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Research Highlights, Activities, and Publications

Vol. 13, Issue 1: Apr-July 2015

NCTR Center Director Presented with 2015 Josef Warkany Lecture Award

William Slikker, Jr., Ph.D., NCTR Director, was presented with the 2015 Josef Warkany Lecture Award at the 55th Annual Meeting of The Teratology Society. The award recognizes a scientist who has significantly contributed to the field of teratology over their career. Dr. Slikker’s multiple contributions include his work on placental transfer of compounds, fetal metabolism of compounds and the fate of those metabolites, and the long-term effects of perinatal exposures.

For additional information visit Birth Defects Research Connection, The Teratology Society.

NCTR/UAMS Systems Pharmacology and Toxicology Workshop

NCTR investigators presented regulatory science perspectives on genetic toxicology, neurotoxicology, nanotoxicology, and metabolomics as part of the NCTR/UAMS Systems Pharmacology and Toxicology (SPaT) Workshop held at NCTR on July 14 and 16, 2015. The SPaT program is designed to provide 2nd- and 3rd-year Ph.D. students with collaborative training opportunities at the University of Arkansas for Medical Sciences (UAMS) Colleges of Medicine, Pharmacy and Public Health; Arkansas Children’s Hospital; the Arkansas Department of Health; and NCTR. The goal is to prepare students for leadership roles as researchers in the pharmacological sciences in academia, industry, and government. The workshop continued at NCTR on July 21 and 23, 2015.

Potential of MRI to Follow the Development of Neurotoxicity

NCTR and CDER scientists demonstrated correlation between quantitative T2 mapping, a parameter of the magnetic resonance imaging (MRI) experiment, and the standard pathology procedures used to evaluate neurotoxicity. Results of MRI and pathology were evaluated at time 0 (untreated) and at 2, 24, and 48 hours. following treatment with kainic acid. No T2 changes or changes in pathology morphology were detected at 2 hours; however, statistically significant changes were detected by MRI at 24 and 48 hours in agreement with pathology. The T2 mapping technique is both quantitative and easily completed, showing its strength as a potential source for evaluation as a non-invasive biomarker of effect. Furthermore, each MRI subject can serve as its own control and be monitored through time, which helps account for individual variability in response encountered even within surrogate inbred animal models of disease and toxicity. A manuscript describing this study is availableonline atToxicological Sciences.

For additional information, please contact Serguei Liachenko, Ph.D., Division of Neurotoxicology, FDA/NCTR, or Joseph Hanig, Ph.D., FDA/CDER

Confirmation of Mutations Detected by Pig-a Assay

NCTR scientists have established a direct connection between the GPI-anchored surface marker deficiency detected by thePig-a assay and mutations in the Pig-a gene in rat t-cells. Rats were treated with a model mutagen, N-ethyl-N-nitrosourea (ENU), which induced lymphocytes with altered cell surface markers (i.e., mutant phenotype). Molecular analysis of these cells revealed mutations in the endogenous X-linked Pig-a gene.

The spectrum of the Pig-amutation was consistent with the types of mutations produced by ENU in other in vivo models. The Pig-a assay, developed through a collaboration between NCTR, the pharmaceutical industry, and contract research organizations, is a novel flow cytometry-based assay for identifying potential mutagens in vivo and may have utility in more comprehensive toxicity assessments of FDA-regulated products. A manuscript describing the results of this study is now available online atMutagenesis.

For additional information, please contact Vasily Dobrovolsky, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.

Effects of Orally Administered BPA on Gene Expression in Prostate and Female Mammary Glands of Rats

NCTR scientists reported that no apparent dose-related gene expression or epigenetic effects were detected in prostates or female mammary glands from rat pups that were daily administered bisphenol A (BPA) across a wide range of doses below the no-adverse-effect level currently used by the FDA. However, a BPA dose of 500,000 times the mean human-exposure level induced gene-expression changes that overlapped partially with those induced by ethinyl estradiol (reference estrogen control), suggesting that BPA has some estrogenic potential at this high dose. These results are consistent with previously reported toxicology endpoints from the same study. This study was conducted at NCTR under the auspices and funding of the Interagency Agreement between FDA/NCTR and NIEHS/NTP. A manuscript describing this study is available online atFood and Chemical Toxicology.

For additional information, please contact Luisa Camacho, Ph.D., or Barry Delclos, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.

Spectral-Data Activity Relationship (SDAR)

NCTR researchers from the Division of Systems Biology are building computational tools for medicinal chemists to use in all aspects of new drug discovery.

SDAR modeling offers fast screening of potential investigational new drugs, which can save millions of dollars and years of developmental time.

SDAR gives a rational basis for selecting a new compound among many candidates, because the models indicate increased efficacy and/or decreased toxicity for that particular candidate. For orphan diseases or markets it can make practical, the development of new drugs or the repurposing of old ones.

A manuscript about SDAR has been published inBioorganic and Medicinal Chemistry.

Biomarkers of Acetaminophen-Induced Acute Liver Injury

Scientists from NCTR, University of Arkansas for Medical Sciences, and Arkansas Children’s Hospital recently published a review which focused on new biomarkers of acetaminophen (APAP) overdose and liver injury. The review summarizes a systems biology process for biomarker identification, analytical validation of biomarkers, and translation of biomarkers to the clinical setting. The potential utility of APAP-protein adducts and microRNAs in plasma for detecting APAP overdose and guiding treatment are also discussed. The review is availableonline at Archives of Toxicology.

For additional information, please contact Richard Beger, Ph.D., Director, Biomarkers and Alternative Models Branch, Division of Systems Biology, FDA/NCTR.

Isolation and Characterization of Nanomaterials in Dietary Supplements

Nanotechnology Core Facility scientists from NCTR and the Office of Regulatory Affairs (ORA) developed methods to separate and characterize silicon dioxide and titanium dioxide nanoparticles commonly added to dietary supplements. Twelve commercially available dietary supplement products were subjected to an acid digestion and centrifugation method to isolate nanoparticles from the product. The resulting nanomaterials were characterized with a battery of standard techniques. These methods are expected to be adaptable to the isolation and characterization of these nanomaterials from multiple FDA-regulated products. This work was supported in part by FDA's Office of Women’s Health. A manuscript describing the study is availableonline at Journal of Agricultural and Food Chemistry .

For additional information, please contact Paul Howard, Director, Office of Scientific Coordination, FDA/NCTR or Sean Linder, FDA/ORA.

Survival of the Burkholderia Cepacia Complex in Antiseptics

Scientists from FDA's National Center for Toxicological Research and Center for Drug Evaluation and Research (CDER), and the University of Michigan have shown that the opportunistic bacterial pathogen, Burkholderia cepacia complex (BCC), can survive and remain viable in solutions of the antiseptics chlorhexidine gluconate and benzalkonium chloride. The survival of 36 BCC strains from clinical and environmental sources was monitored for 14 days in antiseptic solutions with concentrations of 1-500 µg/ ml. The minimum inhibitory concentrations of the antiseptics varied for different BCC strains. BCC has been recovered in recent outbreaks from various pharmaceutical products, including antiseptics and disinfectants. This study provides data on the susceptibility, survival, and detection of BCC in pharmaceutical products containing antiseptics and the importance of proper antiseptic concentrations in pharmaceutical products. This study is availableonline at Journal of Industrial Microbiology & Biotechnology.

For additional information, please contact Carl Cerniglia, Ph.D., Director, Division of Microbiology, FDA/NCTR.

Theme: Regulatory Bioinformatics

Location: Parma, Italy

Date: October 12-13, 2015

For information visit:www.fda.gov/GlobalSummit2015

Female student working with a microscope

8th-Grade Female Science Students Visit NCTR

Eleven eighth-grade female students, part of a University of Arkansas "Biomedical Research" Girls Camp, visited NCTR on June 15. The goals of the camp are to 1) increase interest in science, 2) offer education as an opportunity to improve the quality of life, 3) increase college enrollment, and 4) continue to build relationships with junior high/high school communities across Arkansas.

During the visit the girls toured the zebrafish facility, visited a microbiology lab, and learned about electron microscopes that help with nanotechnology research.