Study identifies genes and molecular pathways most sensitive to chemical exposures

A University of Massachusetts Amherst environmental health scientist has used an unprecedented objective approach to identify which molecular mechanisms in mammals are the most sensitive to chemical exposures.

The study, published in the journal Chemosphere, advances the understanding of the interaction of chemicals, both pollutants and pharmaceuticals, on gene expression and the impact on 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."

Alexander Suvorov, Study Lead Author and Associate Professor, School of Public Health and Health Sciences, University of Massachusetts Amherst

The study identified genes and molecular pathways most sensitive to chemical exposures, including mechanisms involving aging, lipid metabolism and autoimmune disease. "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 says.

To carry out their analysis, Suvorov and five students - undergraduates Victoria Salemme, Joseph McGaunn and Menna Teffera, and graduate students Anthony Poluyanoff and Saira Amir - extracted data on chemical-gene interactions from the Comparative Toxicogenomics Database, which includes human, rat and mouse genes.

The UMass Amherst team created a database of 591,084 chemical-gene interactions reported in 2,169 studies that used high-throughput gene expression analysis, which means they looked at multiple genes. Low-throughout analysis focuses only on a single gene.

"In the recent past, everything that we knew about molecular mechanisms affected by chemicals was coming from low-throughput experiments," Suvorov says, which led toxicology researchers to focus on those already identified genes, rather than looking for chemical sensitivity among a fuller range of genes.

"I wanted to find some approach that would tell us in a completely unbiased way which mechanisms are sensitive and which are not. I wondered if we were missing a significant toxic response just because no one ever looked for it," Suvorov says. "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."

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 says.

The study confirmed the molecular mechanisms that were previously recognized as being sensitive to chemical exposure, such as oxidative stress. The study's 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 such conditions as diabetes, fatty liver disease, lupus and rheumatoid arthritis, among others.

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