhabditis elegans and Corresponding Responses in Zebrafish, Rats, and Rabbits. Environ Health Perspect 124(5):586-593. [Abstract]
Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X, Dereski MO, Ruden DM. 2015. Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. Sci Rep 5:14466. [Abstract]
Chen S, JH Hsieh (NTP), R Huang, S Sakamuru, LY Hsin, M Xia, KR Shockley (DIR), S Auerbach (NTP), N Kanaya, H Lu, D Svoboda (NTP), KL Witt (NTP), BA Merrick (NTP), CT Teng (NTP) and RR Tice (NTP). 2015. Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library. Toxicol. Sci 147(2):446-457. [Abstract]
This work describes a high-throughput, cell-based system that may fill a gap in the pipeline of endocrine disruptor chemical screening by capturing effects on a mechanism known to play a key role in endocrine function, but is not currently assessed in the pipeline.
Tyler CR, Hafez AK, Solomon ER, Allan AM. 2015. Developmental exposure to 50 parts-per-billion arsenic influences histone modifications and associated epigenetic machinery in a region- and sex-specific manner in the adult mouse brain. Toxicol Appl Pharmacol 288(1):40-51. [Abstract]
Using environmentally relevant exposures to arsenic, an element found in some foods and well-based water or released by mining processes, scientists identified sex and region-specific epigenetic changes in the adult offspring’s brains. (b)
Zhao W, Vaithiyalingam S, San Filippo J, Maranon DG, Jimenez-Sainz J, Fontenay GV, Kwon Y, Leung SG, Lu L, Jensen RB, Chazin WJ, Wiese C, Sung P. 2015. Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry. Mol Cell 59(2):176-87. [Abstract]
This work provides mechanistic insight into DNA replication and repair processes using BRCA2, a gene known to increase the risk of breast cancer. (a)
Hewitt SC (DIR), Winuthayanon W (DIR), Pockette B (DIR), Kerns RT (DIR), Foley JF (NTP), Flagler N (NTP), Ney E (NTP), Suksamrarn A, Piyachaturawat P, Bushel PR (DIR) and Korach KS (DIR). 2015. Development of Phenotypic and Transcriptional Biomarkers to Evaluate Relative Activity of Potentially Estrogenic Chemicals in Ovariectomized Mice. Environ Health Perspect 123(4):344-352. [Abstract]
This work describes a mouse model of prepubertal girls and postmenopausal women coupled with a biomarker panel that could be used to identify estrogenic activity of chemicals and relative strength of endocrine disruption. (e)
Davis FM (DIR), A Janoshazi (DIR), KS Janardhan, N Steinckwich (DIR), DM D'Agostin (DIR), JG Petranka (DIR), PN Desai (DIR), SJ Roberts-Thomson, GS Bird (DIR), DK Tucker (NTP), SE Fenton (NTP), S Feske, GR Monteith and JW Putney, Jr. (DIR). 2015. Essential role of Orai1 store-operated calcium channels in lactation. Proc. Natl. Acad. Sci. U. S. A. 112(8):5827-5832. [Abstract]
Using genetic approaches in the mouse, scientists identified novel, required signaling roles for the gene Orai1 in lactation, a normal biological process. (d)
Liu C, Peng J, Matzuk MM, Yao HH (DIR). 2015. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells. Nat Commun 6:6934. [Abstract]
This work identified the origin of a cell type that contributes to the development of ovaries and identified the molecular signaling pathway that allows these cells to function properly. (d)
Shaughnessy DT (DERT), McAllister K (DERT), Worth L (DERT), Haugen AC (DERT), Meyer JN, Domann FE, Van Houten B, Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol RW, Hirschey MD, Ideker T, Santos JH, Copeland WC (NTP), Tice RR (NTP), Balshaw DM (DERT), Tyson FL (DERT). 2014. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 122(12):1271-8. [Abstract]
This review/commentary summarizes key points and ideas emerging from the Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response (MEEED) Workshop, held March 2013.
Markunas CA (DIR), Xu Z (DIR), Harlid S (DIR), Wade PA (DIR), Lie RT, Taylor JA (DIR), Wilcox AJ (DIR). 2014. Identification of DNA Methylation Changes in Newborns Related to Maternal Smoking during Pregnancy. Environ Health Perspect 122(10):1147-1153. [Abstract]
Scientists investigated the effects of maternal smoking during pregnancy and identified epigenetic changes in smoking mother’s newborns. (b)
Chrysovergis K (DIR), X Wang (DIR), J Kosak (DIR), SH Lee, J Sik Kim (DIR), JF Foley (NTP), G Travlos (NTP), S Singh (DIR), S Joon Baek and TE Eling(DIR). 2014. NAG-1/GDF15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism. Int J Obes (Lond) 38:1555-1564. [Abstract]
This work examined the role of the human NAG-1/GDF15 gene in mice and found it alters metabolism by increasing expression of important genes in fat tissue suggesting this could be a target for environmental stressors that increase susceptibility to obesity. (c)
Gosavi RA (DIR), Knudsen GA, Birnbaum LS (OD), Pedersen LC (DIR). 2013. Mimicking of estradiol binding by flame retardants and their metabolites: a crystallographic analysis. Environ Health Perspect. 121(10):1194-9. [Abstract]
Scientists examined the effect of flame retardants, previously shown to cause endocrine disruption, on the structure of estradiol, a sex hormone. (a)
Deroo LA, SC Bolick, Z Xu, DM Umbach, D Shore, CR Weinberg, DP Sandler and JA Taylor. 2013. Global DNA methylation and one-carbon metabolism gene polymorphisms and the risk of breast cancer in the Sister Study. Carcinogenesis 35(2):333-338. [Abstract]
This population-based study found decreased global DNA methylation, an epigenetic regulator of biology, suggested an increased risk of developing breast cancer. (c)
Other Implementation Activities
Toxicology in the 21st Century (Tox21)
The goal of this program is to research, develop, validate, and translate innovative test methods that will better predict how chemicals may affect humans and the environment. Tox21 researchers hope to use these methods to prioritize substances for further in-depth toxicological evaluation; Identify mechanisms of action for further investigation (e.g., disease-associated pathways); and Develop models that better predict how chemicals will affect biological responses (predictive toxicology)
14th Report on Carcinogens
The 14th edition of the Report on Carcinogens was released November 3, 2016 and includes seven newly reviewed substances bringing the cumulative total to 248 listings. The chemical trichloroethylene (TCE), and the metallic element cobalt and cobalt compounds that release cobalt ions in vivo, are being added to the list, as well as five viruses that have been linked to cancer in humans. The five viruses include human immunodeficiency virus type 1, human T-cell lymphotropic virus type 1, Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus, and Merkel-cell polyomavirus. 14th Report on Carcinogens (RoC)
Transform Tox Testing Challenge
Innovative thinkers are sought for a new federal challenge that will help advance the field of predictive toxicology. The Transform Tox Testing Challenge: Innovating for Metabolism, issued on Jan. 8, will provide up to $1 million in total prizes for modifications to existing high throughput screening (HTS) designs and prototypes that allow both chemicals and their metabolite products to be evaluated.
The National Toxicology Program (NTP) has joined with the National Center for Advancing Translational Sciences, also part of the National Institutes of Health, and the U.S. Environmental Protection Agency (EPA) to issue this new challenge. The goal is to improve the relevance and accuracy of toxicity data generated by automated chemical screening technology.
- Natural History of Asthma with Longitudinal Environmental Sampling (NHALES) study will examine how bacteria living in and on humans and in their homes, known collectively as the microbiome, may be associated with asthma activity. The NHALES Study.
NIH Roadmap Epigenomics Program Integrative Analysis of 111 Reference Human Epigenomes
This effort, which is co-led by NIEHS, has now mapped more than 100 types of human cells and tissues. The resulting comprehensive catalog of epigenomic data provides a first-of-its-kind resource that will help researchers make direct comparisons across cell types and tissues. The researchers expect that the data, which is freely available, will be of broad use to scientists for studies of gene regulation, cellular differentiation, genome evolution, genetic variation, and human disease. Integrative analysis of 111 reference human epigenomes..
13th Report on Carcinogens
On 2 October 2014, U.S. Department of Health and Human Services Secretary Sylvia M. Burwell released this report prepared by the NTP, which is headquartered at NIEHS. Ortho-toluidine, used to make rubber chemicals, pesticides, and dyes, has been reevaluated and is now listed as a known human carcinogen. Three substances have been added as reasonably anticipated to be human carcinogens. These include 1-bromopropane, used as a cleaning solvent and spray adhesive; cumene, used to make phenol and acetone, and also found in fuel products and tobacco smoke; and the wood preservative mixture pentachlorophenol. 13th Report on Carcinogens (RoC)..
Chemical Screening Data
On 17 December 2013, the U.S. Environmental Protection Agency (EPA) released new chemical screening information on 1,800 chemicals found in industrial and consumer products, food additives, and drugs. These data were gathered through the NTP-led, interagency Tox21 collaboration.
NTP Nonneoplastic Lesions Atlas
Nonneoplastic diseases are a major cause of morbidity and mortality in humans, and many of these are thought to have environmental causes. The NTP Nonneoplastic Lesion Atlas (NNLA) was launched online. This resource provides diagnostic guidelines for standardizing the terminology of microscopic nonneoplastic lesions in rats and mice to improve the understanding of nonneoplastic lesions and their relevance to human environmental diseases. The NNLA is intended as a dynamic document that will be updated periodically to reflect evolving scientific consensus. NTP Nonneoplastic Lesions Atlas..
Comparative Toxicogenomics Database
Funded in part by NIEHS, scientists at the pharmaceutical corporation Pfizer Inc. and academic researchers affiliated with the Comparative Toxicogenomics Database (CTD) have integrated information about the toxicity of more than 1,200 pharmaceuticals into this publicly available research resource. The database provides chemical-gene-disease information and associated functional and pathway data to connects mechanisms of chemical action to potential impacts on human health. The Pfizer collaboration specifically added data for chemicals that may be involved in cardiovascular, neurological, kidney, and liver disorders. Molecular toxicologist Carolyn Mattingly, Ph.D., associate professor at North Carolina State University is lead researcher on the study and has been directing the development of the CTD with NIEHS support since 2001. According to Mattingly, this is the only database out there that connects mechanisms of chemical action to potential impacts on human health. Comparative Toxicogenomics Database..
The Pregnancy and Childhood Epigenetics (PACE) Consortium
The Pregnancy And Childhood Epigenetics (PACE) consortium is comprised of researchers from around the world who are interested in studying the environmental impacts on human disease using epigenetics. Epigenetics refers to modifications to DNA that do not alter the DNA sequence. PACE grew out of a 2013 meeting organized by NIEHS Epidemiology Branch Senior Investigator and PACE researcher, Stephanie London, M.D., Dr.P.H. The gathering brought together scientists from 12 newborn or child cohorts with Illumina 450K genome wide methylation data. PACE now has more than twice as many cohorts and is investigating methylation in offspring in relation to various in utero exposures, as well as child health outcomes. Pregnancy and Childhood Epigenetics (PACE)