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April-June 2012 Research Highlights
APRIL 2012 RESEARCH HIGHLIGHTS
Role of MicroRNAs in Drug Metabolism
NCTR scientists have published a review on the role of recently discovered microRNAs (miRNAs) in the regulation of drug-metabolizing genes and the cellular responses to environmental-toxicant exposures. miRNAs are short non-coding ribonucleic acid (RNA) molecules that regulate gene expression and may play a role in the proper functioning of the cellular drug-metabolizing system. Exposure to environmental toxicants and therapeutic drugs can alter levels of miRNA expression and may be an underlying mechanism in the development of exposure-related pathologies. Thus, levels of miRNAs in biological fluids may be potential noninvasive biomarkers of exposure/toxicity, and may be important determinants for inter-individual differences in sensitivity to toxicants and can serve as critical biomarkers for identifying sensitive subpopulations.
For additional information, see Expert Opinion on Drug Metabolism & Toxicology (doi:10.1517/17425255.2012.673587) or contact Igor Pogribny, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
Research and Regulatory Aspects of Food Safety at the FDA's Jefferson Laboratories
NCTR staff, along with colleagues from the ORA’s Arkansas Regional Laboratory, hosted nearly 30 scientists from Arkansas-based academic and public health institutions to learn more about the regulatory and research activities associated with food safety being done at FDA’s Jefferson Laboratories. Presentations were provided on NCTR’s research activities and accomplishments related to the safety of foods, ORA’s regulatory roles in food safety, and an overview of the Memorandum of Understanding on Regulatory Science signed between FDA and the State of Arkansas. A poster session and open-discussion forum were held to identify areas related to food safety that could be strengthened through further leveraging and collaboration. The meeting concluded with tours of the Jefferson Laboratory campus.
For additional information, please contact Steven Foley, Ph.D., Division of Microbiology, FDA/NCTR.
Serum Metabolite Biomarkers of Acute Kidney Injury
NCTR scientists, in collaboration with the University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, have used rapid LC/MS-based metabolic profiling to detect sensitive biomarkers of acute kidney injury (AKI). Significant differences in the levels of serum metabolites (substances found in bodily fluid that are produced during metabolism), such as increased serum homocysteine, asymmetric dimethylarginine, pyroglutamate, and acylcarnitine levels, were detected in a small group of hospitalized patients with newly diagnosed AKI, as compared to healthy volunteers. This study demonstrates that metabolomics is a powerful tool in the identification of biomarkers for AKI, and can provide potentially useful clinical information for the diagnosis of AKI. A manuscript describing this study as been published in Journal of Chromatography B (2012, 893-894: 107-113).
For additional information, please contact Richard Beger, Ph.D., Division of Systems Biology, FDA/NCTR.
Stem Cell and Regenerative Medicine Conference—April 17-18
Scientists from NCTR and Arkansas universities participated in the 1st Arkansas Stem Cell and Regenerative Medicine Conference on April 17-18, 2012, to discuss topics related to stem cell research and to provide a venue for networking and developing statewide collaborations. Presentation topics included:
- Stem Cell Biology and Cell-Based Therapy
- Biomaterials, Tissue Engineering, and Regenerative Medicine
- Stem Cell Toxicology, Regulatory Challenges, and Emerging Technologies
For additional information, please contact Deborah Hansen, Ph.D., Division of Personalized Nutrition and Medicine, FDA/NCTR.
Characterization of UGT1A1 Polymorphisms in Breast Cancer
NCTR scientists have shown that specific UGT1A1 (TA) repeat promoter polymorphisms correlate to downregulation of UGT1A1 mRNA expression in breast cancer compared to normal breast tissues. UDP-glucuronosyltransferase (UGT) enzymes maintain the steady state concentration of estrogens and other sex hormones in breast tissues. Since exposure to increased concentrations of estrogens over a prolonged period of time is a major risk factor for breast cancer, alterations in estrogen metabolism via this pathway may result in accumulation of genotoxic estrogen metabolites and increased risk of cancer development. These studies further indicate that UGT1A1 expression changes are associated with ethnicity, menopausal status, and stage of disease; and determining the impact of UGT1A1 promoter polymorphisms on clinicopathological factors is crucial for determining breast cancer risk, treatment response, and patient outcomes. A manuscript detailing this study has recently been accepted for publication in Drug Metabolism & Toxicology (doi: 10.4172/2157-7609.S4-001).
For additional information, please contact Beverly Lyn-Cook, Ph.D., Office of the Director, FDA/NCTR.
MAY 2012 RESEARCH HIGHLIGHTS
Cardiovascular Effects of Bitter Orange Extracts
NCTR scientists, in collaboration with scientists from FDA's Center for Food Safety and Applied Nutrition (CFSAN), have shown that bitter orange extracts (Citrus aurantium) and purified synephrine (active ingredient of bitter orange) alone can increase heart rate and blood pressure in rats during a 28-day study. These effects are more pronounced when the source of synephrine is a multi-component product (bitter orange extract) or when caffeine is added (as is the case with many weight-loss products). A manuscript describing this study was recently accepted for publication in Toxicology and Applied Pharmacology (http://www.sciencedirect.com/science/article/pii/S0041008X12001342). Bitter orange was nominated by CFSAN and the study was conducted at NCTR under an Interagency Agreement with the National Toxicology Program (NTP).
For additional information, please contact Deborah Hansen, Ph.D., Division of Personalized Nutrition and Medicine, FDA/NCTR.
ILSI-HESI Workshop on Genetic Toxicology—April 24-25
NCTR scientists presented talks at the International Life Sciences Institute-Health Environmental Sciences Institute (ILSI-HESI) Workshop “Genetic Toxicology: Opportunities to Integrate New Approaches” held April 24-25, 2012. The NCTR presentations were on 1) Epigenetics and Biomarkers and 2) The Potential for Minimally Invasive Imaging Techniques in Animal Studies.
For additional information, please contact Igor Pogribny, Ph.D., Division of Biochemical Toxicology, FDA/NCTR, or William Slikker, Ph.D., NCTR Director, FDA/NCTR.
In Vitro Genetic Toxicity Testing Project Committee—April 26-27
An NCTR scientist led a discussion on the Pig-a in vivo gene mutation assay at the ILSI-HESI “Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing” held April 26-27, 2012. The discussion focused on the remaining issues in developing an OECD (Organization for Economic Cooperation and Development) Test Guideline for the assay, which is being considered as a potential regulatory safety test by several international organizations, including ILSI-HESI.
For additional information, please contact Robert Heflich, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.
Regulatory Science Research Studies Reviewed—May 8-9
The 39th meeting of the Toxicology Study Selection and Review Committee (TSSRC) was held on May 8-9, 2012, at NCTR, to discuss ongoing studies and newly proposed study designs that are part of the interagency agreement between the 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)
- Cellular Telephone Radiation
The TSSRC was comprised of regulatory scientists and subject-matter experts from the FDA 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 at the FDA White Oak Campus on November 14-15, 2012.
For additional information, please contact Paul C. Howard, Ph.D., FDA Liaison to the NTP.
Animal Models of Pregnancy in Medical Countermeasures—April 30-May 1
NCTR and CDER co-organized a public workshop, “Development of Animal Models of Pregnancy to Address Medical Countermeasures in the “At Risk” Population of Pregnant Women: Influenza as a Case Study,” held at the FDA White Oak Campus on April 30-May 1, 2012. NCTR scientists presented talks on human to animal extrapolations of pharmacokinetic analyses, and the selection of appropriate animal models of pregnancy useful in evaluating medical countermeasures.
For additional information, please contact Suzanne Morris, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.
Safety Evaluation of Antimicrobial Residues in Foods
Scientists from NCTR, the Office of Regulatory Affairs (ORA), and the Center for Veterinary Medicine (CVM) have shown that enrofloxacin (a veterinary antimicrobial closely related to fluoroquinolones used to treat humans) at concentrations potentially ingested by consumers, is largely inactivated (50-60%) when added to human fecal slurries; however, the antimicrobial at this concentration did not affect the intestinal microbiota populations in the samples. This in vitro study addresses some concerns that administration of antibiotics to food-producing animals could result in antibiotic residues in edible tissue and meat products; and that prolonged exposure to these food-borne antimicrobials could perturb the intestinal microbial community and select for antimicrobial resistant strains of potential pathogens in the human intestinal tract. The study provides data on drug inactivation, bioavailability, drug metabolism, and general recommendations to improve safety evaluation of the impact of antimicrobial residues on the gastrointestinal microflora. The results of this study have been published in Regulatory Toxicology and Pharmacology (2012, 62: 74-84).
For additional information, please contact Carl E. Cerniglia, Ph.D., Director, Division of Neurotoxicology, FDA/NCTR.
2012 Global Summit on Regulatory Science—May 9-11
NCTR, FDA Office of International Programs (OIP), Zhejiang University, and the Chinese Academy of Engineering co-sponsored the 2012 Global Summit on Regulatory Science (GSRS-2012) held May 9-11, 2012, in Hangzhou, China. The conference provided a forum for government, industry, and academic scientists from ten countries to discuss innovative technologies and partnerships to enhance translation of basic science into regulatory applications within the global context.
For additional information, please contact William Slikker, Ph.D., Center Director, FDA/NCTR.
Pediatric Anesthesia Research
NCTR presented results from several studies conducted in collaboration with CDER scientists on the neurotoxicity associated with exposure to general anesthesia in pediatric animal models. The first presentation titled “Developmental Effects of the Perinatal Usage of Anesthetics was given at PPTOX (Prenatal Programming and Toxicity) III: Environmental Stressors in the Developmental Origins of Disease: Evidence and Mechanisms, held in Paris, France, on May 14-16, 2012. The second presentation, “Preclinical Neurotoxicity Assessments of Pediatric Anesthetics: Translational Approaches Using a Nonhuman Primate Model”, was presented as part of the SMARTTOTS-sponsored Pediatric Anesthetics Neurotoxicity Panel at the International Anesthesia Research Society (IARS) Annual Meeting held in Boston, Massachusetts, on May 18-21, 2012.
For additional information, or a copy of the PowerPoint presentation, please contact Merle Paule, Ph.D., .
JUNE 2012 RESEARCH HIGHLIGHTS
In Vitro Toxicity Testing—May 22
The CBER- and CDRH-sponsored Regenerative Medicine Seminar Series: Innovative Approaches for In Vitro Toxicity Testing and Drug Screening hosted NCTR scientist, Amy Inselman, Ph.D., at the FDA White Oak Campus on May 22, 2012. Dr. Inselman's presentation and discussion focused on the development of the mouse embryonic stem cell test, which recently has been validated by the European Centre for the Validation of Alternative Methods (ECVAM), as a possible screen for developmental toxicity. The test evaluates the ability of chemicals to inhibit the differentiation of mouse embryonic stem cells to beating cardiomyocytes; modifications to be tested include examination of additional endpoints, additional cell lines, and differentiation to additional cell lineages.
For additional information, please contact Dr. Amy Inselman, Division of Systems Biology, FDA/NCTR.
Medical Countermeasures Symposium Awards—June 5-6
Jon Wilkes, Ph.D., and Dan Buzatu, Ph.D., received the Most Innovative and the Best Poster awards for their poster presentation on the RAPID-B™ technology at the Regulatory Science Symposium sponsored by the Medical Countermeasures Initiative (MCMi) held on June 5-6, 2012, at the FDA White Oak campus. RAPID-B is a specialized flow cytometric-based approach developed at NCTR for rapid bacteria detection on contact surfaces, food, and human sputum.
For additional information, please contact Drs Jon Wilkes or Dan Buzatu, Associate Co-Directors, Division of Systems Biology.
Systems Biology Approach to Predictive Biomarkers
Donna Mendrick, Ph.D., was an invited speaker at the Spring Symposium of the National Capital Area SOT Regional Chapter on “Systems Toxicology” held at the National Institutes of Health (NIH) campus in Bethesda, Maryland. The presentation focused on the use of omics technologies to identify new predictive biomarkers of potential adverse effects.
For additional information, please contact Dr. Donna Mendrick, Director, Division of Systems Biology.
Prediction System for the Rapid Identification of Salmonella Serotypes
NCTR scientists, in collaboration with FDA's Center for Food Safety and Applied Nutrition (CFSAN), Centers for Disease Control and Prevention (CDC), and Feng Chia University, developed a prediction model for the rapid identification of Salmonella serotypes based on pulsed-field gel electrophoresis (PFGE) fingerprints with an overall accuracy of 96%. The classification model was developed using random forest and support vector machine algorithms and was applied to a database of 45,923 PFGE patterns. These patterns were randomly selected from all submissions to CDC PulseNet from 2005 to 2010, which included the top 20 most frequent serotypes and 12 less frequent serotypes from various sources. This prediction tool provides a fast and accurate prediction of serotypes of Salmonella isolates from outbreaks before the conventional serotyping method is completed. The results of this study were recently published in the Journal of Clinical Microbiology (2012, 50:1524-1532).
For additional information, please contact James J. Chen, Ph.D., Director, Biostatistics Branch, Division of Bioinformatics and Biostatistics, FDA/NCTR.
ILSI-HESI Workshop on Genetic Toxicology Held April 24-25, 2012 (Update)
A summary of presentations at the International Life Sciences Institute-Health Environmental Sciences Institute (ILSI-HESI) Workshop “Genetic Toxicology: Opportunities to Integrate New Approaches” has been posted on the Internet at the following URL: http://www.hesiglobal.org/i4a/pages/index.cfm?pageid=3596. The workshop, which included several presentations by FDA scientists, considered current and future prospects for employing new in vitro and animal models, epigenetic biomarkers, high-throughput screening (Tox21), and imaging in genetic toxicology regulatory paradigms.
For additional information, please contact Mugimane Manjanatha, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.
American Society for Microbiology Meeting
NCTR scientists presented their research results during the 112th American Society for Microbiology Meeting held June 16–19, 2012 in San Francisco, CA. The topics of their presentations included:
- Diagnostic molecular virology
- Comparative genomics of foodborne bacterial pathogens
- Rapid and emerging diagnostic techniques
- Novel mechanisms of antimicrobial resistance and virulence in human clinical and foodborne microbial isolates
- Microbiome influences on human health
- The evolutionary genomics, proteomics, and metabolomics of microorganisms used in environmental biotechnology to degrade toxic chemicals
For additional information, please contact Carl E. Cerniglia, Ph.D., Director, Division of Microbiology, FDA/NCTR.
Toxicological Significance of Azo Dye Metabolism
NCTR scientists have published a review (Frontiers in Bioscience, 2012, E4, 568-586) that addresses the toxicological significance of azo dye metabolism by human intestinal microbiota. Azo dyes are frequently used in the food industry to enhance the color of manufactured foods and account for 60-70% of all dyes used in the food process; while Sudan dyes (non-ionic fat-soluble azo dyes) are illegally used food contaminants. This review provides information on the structure and sources of commonly used azo dyes, their metabolism and enzymatic reduction by the human intestinal microbiota, and the potential toxicity of azo dyes and their metabolites.
For additional information, please contact Huizhong Chen, Ph.D., Division of Microbiology, FDA/NCTR.
NCTR Scientist Co-Chairs International Metabolomics Meeting
Richard Beger, Ph.D., co-chaired the 8th Annual International Meeting of the Metabolomics Society held June 25-28, 2012, in Washington, D.C. The meeting featured workshops and parallel sessions on topics including:
- Biomarkers of human health
- Safety monitoring
- Systems biology
- New technologies
- Data analysis
Presentations by NCTR researchers included:
- Clinical biomarkers of acute kidney injury
- Preclinical biomarkers of hepatotoxicity
- Clinical biomarkers of acetaminophen-induced toxicity in pediatric patients
- An in vitro study on fructose in adipocytes
For additional information, please contact Dr. Richard Beger, Director, Biomarkers and Alternative Models Branch, Division of Systems Biology, FDA/NCTR.
NCTR Center Director Gives Plenary Lecture
William Slikker, Jr., Ph.D., presented the results of collaborative studies between NCTR and FDA's Center for Drug Evaluation and Research in a plenary lecture at the British Journal of Anesthesia Special Workshop on Anesthesia, Neurotoxicity, and Neuroplasticity held in Salzburg, Austria. The presentation focused on the use of behavioral studies, microPET imaging, and omics approaches in preclinical models for safety assessments of pediatric anesthetics.
For additional information, please contact Dr. William Slikker, Jr., Director, FDA/NCTR.