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NCTR Research Highlights July - September 2009


In vivo Translational Biomarker for Nerve-Cell Death

National Center for Toxicological Research (NCTR) Scientists have completed experiments that demonstrate Positron Emission Tomography (PET) imaging, in combination with the annexin V molecular tracer, provide a minimally invasive approach for monitoring neuronal-cell death with enough sensitivity to resolve different brain areas. Ketamine, a dissociative anesthetic widely used in pediatric medicine, was injected into rat pups during the brain-growth spurt on postnatal-dat 7. Annexin V, a compound used to label dying cells, was injected into rat pups on postnatal-day 35. Annexin V levels were much higher and remained longer in the animals exposed to ketamine suggesting that cell death from ketamine exposure continues much longer than previously thought. Concern over the use of ketamine anesthesia in pediatric medicine increased after animal experiments demonstrated increased neuronal-cell death when exposures occur during periods of rapid-brain development. Neuronal-cell death is accompanied by the exposure phosphatidylseine on the cell surface that is selectively labeled by the annexin V molecule. Experiments continue to evaluate the limits of sensitivity and validity of the method for clinical application. PET is commonly utilitzed in the clinic to trace biological processes related to disease and therapeutic efficacy. Results were presented at the 49th Annual Meeting of the Teratology Society, June 29-July1, 2009. 

For further information, contact Dr. William Slikker, Jr., Ph.D., Director, NCTR.

Debating DNA Microarray Results for Cancer Prognosis

National Center for Toxicological Research (NCTR) scientists have entered the debate. Their comparative reanalysis of well-known cancer-gene expression datasets by several popular approaches demonstrated that the reliability of prognosis-prediction models substantially depends on gene selection, predictive modeling, and validation methodologies. this result is not unexpected and is consistent with results of the MicroArray Quality Control (MAQC) consortium, which performed and analyzed very highly controlled DNA microarray experiments. The MAQC experiments were used to define best practices for quality control in the laboratory and to evaluate multiple-analysis approaches for determining a stable-gene signature over different array technologies and different laboratories. Clearly, the utilization of molecular signatures obtained from DNA microarray technologies as a predictor of cancer prognosis is still in its infancy, and results must be used with caution. More work is required before generalized conclusions for this technology can be established.

For further information, contact Dr. William Slikker, Jr., Ph.D., Director, NCTR.

Human Cancer Risk from Dietary Acrylamide

The results from National Center for Toxicological Research (NCTR) cancer bioassays for acrylamide and its mutagenic metabolite, glycidamide, were presented at the 32nd Annual Meeting of the United Kingdom Environmental Mutagen Society held July 12-15, 2009 in Leeds.

The results of the two-year drinking water studies with rats and mice, and the neonatal mouse assay, strongly supported the crucial role of glycidamide in directly mutagenizing (causing mutation of) DNA as the mechanism of action (MOA) for acrylamide's ability to cause tumors.

Further support for the conclusions of the tumor studies was obtained from the isolation and characterization of glycidamide-DNA and glycidamide-hemoglobin adducts in the same models.

Acrylamide is a contaminant in baked and fried starchy foods (e.g., french fries, potato chips, and bread) and is present in coffee, Postum (coffee substitute), olives, and certain breakfast cereals. Acrylamide causes cancer in laboratory animals, and the data from NCTR's recent research will help resolve the controversy regarding its MOA, which is crucial for the evaluation of cancer risks in humans from dietary exposures. NCTR's fully peer-reviewed Good Laboratory Practices studies will be presented to NCTR's IAG partner, National Toxicology Program/National Institute of Environmental Health Sciences.

For more information, contact Dr. Fred Beland, Director, Division of Biochemical Toxicology, NCTR, or Dr. William Slikker, Jr., Director, NCTR.

NTP Board of Scientific Counselors Recommendations

The National Toxicology Program (NTP) Board of Scientific Counselors met on July 23-24, 2009 on the National Institute of Environmental Health Sciences (NIEHS) campus and recommended that NTP move forward with toxicological studies on:

  • alkylanilines
  • p-chlorobenzotrifluoride
  • deoxynivalenol (food contaminant)
  • dong quai (dietary supplement)
  • indium tin oxide
  • tris (4-chlorophenyl) methane and related compounds

The Board of Scientific Counselors accepted reports on the following compounds:

  • goldenseal root powder
  • androstenedione
  • beta-myrcene
  • tetralin
  • pentachlorobiphenyl
  • tetracloroaxobenzene

NTP's Interagency Agreements with National Center for Toxicological Research (NCTR) and National Institute for Occupational Safety and Health (NIOSH) were also reviewed. The NTP was organized in 1978 through the action of three agencies, which form the steering committee of the NTP:

  • NIEHS/National Institutes of Health (NIH)
  • NIOSH/Centers for Disease Control (CDC)
  • NCTR/Food and Drug Administration (FDA)

NCTR/FDA maintains permanent membership on NTP Committees, with Dr. Paul C. Howard serving on the NTP Board of Scientific Counselors.

Please contact Paul C. Howard for more information regarding the NTP, how to nominate chemicals/substances for toxicity testing by the NTP, or for access to NTP data.

NCTR Women's Health & Safety Day

Shiew-Mei Huang, Ph.D., Deputy Director, Office of Clinical Pharmacology/Office of Translational Sciences, Center for Drug Evaluation and Research, provided the keynote address on July 28, 2009 at the NCTR Women's Health and Safety Day Sponsored by NCTR's Office of Regulatory Activities. The address highlighted FDA's knowledge gaps and research needs in the area of drug-drug interactions and drug transporters. Seminars on Office of Women's Health (OWH) program initiatives were presented by Ameeta Parekh, Ph.D. and Beverly Galluresi, RN, MPH. Beth Calvey, Ph.D., OWH Liaison, Center for Food Safety and Nutrition (CFSAN) presented the CFSAN research areas impacting women's health. The program improved NCTR's understanding of the research needs of FDA and OWH.

For more information, contact Dr. Margaret Miller, Associate Director for Regulatory Activities, NCTR. 


National Center for Toxicological Research (NCTR) Science Advisory Board (SAB) Subcommittee Review

As part of NCTR's efforts to ensure the quality and relevance of its research programs, the Center hosted a Subcommittee Review of the Division of Genetic and Reproductive Toxicology on July 29 and 30, 2009. The subcommittee consisted of three members of the NCTR SAB and three expert consultant scientists. Representatives from all product centers and the Office of Women's Health also participated in the meeting. The Division presented recent accomplishments, ongoing research, and the strategy for future research, which includes:

  • research on current regulatory assays
  • development of new approaches for assessing genetic toxicity
  • investigations of chemical-specific genetic toxicity
  • research to support improvement of risk assessment

The subcommittee will prepare a report of the site visit, which will be presented at the NCTR SAB meeting on November 17-18, 2009.

Science Advisory Board Review

A subcommittee of the National Center for Toxicological Research (NCTR) Science Advisory Board (SAB) conducted an in-depth program review of the newly formed Division of Personalized Nutrition and Medicine on August 11 and 12, 2009, at the White Oak Conference Center. The subcommittee consisted of two members of the NCTR SAB and four expert consultant scientists. Twenty Food and Drug Administration scientists representing all the product centers, Office of Regulatory Affairs, and Office of Women's Health also participated in the meeting. The division presented ongoing research in the areas of biostatistics, biology, and genomics for personalization, and the strategy for future research. The subcommittee will prepare a report of the program review, which will be presented to the full NCTR SAB on November 17-18, 2009, in Jefferson, Arkansas.

International Drug Abuse Research Society Meeting

National Center for Toxicological Research scientists presented original research papers on the following topics at the International Drug Abuse Research Society in Seoul, Korea.

  • Effects of aging on the blood-brain barrier
  • Changes in gene expression and cognitive function after developmental exposure to the pediatric anesthetic agent, ketamine
  • EEG (electroencephalographic) and gene expression changes associated with exposure to the date-rape drug, GHB (gamma hydroxy butyrate)

The theme of this year’s meeting, attended by scientists from 14 countries, was "Recent Frontiers and Advances in Drug Addiction." The International Drug Abuse Research Society is a new organization that seeks to bring together scientists from all over the world to discuss mechanisms of drug action and, in particular, those that relate to cellular mechanisms of action, biomarker and methods development, and safety assessment.


Food Safety—From Farm to Fork

National Center for Toxicological Research (NCTR) scientists have published a review describing molecular typing methods used to fingerprint bacteria and discriminate within individual species. These methods can be used to track the source of Salmonella contamination in the preharvest, poultry-production environment. They can also delineate bacterial movement and horizontal-transmission pathways during the growth-production cycle. These methods and strategies enable Food and Drug Administration epidemiological investigators to identify the sources of bacterial contamination in the farm-to-fork continuum and suggest intervention strategies. [Journal of Animal Sciences (2009) 9:430-440]

For further information, please contact Dr. Rajesh Nayak or Dr. Carl E. Cerniglia, NCTR.

Personalized Medicine—DNA Methylation Levels

National Center for Toxicological Research (NCTR) scientists have completed an invited manuscript reviewing the evidence suggesting the involvement of DNA hypomethylation in the development of several major human diseases, including atherosclerosis, Alzheimer's disease, psychiatric disorders, and cancer. DNA hypomethylation signifies one of the major DNA methylation states that refer to a relative decrease from the "normal" levels.

Hypomethylation, as well as hypermethylation, can have an impact on the predisposition to pathological states and disease development. Methylation states of DNA, "increased," "normal," and "decreased," produce heritable changes in gene expression that are not due to any alteration in DNA sequence itself, a phenomenon described as "epigenetics." One remarkable feature of epigenetic abnormalities, including DNA hyomethylation, is their potential reversibility. Timely correction and proper maintenance of DNA methylation levels is a promising avenue to prevent the development of chronic disease. 

For further information or preprint requests, please contact Dr. Igor Pogribny, NCTR.

Postmarket Review—Nevirapine

Nevirapine is an effective drug for prevention of mother-to-child transmission of HIV-1 virus. Reports of severe nevirapine-induced hepatotoxicity and serious adverse cutaneous effects have raised concern about its use. Scientists from National Center for Toxicological Research (NCTR) and Lisboa, Portugal, have demonstrated that metabolites of nevirapine bind chemically with amino acids suggesting that nevirapine modification of proteins could be a factor in nevirapine toxicity. Additional work may lead to safer drug design and/or safer regimens of drug administration to reduce toxic effects.

NCTR/ORA Core Facilities Infrastructure

Consultants from the KlingStubbins engineering firm met with NCTR scientists and engineers the week of September 14, 2009 as a first step in developing the facilities infrastructure required to support development of joint-use core facilities by NCTR and the Office of Regulatory Affairs for bio-imaging, nano-sized characterization, and cell-sorting laboratories.

For further information or preprint requests, please contact Dr. William Slikker, Jr., Ph.D., Director, NCTR.

Women's Health—New Procedures to Advance SLE Research

The onsite pathology contractor for the National Center for Toxicological Research (NCTR), Toxicologic Pathology Associates, announced this week the development of several procedures for identifying cytokines (IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-alpha, and IFN-gamma) which are secreted by cells in the immune system. The new capabilities were developed to support the Office of Women's Health-funded NCTR study titled, "Sex Differences in Systemic Lupus Erythematosus (SLE) and Individual Response to Prasterone Therapy." The new cytokine testing capability can be utilized by all FDA investigators.

SLE is a complex, debilitating, and potentially fatal autoimmune disease affecting approximately 1.4 - 2.0 million Americans. Hormones and cytokines have been demonstrated to play critical roles in the development and progression of the disease.

For more information, contact Dr. William Slikker, Ph.D., Director, NCTR.

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