Scientists at the University of Massachusetts, Amherst, have used what they claim is an unprecedented objective approach to identify which genes and molecular pathways— including mechanisms involving aging, lipid metabolism, and autoimmune disease—are most sensitive to chemical exposure. Headed by environmental health scientist Alexander Suvorov, PhD, the research findings could help to improve our understanding of how chemicals, including pollutants and pharmaceuticals, interact to impact gene expression, and potentially human health.

“When we identified all the sensitive genes, we were very much surprised that almost every well-known molecular pathway is sensitive to chemicals to a certain degree,” said Suvorov, who is an associate professor in the School of Public Health and Health Sciences. “These findings for the first time prove that current epidemics in metabolic and autoimmune disorders may be partly due to a very broad range of chemical exposures.” Suvorov is first author of the team’s published paper in Chemosphere, which is titled, “Unbiased approach for the identification of molecular mechanisms sensitive to chemical exposure.”

Research estimates that the total burden of disease costs associated with exposure to environmental chemicals could be more than 10% of global domestic product, the authors commented. The number of new chemicals is also on a rapid increase, with the Chemical Abstract Service Registry increasing from 20 million to 156 million chemicals between 2002 and 2019. “This situation poses a significant challenge for regulatory toxicology and requires the development of new, rapid, cost-efficient, and reliable methods of toxicity testing,” Suvorov and colleagues commented.

Today, toxicologists recognize many molecular mechanisms that are key to a significant portion of all toxicity events, but all of these mechanisms were identified when there were no high-throughput methods for use in toxicology research. “In the recent past, everything that we knew about molecular mechanisms affected by chemicals was coming from low-throughput experiments,” Suvorov said, which led toxicology researchers to focus on those already identified genes, rather than looking for chemical sensitivity among a fuller range of genes.

What hasn’t been known is whether all of the major mechanisms of toxicity have already been discovered using such historical approaches, or if there may be others that have been overlooked. “Here, we hypothesized that data from toxicological omics experiments rapidly accumulating in publicly accessible databases may help to answer this question,” the investigators commented.

To carry out their analysis, Suvorov and five students—undergraduates Victoria Salemme, Joseph McGaunn, and Menna Teffera, and graduate students Anthony Poluyanoff, PhD, and Saira Amir, PhD—extracted data on chemical-gene interactions from the Comparative Toxicogenomics Database (CTD), which includes human, rat, and mouse genes. “In this study, we use publicly available data from the CTD, on changes in gene expression in response to a broad range of chemical compounds to identify, in an unbiased manner, the molecular mechanisms most sensitive to chemical exposure,” the scientists noted. They created a database of 591,084 chemical-gene interactions reported in 2,169 studies that used high-throughput gene expression analysis, meaning that they looked at multiple genes; low-throughout analysis focuses only on a single gene.

“I wanted to find some approach that would tell us in a completely unbiased way which mechanisms are sensitive and which are not,” Suvorov said. “I wondered if we were missing a significant toxic response just because no one ever looked for it. By overlaying many high-throughput studies, we can see changes in the expression of all genes all at once. And that is unbiased because we are not cherry-picking any particular molecular mechanisms.”

Alexander Suvorov is an associate professor in the UMass Amherst School of Public Health and Health Sciences. [UMass Amherst]

The interactions analyzed encompassed 17,338 unique genes and 1,239 unique chemicals. The researchers split their database of chemicals into two parts, pharmaceutical chemicals—which are designed to target known molecular cascades—and other chemicals such as industrial, agricultural, cosmetics, and pollutants. When the sensitivity of genes to pharmaceutical chemicals was compared to the sensitivity of genes to the other chemicals, the results were the same. “That proves that when analysis is done on really big numbers of chemicals, their composition does not matter,” Suvorov said.

The study confirmed the molecular mechanisms that had previously been recognized as being sensitive to chemical exposure, such as oxidative stress. But the new findings that the pathways involving aging, lipid metabolism, and autoimmune disease are also highly sensitive, suggest that chemical exposures may have a role in conditions such as diabetes, fatty liver disease, lupus, and rheumatoid arthritis. Many of the pathways identified play important roles in different kinds of cancer, for example. “Among the highest-scoring genes for suppressive interactions, there were important members of the GH-IGF signaling cascade (GHR, IGFBP3, and IGF1), cytokines (CXCL8, CXCL12, CCL2), cyclins (CCNB1, CDK1, CCNA2, CCND1), lipid metabolism genes (THRSP, HMGCS1, FASN), and more,” the team reported. “One important question that remains unanswered is what pathways should be covered by in vitro assays to ensure that we do not miss possible toxicities of chemicals using this new paradigm of toxicity testing. Should there be evidence connecting these pathways with adverse outcomes, these pathways must be included in the list of targets for in vitro testing.”

The researchers said the results indicate that the majority of known molecular pathways are sensitive to chemical exposure. “Our data suggest that almost every known molecular pathway may be affected by chemical exposures,” they wrote. Lipid metabolism was one mechanism that was found to be sensitive to a broad range of chemical agents. “This finding may have significant public health implications and requires additional research,” the team commented. Another group of molecular pathways identified as highly sensitive to chemical exposures consists of immune response pathways. “The ability of a broad range of chemicals to suppress expression of genes essential for beta-cell development and function may be a significant factor that predisposes the modern population to diabetes development,” they continued. Immune mechanisms that are dysfunctional in allergy and autoimmunity were also among those that were found to be highly sensitive to chemical exposures.

Suvorov concluded, “This study represents a significant step forward in the use of genomic data for the improvement of public health policies and decisions … and the public health field will benefit from a future focus of toxicological research on these identified sensitive mechanisms.”

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