Environmental Factor, May 2010, National Institute of Environmental Health Sciences
Metabolomics - A New Direction in Toxicology?
By Mamta Behl
As part of its High Throughput Screening (HTS) Initiative, the National Toxicology Program (NTP) welcomed guest lecturer Sury Vulimiri, D.V.M., Ph.D., to NIEHS April 9th to speak on the potential of integrating metabolomics into the emerging science of predictive toxicology.
A toxicologist working in the U.S. Environmental Protection Agency (EPA) Office of Research and Development at the National Center for Environmental Assessment in Washington, D.C., Vulimiri focuses on the application of modes of action (MOA) information of xenobiotics in dose-response analysis. He is exploring the use of metabolomics, an evolving complementary approach that utilizes the systematic study of unique biochemical fingerprints altered by exposure to environmental chemicals and xenobiotics. NTP Biomolecular Screening Branch Chief Ray Tice, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/bmsb), hosted the talk as part of his ongoing efforts to familiarize NTP scientists with new approaches for conducting hypothesis-driven and discovery toxicology studies.
Toxicity in the 21st century
Vulimiri opened the talk by emphasizing the increasing need for new approaches such as 'omics technologies in toxicity testing for the 21st century, specifically the potential role of metabolomics in the Tox21 program. Tox21 is a joint endeavor by the NTP, the NIH Chemical Genomics Center (NCGC)(http://www.ncgc.nih.gov/) , and EPA, to implement state-of-the-art HTS tools including biochemical methods and cell-based assays to develop better predictive models of human response to toxicants (see related story(http://www.niehs.nih.gov/news/newsletter/2008/october/ntpholdsmeeting.cfm)).
As Vulimiri explained, "Current methods in toxicity testing involve the use of a large number of animals and depend on the detection of pathological end-points. Hence, there is a need to develop alternate methods to use resources economically." He also pointed to the benefits of the 3R concept of replacement, reduction and refinement in decreasing the use of animals in toxicology studies, while simultaneously obtaining a range of valuable information on pathway activation of xenobiotics using human cell culture systems that are relevant to a target organ of interest. Vulimiri said the 'omics approach offers investigators increased ability for predicting early toxicity of xenobiotic compounds prior to the development of overt pathology and adverse outcomes.
Adding versatility to toxicology studies
According to Vulimiri, metabolomics is a medium- to high-throughput screening technique for measuring small molecular weight metabolites based on a combination of platforms, which can be used either as targeted or global approaches depending on the availability of a priori information on the test compound. He systematically compared and contrasted metabolomics with other omics technologies, such as transcriptomics, proteomics, and genomics, and explained the need for integration of these various technologies.
Vulimiri then enumerated the specific advantages and limitations of metabolomics and cautioned researchers about the importance of gender differences, a parameter often ignored when interpreting results of metabolic profiles. Citing several examples from the literature, Vulimiri explained how parameters such as dose-response and different MOAs of xenobiotics, crosstalk, specificity, and phenotypic effects can be distinguished with the metabolomics approach. He also underscored the utility of this approach in identifying different biomarkers to distinguish the effects of drugs, diet, diseases and cancer. He illustrated the use of metabolomics as an early predictor of toxicity by providing a case study on carbon tetrachloride, a known hepatotoxin and carcinogen (see text box for this and other citations).
The presentation concluded with Vulimiri effectively persuading the audience about the immense potential of metabolomics approach in generating and testing hypotheses, and in its ability to measure several MOAs of xenobiotics such as lipid peroxidation, oxidative stress, genotoxicity, regenerative cell proliferation, and inflammation using pathway metabolites as biomarkers. The talk stirred up an interesting and lively discussion addressing the current status of metabolomics, its promising potential in future NTP studies, and its advantages as a tool for toxicity testing in the 21st century.
(Mamta Behl, Ph.D., is a research fellow in the NTP Toxicology Branch)
Additional Research by Vulimiri and Other Relevant Review Articles
- Vulimiri SV, Berger A, Sonawane B.(http://www.ncbi.nlm.nih.gov/pubmed/20188855) 2010. The potential of metabolomic approaches for investigating mode(s) of action of xenobiotics: Case study with carbon tetrachloride. Mutat Res Feb. 25. [Epub ahead of print]
- Vulimiri, S.V., Misra, M., Hamm, J.T., Mitchell, M. and Berger, A.(http://www.ncbi.nlm.nih.gov/pubmed/19161311) 2009. Effects of mainstream cigarette smoke on the global metabolome of human lung epithelial cells. Chem Res Toxicol Jan. 22:492-503.
- Kim KB, Chung MW, Um SY, Oh JS, Kim SH, Na MA, et al.(http://springerlink.metapress.com/content/f15067nwn22t821x/?p=29595a1d8ae64432ab2e09117afbc32f&pi=8) 2008. Metabolomics and biomarker discovery: NMR spectral data of urine and hepatotoxicity by carbon tetrachloride, acetaminophen, and D-galactosamine in rats. Metabolomics, 4, 377-392.
- Chen C, Gonzalez FJ, Idle JR.(http://www.ncbi.nlm.nih.gov/pubmed/17786640) 2007. LC-MS-based metabolomics in drug metabolism. Drug Metab Rev, 39(2-3):581-597.
- Bajad S, Shulaev V.(http://www.ncbi.nlm.nih.gov/pubmed/19756204) 2007. Highly-parallel metabolomics approaches using LC-MS2 for pharmaceutical and environmental analysis Trends Analyt Chem 26(6):625-636.
- Manibusan MK, Odin M, Eastmond DA.(http://www.ncbi.nlm.nih.gov/pubmed/17763046) 2007. Postulated carbon tetrachloride mode of action: a review. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev, 25(3):185-209.