High-Throughput Screening to Identify Chemical Cardiotoxic Potential.

Area of Science:

• Environmental toxicology
• Cardiovascular toxicology
• Computational toxicology

Background:

• Cardiovascular disease (CVD) is a major public health issue.
• Environmental chemicals are increasingly recognized as contributors to the CVD burden.
• Understanding chemical impacts on cardiovascular health is crucial for public health risk assessment.

Purpose of the Study:

• To profile the Tox21 chemical library for cardiotoxicity using high-throughput screening (HTS) assays.
• To generate novel hypotheses regarding environmental chemicals associated with adverse cardiovascular outcomes.
• To identify potential cardiovascular risks from environmental chemical exposures using Tox21/ToxCast data.

Main Methods:

• Cross-referencing molecular and cellular events of six cardiovascular toxicity failure modes with 1399 Tox21/ToxCast assays.
• Utilizing the ToxPi visualization tool and ranking system to integrate data from 40 targets across 314 assays.
• Filtering for cytotoxicity and cell stress to isolate cardiovascular-specific effects and clustering for bioactivity and structure-based analysis.

Main Results:

• Prioritized 1138 chemicals based on integrated data, identifying known cardiotoxic drugs (e.g., clomiphene, amiodarone, chlorpromazine).
• Detected significant bioactivity against cardiovascular targets in environmental chemical classes like organotins, bisphenol-like compounds, pesticides, and quaternary ammonium compounds.
• Identified subgroups of chemicals affecting ion channels and vascular tissue biology.

Conclusions:

• The study successfully identified known cardiotoxic drugs and flagged environmental chemical classes for further investigation.
• This approach provides a robust framework for prioritizing environmental chemicals with potential cardiovascular toxicity.
• Findings support the need for further research and risk assessment of identified chemical classes regarding cardiovascular health.