January-March 2012 Research Highlights
JANUARY 2012 NCTR RESEARCH HIGHLIGHTS
Validation of the Pig-a Genotoxicity Assay
The results of an international validation trial of the in vivo Pig-a gene mutation assay has been published in a special issue of Environmental and Molecular Mutagenesis (2011; Vol. 52, Issue 9). The mutation assay, which is translatable across species including the human, was demonstrated to be transferrable between laboratories, to produce reproducible mutant frequencies, and to be easily integrated into standard 28-day repeat dose toxicology study designs. This in vivo test is especially relevant to assessing genotoxicity hazard in that it incorporates in vivo metabolism, pharmacokinetics and DNA-repair processes in generating the response. FDA scientists have been developing this assay for use in regulatory science as a rapid, sensitive in vivo assay to measure mutation in the blood cells of humans and laboratory animals.
For more information, contact Robert H. Heflich, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR, or Martha M. Moore, Ph.D., Director, Division of Genetic and Molecular Toxicology, FDA/NCTR.
Joint Center for Tobacco Products/NCTR Planning Meeting—January 10
NCTR scientists visited the Center for Tobacco Products (CTP) on January 10, 2012, to discuss the legislative mandate concerning tobacco product regulation. The participants reviewed the newly finalized SOP and current research plans and projects in the areas of addiction, biomarkers, inhalation studies, and toxicology related to tobacco products and outlined additional research priorities and strategies to address these priorities.
For additional information, please contact Bradley J. Schnackenberg, Ph.D., Office of Research, FDA/NCTR.
Drug-Induced Liver Injury Prediction System (DILIps)
NCTR scientists have developed a predictive in silico model for drug-induced liver injury (DILI) that has a high positive predictive value for drugs that cause severe DILI. The DILIps was developed by utilizing a consensus strategy (similar to current medical practice wherein multiple parameters are used for diagnosis) to combine individual QSAR models predictive of 13 types of hepatotoxicity. DILI is one of the most frequent causes of drug failure and is one of the most difficult clinical endpoints to predict from preclinical studies. The DILIps has potential as an evaluation tool to screen new drug candidates for potential liver toxicity; and the methodology could also be extended to address other drug safety issues, such as renal and cardiovascular toxicity. The development of this system is described in a recent publication in PLOS Computation Biology [7(12): e1002310].
For additional information, please contact Weida Tong, Ph.D, Division of Systems Biology, FDA/NCTR.
Genomic Biomarkers of Liver Toxicity
An NCTR scientist has published an invited review on the development and use of toxicogenomics in the identification of potential genomic biomarkers of drug-induced liver toxicity (DILI). The review discusses a number of crucial issues with genomic biomarkers in toxicology studies, including the type of biomarker, experimental design, experimental models, handling and analyzing of large data sets, and validation. The identification of genomic biomarkers for distinguishing susceptible patients and recategorizing drugs accordingly will be critical to achieve the goals of personalized medicine.
For additional information, see Personalized Medicine (2012, 9(1): 1-3) or contact Ching-Wei Chang, Ph.D, NCTR/FDA.
Detection of Multiple Antimicrobial Resistance Genes in a Single Assay
NCTR scientists have developed a transcriptomic array technique to simultaneously detect the presence of 131 antimicrobial resistance genes that confer resistance to 22 different antibiotics used either in human clinical or veterinary practice. This transcriptomic array method is more cost-effective and provides more information on mechanisms of antimicrobial resistance, gene expression, intrinsic resistance, and cross-resistance than current genomic DNA labeling and PCR detection methods. This technique has potential utility for surveillance of antimicrobial resistance dynamics and for preclinical testing of new drug candidates to identify gene expression patterns indicative of antimicrobial resistance. This study has been published in Agriculture, Food & Analytical Bacteriology (2011) 2:123-129.
For additional information, please contact Saeed A. Khan, Ph.D., Microbiologist, Division of Microbiology, FDA/NCTR.
Degradation of Cephalosporin Antibiotics by Bovine Intestinal Bacteria
NCTR scientists have shown that bovine intestinal bacteria rapidly degrade the cephalosporin antibiotic ceftiofur, thus reducing the antimicrobial drug residues excreted into the environment and minimizing the selective pressures for the development of antibiotic resistant bacteria. Ceftiofur is widely used to treat a variety of bacterial infections in cattle and may promote the spread of bacteria with cross resistance to the structurally similar ceftriaxone used in human therapy. The results of this study provide data on the fate of antimicrobial agents used in food animals, which will aid in the evaluation of approaches to preserve clinically important antimicrobial agents. This work was performed under a Cooperative Research and Development Agreement (CRADA) with Pfizer Animal Health Company. The results of this study have been published in Antimicrobial Agents and Chemotherapy (2010), 55: 4990-4998.
For additional information, please contact R. Doug Wagner, Ph.D., Microbiologist, Division of Microbiology, FDA/NCTR.
FEBRUARY 2012 NCTR RESEARCH HIGHLIGHTS
MicroRNA Biomarkers of Hepatotoxicity
An NCTR scientist gave a presentation titled “Using microRNA as Biomarkers of Drug-Induced Liver Injury” at the Critical Path Institute (C-Path) Predictive Safety Testing Consortium meeting held on January 31 at FDA’s White Oak facilities. The presentation provided an overview of miRNA’s potential use as biomarkers for DILI and recent research data using urinary miRNA levels to identify hepatoxicity in rats and humans exposed to acetaminophen.
For additional information, contact William Salminen, Ph.D., Division of Systems Biology, FDA/NCTR.
NTP Technical Report Peer Review Panel—February 8-9
The National Toxicology Program (NTP) convened a Technical Report Peer Review Panel on February 8-9, 2012 at the NIEHS campus. The panel reviewed NTP Technical Reports on studies in mice or rats on:
- N,N’-dimethyl-p-toluidine (dental materials and bone cements)
- ginko biloba (herbal supplement)
- beta-picoline (insecticides)
- pyrogallol (decomposition by-product of plant tannins)
- trimethylolpropane triacrylate (acrylic glues, adhesives, and selants)
- AZT (antiviral therapeutic alone and in combination with other antiviral compounds)
The latter studies on antiviral therapeutics were conducted at NCTR as part of an Interagency Agreement between NIEHS/NTP and FDA/NCTR and were presented by an NCTR investigator.
For additional information, contact Julian Leakey, Ph.D., or Paul Howard, Ph.D., Associate Director, Office of Scientific Coordination and FDA Liaison to NTP, FDA/NCTR.
Magnetic Resonance Spectroscopy (MRS) in Non-invasive Cancer Diagnostics
Richard Beger, Ph.D., was selected to provide a lecture at a symposium titled “Cancer Metabolomics: Elucidating the Biochemical Programs that Support Cancer Initiation and Progression” at the New York Academy of Sciences held on February 3, 2012. The presentation centered on application of preprocessing methods to Magnetic Resonance Spectroscopy (MRS) spectra of brain scans. The processed brain spectra could then be subject to computerized-pattern analysis to detect and classify eight different types of brain lesions from “normal” brain tissue with accuracies of >96%. MRS spectra are typically evaluated visually by pathologists and diagnosis determined by surgical intervention. These advances provide a significant advance in the use of the MRS as a diagnostic tool for the clinician and have the potential to reduce the use of invasive biopsy procedures.
For additional information, please contact Dr. Richard Beger, Division of Systems Biology, FDA/NCTR.
Pediatric Medical Countermeasures—February 15-16
NCTR scientists served as panelists at the Public Workshop on Ethical and Regulatory Challenges in the Development of Pediatric Medical Countermeasures held in Rockville, Maryland, on February 15-16, 2012. The FDA Medical Countermeasures Initiative workshop provided a forum for stakeholders (scientists, policymakers, and the public) to discuss the scientific, ethical, and regulatory issues involved in pediatric medical countermeasures and public health preparedness.
For additional information, please contact Donna Mendrick, Ph.D., Director, Division of Systems Biology, FDA/NCTR, or Suzanne Morris, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR
NCTR Strategic Planning—February 21-22
On February 21-22, 2012, NCTR senior staff met to discuss and develop NCTR’s Strategic Plan for 2012-2016. The discussion focused on refining the NCTR portfolio of research goals, objectives, and outcomes in support of the FDA mission.
MARCH 2011 NCTR RESEARCH HIGHLIGHTS
BPA U01 Consortium Meeting—March 1
A meeting of the Bisphenol A (BPA) U01 Consortium was held at NCTR on March 1, 2012, to discuss the development of a National Toxicology Program (NTP)-funded two-year chronic toxicology study of BPA in rats. The meeting was attended by representatives of NCTR, the Center for Food Safety and Applied Nutrition (CFSAN), the National Institute of Environmental Health Sciences (NIEHS)/NTP, and 12 NIEHS-funded academic grantees. The grantees will utilize siblings of animals used in the chronic two-year study and will evaluate molecular, structural, and functional endpoints that were selected on the basis of previous findings in animal and epidemiological studies involving BPA. This design will provide a blend of traditional toxicology endpoint assessments with novel endpoints not typically conducted in two-year chronic studies.
For additional information, please contact Barry Delclos, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
Genetic Variants in Pancreatic Cancer
NCTR scientists have demonstrated a potential genetic contribution to pancreatic cancer using an in vitro transfection analysis of two pancreatic-cancer cell lines. The current study demonstrates that DNA methyltransferase 3B (DNMT3B) promoters with allele -149T, exhibited increased activity in female pancreatic cell lines as opposed to cell lines of male origin. This is consistent with previous studies that suggest the -149T allele is associated with a higher risk for various cancers in women. These studies were recently published in Biochemical and Biophysical Research Communications (doi: 10.1016/j.bbrc.2011.07.115).
For additional information, please contact Beverly Lyn-Cook, Ph.D., Office of the Director, FDA/NCTR.
Alternative Models in Developmental Toxicology
Development and acceptance of accurate and more cost-effective screens to detect potential reproductive and developmental toxicants remains a barrier to rapid drug development. NCTR scientists have reviewed the current state of three of the most commonly used surrogate models that show the greatest potential for developmental toxicity screening and testing:
- whole embryo culture (WEC)
- mouse embryonic stem cell test (mEST)
The review addresses the advantages, disadvantages, and potential of these models for screening and for prioritization of chemicals as candidates for further drug development. Their analysis concludes that the most appropriate approach to in vitro developmental toxicity testing may be the utilization of test batteries (Systems Biology in Reproductive Medicine, 2012, 58:10-22).
For additional information, please contact Deborah Hansen, Ph.D., Division of Personalized Nutrition and Medicine, FDA/NCTR.
Roundtable Discussion on BPA Exposures
Scientists from NCTR, the Pacific Northwest Regional Laboratory, and the University of Edinburgh held a roundtable session at the Annual Society of Toxicology Meeting in San Francisco, California, on March 14, 2012, to discuss population exposures to bisphenol A (BPA) and the recent results of an NCTR 90-day rat toxicity study. From an epidemiological point of view, there are unanswered confounding factors concerning exposure to BPA. In this session, the pharmacokinetics of BPA in laboratory species and humans were compared, and human biomonitoring data from several studies were evaluated.
Pharmacokinetics of Melamine and Cyanuric Acid
NCTR scientists have shown that oral coadministration of melamine and cyanuric acid in rats did not significantly alter the pharmacokinetic profiles compared to individual administration of the compounds. However, administration of the compounds as a preformed melamine-cyanurate complex significantly altered the pharmacokinetics, with reduced bioavailability of both compounds. These results indicate that the mode of administration of melamine and cyanuric acid may have a profound effect on the nephrotoxic potential, and that experimental designs that allow the preformation of melamine cyanurate may underestimate the nephrotoxic potential of the mixture. This study was supported through an interagency agreement with the National Toxicology Program at the National Institute of Environmental Health Sciences. A manuscript detailing this study was recently published in Toxicological Sciences (2012, 126: 317-324).
For additional information, please contact Goncalo Gamboa da Costa, Ph.D. Division of Biochemical Toxicology, FDA/NCTR.
Novel Algorithm to Identify Susceptible Patient Subpopulations
NCTR scientists have developed a statistical model to identify subgroups susceptible to drug-induced toxicity for preclinical safety studies. The approach involves the identification of biomarkers of susceptibility and the development of a prediction model based on these biomarkers to identify a small number of susceptible patients. The importance of biomarker selection and large sample sizes to prediction accuracy are also addressed. Pharmacogenomics aims to identify interindividual variability in drug or treatment responses to guide personalized medicine and avoid adverse drug events. The results of this study are published in Pharmacogenomics (2012, 13: 147-157).
For additional information, please contact James Chen, Ph.D., Division of Personalized Nutrition and Medicine, FDA/NCTR.
Brain Awareness Week—March 17
NCTR scientists participated in Brain Awareness Day on March 17, 2012 Museum of Discovery in Little Rock, Arkansas. This annual event introduces school-age children and adults (over 1000 visitors) to neuroscience research through educational displays and hands-on activities. Brain Awareness Week is a global campaign sponsored by the Society for Neuroscience, along with universities and schools, hospitals, government agencies, museums, and professional associations, to increase public awareness of the progress and benefits of brain research.