Environmental chemicals and cardiotoxicity
Researchers from the Division of the National Toxicology Program identified several pharmaceutical drugs and environmental chemicals that have cardiotoxic potential based on patterns of activity observed in in vitro assays.
Cardiovascular (CV) disease, the leading cause of death in the United States, is a major public health concern. Lifestyle and genetic predisposition are well established risk factors for CV disease. The contribution of environmental chemicals to CV disease burden is less well-studied. Many assessments of environmental chemical hazards are performed in animal models, which are functionally different from the human CV system.
To overcome this limitation, this study precisely defined six modes of CV failure and their molecular targets. Then, researchers harnessed data available from programs like Toxicology Testing in the 21st Century(https://ntp.niehs.nih.gov/whatwestudy/tox21/index.html) (Tox21) and EPA’s Toxicity Forecaster (ToxCast). By profiling the Tox21/ToxCast chemical library for cardiotoxicity and focusing on in vitro high throughput screening assays, investigators identified several drugs and chemicals with bioactivity against the molecular targets of CV failure modes.
This analysis revealed environmental chemicals that were active at concentrations lower than those toxic to cells. The researchers used structural profiling to identify clusters of chemicals enriched for bioactivity. The study provides a novel approach that combines in vitro and in silico models for identifying and prioritizing chemicals for further cardiotoxicity testing. (VP)
Citation: Krishna S, Berridge B, Kleinstreuer N. 2020. High-throughput screening to identify chemical cardiotoxic potential. Chem Res Toxicol; doi: 10.1021/acs.chemrestox.0c00382 [Online 21 December 2020].