Unbiased Approach for the Identification of Molecular Mechanisms Sensitive to Chemical Exposures

Abstract

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.

Chemical exposures affect innate immune response to SARS-CoV-2

“…Additionally, the direction of change in gene expression was not considered when sensitivities of genes to chemical exposures were calculated. In fact, our previous study demonstrated that the absolute majority of highly chemically-sensitive genes are induced and suppressed by almost equal number of compounds [15]. Similarly, high level of generalization does not allow accounting for individual differences in patients' response to COVID-19, including differences determined by age, sex, race, comorbidities, and other factors.…”

“…According to our hypothesis, speci c immune response mechanisms may be synergistically affected by chemical exposures and SARS-CoV-2, resulting in increased severity of the disease. To test this hypothesis, we rst used data on the sensitivity of mammalian genes to chemical exposures identi ed in our previous research [15,17] by overlaying transcriptomic datasets from many individual toxicological genomic studies. This allowed the identi cation of genes that respond most often to a variety of chemical exposures (Fig.…”

“…The unbiased approach for the identi cation of genes sensitive to chemical exposures was developed in our previous studies [15,17]. A database was created by extracting data on chemical-gene interactions from the Comparative Toxicogenomics Database CTD [30] (Fig.…”

“…We propose to gain mechanistic knowledge on the interaction between SARS-CoV-2 infection and chemical exposures using in-silico approaches, which rely on existing data. In our recent study, we attempted to identify genes and molecular pathways most sensitive to chemical exposures using an unbiased big-data approach by overlying transcriptomic datasets from 2,169 individual studies [15]. This unbiased analysis demonstrated that immune response pathways, including interferon signaling and cytokine signaling, are pathways highly sensitive to chemical exposures [15].…”

“…In our recent study, we attempted to identify genes and molecular pathways most sensitive to chemical exposures using an unbiased big-data approach by overlying transcriptomic datasets from 2,169 individual studies [15]. This unbiased analysis demonstrated that immune response pathways, including interferon signaling and cytokine signaling, are pathways highly sensitive to chemical exposures [15]. Emerging data on SARS-CoV-2 indicate that the disease severity is linked to a highly dysregulated innate immune response characterized by a delayed interferon response and exuberant in ammatory response [16].…”