AMHERST, Mass.—An unprecedented approach by environmental health researchers from the University of Massachusetts Amherst (UMass Amherst) has been used to identify which molecular mechanisms in mammals are the most sensitive to chemical exposures.
“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 lead author Dr. Alexander Suvorov, who is associate professor in the School of Public Health and Health Sciences at UMass Amherst.
Researchers 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.
“In the recent past, everything that we knew about molecular mechanisms affected by chemicals was coming from low-throughput experiments. 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,” added Suvorov. “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.”
“One important finding of this study consists in the observation that the majority of known molecular pathways are sensitive to chemical exposures,” notes the article. “In fact, out of 1168 combined Hallmark, KEGG and Reactome datasets, 1091 (93.4%) were positively enriched in GSEA [gene-set enrichment analysis] … and 552 (47.3%) were significantly positively enriched (NES [normalized enrichment scores] ≥ 1.9 or ≤ −1.9 and FDR q ≤ 0.05). The numbers of negative and significant negative enrichment (corresponding pathways were non-sensitive to chemical exposures) were 77 (6.6%) and 4 (0.3%), respectively.”
The study identified the genes and molecular pathways most sensitive to chemical exposures. These included mechanisms involving aging, lipid metabolism and autoimmune disease.
“The sensitivity of lipid metabolism pathways to chemical exposures may be relevant to the current epidemic of metabolic disease, one of the biggest public health issues in the modern day … Our data provide unbiased evidence, supporting sensitivity of lipid metabolism to a broad range of chemical agents,” the study explains. “This finding may have significant public health implications and requires additional research.”
“AhR-regulated CYP1A1 and CYP1B1 were in the list of top 20 genes with the highest numbers of chemical-gene interactions (Table 2),” continues the article. “Many microsomal and cytosolic oxidoreductases were also among the highest-scoring genes for activating chemical-gene interactions … Some genes of the oxidative stress response pathway are among the highest scoring for the number of activating chemical-gene interactions (Table 3), although this pathway was highly enriched by both activating and suppressive chemical-gene interactions (Table 5).”
The interactions that the researchers analyzed involved 17,338 unique genes and 1,239 unique chemicals. The team split the chemicals database into two sections: pharmaceutical chemicals, and chemicals from sources like industry, agriculture, pollution and cosmetics. When the sensitivity of genes to pharmaceutical chemicals was compared to the sensitivity of genes to 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 stated.
“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. Our data suggest that almost every known molecular pathway may be affected by chemical exposures,” adds the study. “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 study confirmed the molecular mechanisms previously recognized as sensitive to chemical exposure, like oxidative stress. 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 like diabetes, fatty liver disease, lupus and rheumatoid arthritis, among others.
“The number of chemical compounds covered in this study (1,239) is high, but still it represents only very small portion of more than 156 million registered man-made chemicals,” the article says. “Additional research is needed to test if major findings of our study stay true as transcriptomic toxicological data is becoming available for more chemicals.”
“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,” concluded Suvorov.