Unbiased Approach for the Identification of Molecular Mechanisms Sensitive to Chemical Exposures
Autor: | Victoria Salemme, Joseph McGaunn, Alexander Suvorov, Saira Amir, Menna Teffera, Anthony Poluyanoff |
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Rok vydání: | 2020 |
Předmět: |
Environmental Engineering
Health Toxicology and Mutagenesis media_common.quotation_subject Longevity 0208 environmental biotechnology 02 engineering and technology Computational biology Computational toxicology 010501 environmental sciences Biology 01 natural sciences Adverse Outcome Pathway Animals Humans Environmental Chemistry PI3K/AKT/mTOR pathway 0105 earth and related environmental sciences media_common molecular_biology Public Health Environmental and Occupational Health Lipid metabolism Environmental Exposure General Medicine General Chemistry Pollution 020801 environmental engineering Highly sensitive Molecular mechanism Identification (biology) Toxicogenomics Drug metabolism |
Popis: | Background: Targeted methods that dominated toxicological research until recently did not allow for screening of all molecular changes involved in toxic response. Therefore, it is difficult to infer if all major mechanisms of toxicity have already been discovered, or if some of them are still overlooked. Objectives: To identify molecular mechanisms sensitive to chemical exposures in an unbiased manner. Methods: We used data on 641,516 unique chemical-gene interactions from the Comparative Toxicogenomic Database. Only data from high-throughput gene expression experiments with human, rat or mouse cells/tissues were extracted. The total number of chemical-gene interactions was calculated for every gene, and used as a measure of gene sensitivity to chemical exposures. These values were further used in enrichment analyses to identify molecular mechanisms sensitive to chemical exposures. Results: Remarkably, use of different input subsets with non-overlapping lists of chemical compounds identified largely the same genes and molecular pathways as most sensitive to chemical exposures, indicative of an unbiased nature of our analysis. One of the most important findings of this study is that almost every known molecular mechanism may be affected by chemical exposures. Predictably, xenobiotic metabolism pathways and mechanisms of cellular response to stress and damage were among the most sensitive. Additionally, our analysis identified a range of highly sensitive molecular pathways, which are not widely recognized by modern toxicology as major targets of toxicants, including lipid metabolism pathways, longevity regulation cascade and cytokine mediated signaling. Discussion: Molecular mechanisms identified as the most sensitive to chemical exposures are relevant for significant public health problems, such as aging, cancer, metabolic and autoimmune disease. Thus, public health system will likely benefit from future research focus on these sensitive molecular mechanisms. Additionally, approach used in this study may guide identification of priority adverse outcome pathways (AOP) for in-vitro and in-silico toxicity testing methods. |
Databáze: | OpenAIRE |
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