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October-December 2011 Research Highlights
Titanium Dioxide Exposure Induces Proteomic Alterations in Lymph Nodes
NCTR scientists have identified 33 proteins with significantly altered expression in the lymph nodes of mice, 24 hours after injection with titanium dioxide (TiO2) nanoparticles. Previous studies have shown that TiO2 levels were significantly increased in tissues, such as lymph nodes after injection. The identified proteins were mainly associated with:
- immune response
- lipid and fatty acid metabolism
- mRNA processing
- nucleosome assembly
Network analysis showed the main regulators of protein expression could be estrogen receptor, PPARg and c-Myc signaling. The differentially expressed proteins identified in this study could represent early response proteins to TiO2 nanoparticle exposure. TiO2 nanoparticles are increasingly being used in pharmaceutical and cosmetic products. The results of this study were recently accepted for publication in the Journal of Proteomics (DOI: 10.1016/j.jprot.2011.08.009).
For additional information, please contact Li-Rong Yu, Ph.D., Director, Center for Proteomics, NCTR/FDA.
Mechanism for Combinatorial Therapy in Pancreatic Cancer Treatment
NCTR scientists have shown that the dietary agent indole-3-carbinol (I3C) in combination with the anti-pancreatic cancer drug, gemcitabine, enhances cell death through up-regulation of human equilibrative nucleoside transporter 1 (hENT1) in pancreatic cancer-cell lines, but not in normal pancreatic-cell lines. hENT1 is the most abundant and widely distributed plasma membrane transporter by which gemcitabine enters cells. These results suggest that variations in hENT1 expression may partially account for interindividual differences in the clinical effect of gemcitabine and that up-regulation of hENT1 expression may be a promising strategy to improve the effectiveness of gemcitabine. This study was recently published in Anticancer Research (2011, 30: 3171-3180).
For additional information, please contact Beverly Lyn-Cook, Ph.D., Office of the Director, FDA/NCTR.
Metabolic Network for Bioremediation Applications
NCTR scientists and collaborators from Stony Brook University, the National Cancer Institute, and Dankook University have developed a metabolic network from Mycobacterium vanbaalenii PYR-1 to provide insight into the mechanism of bacterial degradation and detoxification of polycyclic aromatic hydrocarbons (PAHs). The network integrated genomics, proteomics, molecular, ecological, and metabolism data for application in bioremediation efforts in PAH-contaminated environments. PAHs are toxic components of crude oil, which bioaccumulate in the environment and include the food chain. Reducing environmental levels of PAHs by microbial degradation could be an important step in minimizing the potential for PAH contamination of seafood after an event such as the Deepwater Horizon oil spill. This study was recently published in the Journal of Bacteriology (2011, 193: 4326-4337).
For additional information, please contact Carl E. Cerniglia, Ph.D., Director, Division of Microbiology, FDA/NCTR.
NCTR welcomed two speakers for seminars and discussions with the science staff during the week of October 17:
- James P. O’Callaghan, Ph.D., National Institute for Occupational Safety and Health/Centers for Disease Control and Prevention, gave a seminar on the roles of glial activation and inflammation in neurotoxicity.
- Jeffrey R. Morgan, Ph.D., Brown University, gave a seminar on self-assembled 3D microtissues and their potential utility in toxicity testing of compounds.
Environmental Mutagen Society Meeting—October 15-19
NCTR scientists presented their research results at the 42nd Annual Meeting of the Environmental Mutagen Society (EMS) held in Montreal, Canada. The topics of their presentations included:
- Cancer biomarker methodology developed at NCTR
- New method to detect mutations induced by drugs or environmental chemicals
The EMS promotes “critical scientific knowledge and research into the causes and consequences of damage to the genome and epigenome in order to inform and support national and international efforts to ensure a healthy, sustainable environment for future generations.”
Fluoroquinolone-Resistant Salmonella Schwarzengrund from Imported Foods
NCTR scientists have identified fluoroquinolone-resistant strains of Salmonella enterica serovar Schwarzengrund and characterized the antimicrobial-resistance determinants in isolates collected by the FDA Pacific Regional Laboratory from food imported to the USA. Salmonella Schwarzengrund is spreading internationally and is one of few serovars causing invasive salmonellosis. With limited numbers of antibiotics available for treatment, antibiotic resistance may increase the risk of invasive salmonellosis, which has a high hospitalization rate. A manuscript describing the results of this study was recently accepted for publication in the Journal of Antimicrobial Chemotherapy (DOI: 10.1093/jac/dkr414).
For additional information, please contact Ashraf Khan, Ph.D., Division of Microbiology, FDA/NCTR.
South Central Chapter of the Society of Toxicology—October 27-29
William Slikker, Jr., Ph.D., Director, NCTR, gave the keynote address, “The Promise of Regulatory Science,” at the Joint Regional Meeting of the South Central and Gulf Coast Chapters of the Society of Toxicology held October 27-29, 2011 in New Orleans, Louisiana. Additionally, NCTR scientists gave platform presentations on their research that included:
- circadian variations of neurometabolites
- anesthetic-induced neuronal damage
- effects of silver nanoparticles on micronucleus induction
- analysis of cigarette smoke condensates by Mouse Lymphoma Assay
- mechanistic studies of herbal dietary supplement toxicity
- development of biologically based dose-response models for the thyroid axis during human pregnancy
NCTR Science Advisory Board Meeting—November 8-9
The annual NCTR Science Advisory Board (SAB) meeting was held November 8-9, 2011. The FDA Science Board was represented by Lynn Goldman, Ph.D., Dean of The George Washington University School of Public Health and Health Services. The Board heard presentations on the current NCTR Strategic Plan and brief overviews from the six division directors, including a response by Merle Paule, Ph.D., to the SAB review of the Division of Neurotoxicology. Capt. Carmen Maher, Office of the Commissioner, presented an overview of the Medical Countermeasures Initiative and each of the Center representatives presented the priorities and research views of their respective FDA product centers and the Office of Regulatory Affairs. The report of the SAB Nanotechnology Core Facility Subcommittee site visit was presented and discussed. Following all presentations, the Board members discussed the future strategic direction for research at NCTR. The next meeting of the NCTR SAB will be held during the fall of 2012.
Regulatory Science Research Studies Reviewed—November 15-16
The 38th meeting of the Toxicology Study Selection and Review Committee (TSSRC) was held on November 15-16, 2011, at the FDA White Oak Campus, to discuss ongoing studies and newly proposed study designs that are part of the interagency agreement between FDA and the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) that support the FDA risk-assessment process.
Ongoing studies in the following areas were discussed:
- Food contaminants (Bisphenol A, Furan, Nanoscale Silver, Melamine, and Acrylamide/Glycidamide)
- Dietary supplements (Aloe vera and Glucosamine)
- Topically applied compounds (Oxybenzone and Retinyl Palmitate)
- Medical-device components (Nanoscale Silver)
- Antibacterial chemicals (Triclosan)
- Cell-phone Radiation
The TSSRC was comprised of regulatory scientists and subject-matter experts from the FDA Product Centers (CBER, CDER, CDRH, CFSAN, and CVM), the NIEHS/NTP, and the National Institutes of Health (NIH). The committee meets twice each year and is responsible for scientific oversight of study design and progress of ongoing work under this interagency agreement. The next meeting of the TSSRC will be held at NCTR, May 8-9, 2012.
For more information, contact Paul C. Howard, Ph.D., Associate Director, Office of Scientific Coordination, NCTR/FDA and FDA Liaison to the NTP.
Rapid, High-Sensitivity Detection of E. coli O157
NCTR scientists have developed a standard operating procedure (SOP) for the rapid determination of E. coli O157 in complex food matrices using flow cytometry, especially as incorporated in a combination instrumental and selective reagent system called RAPID-B™. In this study, the SOP was used to detect E. coli O157 in 25 grams of fresh spinach after a 4-hour growth period, and the results showed a time-to-results of less than 4.5 hours and a projected limit-of-detection of 1 viable cell per 25 grams with 94% accuracy. The SOP reduces interference from complex matrices by accelerating culture growth and reducing background counts through sample preparation and multi-dimensional gating techniques. E. coli O157 may be found in foods and can cause hemorrhagic diarrhea in individuals exposed to as few as ten viable cells. Although this study is selective for E. coli O157, the results should be generally applicable to any RAPID-B™ pathogen-specific flow cytometry assay. A manuscript describing this study has recently been accepted for publication in Food Microbiology (doi: 10.1016/j.fm.2011.11.002).
For additional information, please contact Jon Wilkes, Ph.D., or Dan Buzatu, Ph.D., Division of Systems Biology, FDA/NCTR.
Urinary MicroRNA Profiles as Biomarkers for Hepatotoxicity
NCTR scientists have shown that a single, high dose of acetaminophen (1250 mg/kg) or carbon tetrachloride (2000 mg/kg) administered orally to rats, increased the urinary levels of 44 and 28 miRNAs, respectively, and 10 of these miRNAs were common to both. Further analysis suggested that the liver was the source of the increased urinary miRNAs and gene-expression profiling identified eight putative miRNA target genes to be significantly altered in the liver of hepatotoxicant-treated animals. This study indicates that urinary miRNA profiling may be useful as both biomarkers of overall liver injury and for the classification of specific toxicants. A manuscript describing this study has recently been accepted for publication in Toxicological Sciences (doi:10.1093/toxsci/kfr321).
For additional information, please contact William Salminen, Ph.D., Division of Systems Biology, FDA/NCTR.
Joint FAO/WHO Expert Committee on Food Additives—November 7-17
Carl Cerniglia, Ph.D., Director, Division of Microbiology, served as a scientific expert at the 75th Joint FAO/WHO Expert Committee on Food Additives (JECFA) meeting held November 7-17, 2011, in Rome, Italy. The Expert Committee provided scientific advice in the evaluation of toxicological and microbiological data on residues of veterinary drugs in foods. Recommendations were made on acceptable daily intake and long-term dietary intake levels for consumption of residues in foods that does not represent a hazard for human health.
Pharmacoproteomics and Toxicoproteomics
Li-Rong Yu, Ph.D., guest edited and contributed an editorial for the Special Issue “Pharmacoproteomics and Toxicoproteomics” of the Journal of Proteomics. The editorial discusses the current research areas, challenges, and future trends of proteomics in pharmacology and toxicology in the identification of drug targets, elucidation of mechanisms of action, and development of biomarkers and assays for the assessment of drug efficacy and toxicity.
For additional information, please contact Dr. Li-Rong Yu, Division of Systems Biology, FDA/NCTR.
Scientific Panel on Contaminants in the Food Chain—November 29 - December 1
Daniel R. Doerge, Ph.D., was a panel member at the 49th Plenary Meeting of the Scientific Panel on Contaminants in the Food Chain (CONTAM) for the European Food Safety Authority held November 29 – December 1, 2011, in Parma, Italy. The Panel adopted Scientific Opinions on both tetrabromobisphenol A and T-2 and HT-2 mycotoxins in food and feed. Dr. Doerge also served as Chair of the Phomopsins Working Group and as an expert for the Ergot Alkaloids Working Group. CONTAM is an independent panel that conducts risk assessments and drafts scientific opinions to inform European policies and legislation concerning food safety.
Improved Culture Method for Human Intestinal Microbiota
NCTR scientists have developed an improved method for the in vitro culture of complex intestinal microbiota that more closely mimics the conditions of the human gastrointestinal tract than current methods. The study used pyrosequencing to analyze the microbial community and demonstrate the effectiveness of the enhanced-growth conditions to maintain the complexity of the intestinal microbiota throughout an 18-hour culture period. These culture conditions support a wide range of intestinal bacteria and can be applied in future research to determine the impact of antimicrobial agents, food contaminants, xenobiotics, probiotic, and dietary supplements on the human intestinal microbiota. The results of this study have recently been published in the Journal of Biomedicine and Biotechnology (doi: 10.1155/2011/838040).
For additional information, contact Carl E. Cerniglia, Ph.D., Division of Microbiology, FDA/NCTR.
NTP Board of Scientific Counselors—December 15
The National Toxicology Program (NTP) Board of Scientific Counselors (BSC) met December 15, 2011, at the National Institute of Environmental Health Sciences in Research Triangle Park, NC. The agenda included the review of:
- Conclusions of technical reports presented in April 2011 (Acrylamide, Aloe vera, AIDS therapeutics, and Senna)
- Toxicology study proposals ( phenolic benzotriazoles, UV stabilizers in some FDA products; sulfolane, oil industry solvent; trimethylsilyldiazomethane, methylating agent)
- Outline of a proposed workshop on “permanent hair dye chemicals”
- Report on a workshop on the “role of environmental chemicals in the development of diabetes and obesity”
- Proposed changes to the review process for the NTP Report on Carcinogens
The BSC is a federally chartered advisory committee that provides scientific advice to the NTP Director (Director of NIEHS) and evaluates the scientific merit of the NTP’s intramural and collaborative projects.
For additional information, please contact Paul Howard, Ph.D., Associate Director, Office of Scientific Coordination, NCTR/FDA, FDA Liaison to the NTP, and representative on the BSC.