Toxicogenomics

The field of toxicogenomics investigates how the genome responds to environmental substances. Chemicals can change the expression of genes, proteins, and metabolites in living cells. Measuring genome-wide changes in affected tissues is useful for finding markers of toxicity or disease, and for understanding how genetic variation among individuals can influence sensitivity to a substance. Finding the doses at which a substance can cause changes in gene expression and other genome-related endpoints is also important in risk assessment.

To learn more about this area, NTP has added the latest technologies to its testing program, including microarrays, next-generation sequencing (NGS), proteomics, and metabolomics. Biological samples may be from animals or from cell culture studies. Study proposals are reviewed by the Toxicogenomics Faculty at NTP.

5-Day Rodent Toxicogenomic Studies

NTP uses a short-term exposure test in rodents to gather information on how test substances affect gene expression. The changes produced in tissue gene expression can be modeled to predict toxic properties of the substance being studied. In these 5-day toxicogenomic studies, substances are tested in rats or mice at a wide range of dose levels for their potential to cause changes in specific organs. Target organs are chosen based on several factors, including:

• Earlier studies of the test substance
• Existing data on chemicals with similar structures
• Predicted toxicity based on chemical structure
• The general sensitivity of specific organs to chemical toxicity

The substance is usually delivered into the stomachs of rodents to ensure accurate dosing over the short study time. Rodents are exposed to the substance starting at six to eight weeks of age, receiving one dose per day for five days. Depending on the characteristics of the substance, the exposure period may be modified. The rodents are monitored throughout the study for signs of toxicity.

At necropsy, samples of organs and tissues are taken for genomic analysis. The data from the animals exposed to the substance are compared to the data from control animals to identify any possible effects at the dose range tested. The genomic data undergo dose-response modeling using BMD Express to identify the doses of the test substance that produce no change. Gene expression changes can also be compared to other known substances in NTP's DrugMatrix database and ToxFx analysis tools. Additional biological samples may be evaluated by metabolomics, clinical chemistries, hematology, or other tests. Tissues samples may also be frozen and stored for future analysis.