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FDA/NCTR Research Highlighted in the Quarter Page 2

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Research Highlights, Activities, and Publications                                                   

Jan 2017-Mar 2017

Diverse group of people

Sex and Age Differences in miRNA Expression

NCTR scientists have shown that a set of 214 miRNAs exhibited differential expression in the liver of untreated rats based on age and/or sex. Of the 214 miRNAs, 212 showed age-related differences while 65 showed sex-related differences. In general, miRNA expression was largely stable between sexes and across the rat life span, with the notable exception of 38 miRNAs at 2 weeks of age, which is consistent with early developmental proliferation and differentiation. 
As rats mature from adults to old age, miRNAs involved in cell death, cell proliferation, and cell cycle were found to change expression. The results of this study will improve our understanding of epigenetic regulation of hepatic gene expression. Furthermore, these miRNA changes may be a factor in observing differences in age- and sex-dependent susceptibilities to toxicity. This study is available online at Biology of Sex Differences.  
For more information, please contact James Fuscoe, Ph.D., Director, Personalized Medicine Branch/Division of Systems Biology.

Evaluation of Antimicrobial Effects of Silver-Containing Food Contact Materials

Food contact materials
NCTR scientists demonstrated that silver-containing food contact materials (FCM) varied in the pattern of silver release into various food simulants and showed slight effects of delayed growth or no antibacterial activity on the foodborne pathogen, Salmonellatyphimurium under various food storage conditions that included pH and temperature. The study evaluated total silver content, release capacity, and antibacterial activity of various FCMs, including food-storage containers, food wrapping paper, and a plastic cutting board. The limited antibacterial activity of silver ions leached from FCM was not related to the silver-resistance genetic mechanism, since the tested food pathogen was not positive for such genes. 
This study suggests that silver-containing FCMs may not be effective at preventing the growth of common foodborne pathogens. The study is currently available online at Food and Chemical Toxicology
For more information, please contact Sangeeta Khare, Ph.D., Division of Microbiology.

Cadmium on periodic table

Cadmium Affects Gene Expression During Differentiation of Mouse Embryonic Stem Cells    

Scientists from FDA’s National Center for Toxicological Research and Center for Drug Evaluation and Research determined the gene-expression profiles of mouse embryonic stem cells (mESCs) during early differentiation under osteoblast culture conditions and demonstrated that exposure to cadmium sulfate inhibited mESC differentiation and disrupted gene expression profiles. Analysis of gene-expression microarrays demonstrated a down-regulation of pluripotency genes, while genes involved in bone and skeletal development were up-regulated over time. Treatment with cadmium, an embryotoxin known to affect multiple organ systems including bone and kidney, resulted in dysregulation of genes involved in skeletal development and renal and reproductive function. 
These results suggest that gene-expression analyses may provide sensitive indicators of early mESC differentiation and may improve the predictivity of the mouse embryonic stem cell test (mEST) by identifying potential modes of action for tested chemicals. A manuscript describing this study is available online at Reproductive Toxicology.  
For more information, please contact Amy Inselman, Ph.D., Biomarkers and Alternative Models Branch/Division of Systems Biology.

In Vitro to In VivoExtrapolation (IVIVE) for Drug-Induced Liver Injury (DILI)

Preclinical animal-toxicity studies may not accurately predict hepatotoxicity in humans. In light of this, in vitro systems have been developed that have the potential to supplement or even replace animal use. 
Scientists from NCTR, in collaboration with scientists from Hannover Medical School in Germany and University of Birmingham in UK, conducted an in vitro to in vivo extrapolation (IVIVE) using gene-expression data. The data was based on rats treated with 131 compounds for 28 days and two in vitro data sets (rat or human primary hepatocytes) treated with the same compounds for 24 hours. A high IVIVE potential was noted for rat primary hepatocytes, whereas the IVIVE potential for human primary hepatocytes was lower, indicating species difference playing a critical role in IVIVE. When limiting the analysis to only those drugs causing DILI, the IVIVE potential was improved for both rats and humans. 
The study concluded that rat or human gene-expression data generated in vitro could supplement the standard rodent in vivo study, particularly for severe hepatotoxic endpoints. This publication is now available online at ALTEX: Alternatives to Animal Experiments.
For more information, please contact Zhichao Liu, Ph.D., Division of Bioinformatics and Biostatistics or Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics.

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