People are routinely exposed to thousands of man-made chemicals, some with known health effects, but most are far from fully understood.
Only 250 of the 84,000 chemicals registered for commercial use in the United States have been tested by government agencies, according to research by the Center for Effective Government.
Unbiased Approach
For our study, my research colleagues and I used data from the Comparative Toxicogenomic Database. The database collects information from thousands of published studies on how chemicals change the activity of genes. Genes are sections of DNA that encode proteins that perform a broad range of functions in cells, from building tissues to metabolizing nutrients. When chemicals affect genes, that results in increased or decreased production of proteins.Modern methods of molecular biology can detect changes in the activity of all genes in the genome in response to a chemical insult. I developed an approach that overlays lists of altered genes from different studies to calculate how many times each gene was affected. The resulting numbers reflect sensitivities of genes to chemicals generally.
Using 2,169 studies on mice, rats, humans and their cells, my research group ranked the sensitivity of 17,338 genes to chemical exposures. These studies tested the impact of 1,239 diverse chemicals ranging from prescription drugs to environmental pollutants.
Cellular Defense System Responds to Chemicals
Our cells aren’t completely helpless when exposed to chemical insults. In fact, they possess strategies for dealing with stress and damage induced by chemicals. Our data confirm that these safeguards become active in response to exposures.Metabolism of Lipids and Carbohydrates Is Vulnerable
Surprisingly, we found that molecular networks involved in the regulation of cellular metabolism are most sensitive to chemical exposures. One of them is PPAR signaling. PPARs are a group of proteins that regulate energy balance and metabolism of lipids and glucose.We also discovered that genes involved in the development of pancreatic beta cells, which secrete insulin and play a key role in glucose metabolism, are suppressed by a majority of chemicals in our list. The dysfunction of beta cells results in diabetes. Thus, cumulative chemical exposures may be a significant risk factor for diabetes.
Growth, Aging, and the Immune System
Two hormones involved in growth—growth hormone (GH) and insulin-like growth factor (IGF1)—are also affected by exposure to chemicals.Our analysis indicates that genes that control the immune response are also highly sensitive to chemicals.
All Molecular Pathways are Sensitive to Chemicals
Overall we found that almost every known pathway may be affected by chemicals. That finding has significant implications for regulatory toxicology.One important question that remains unanswered is what pathways should be covered by testing to ensure that regulators don’t approve chemicals that harm or disrupt critical molecular circuits. Our data suggest that we need to develop tests that cover every known molecular pathway without exception.
Our study outlines new priorities for toxicological research, including the role of chemical exposures for metabolic health, immune system, development, and aging.
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