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High-Throughput Screening to Identify Chemical Cardiotoxic Potential
Shagun Krishna1, Brian Berridge1, Nicole Kleinstreuer1
1Division of the National Toxicology Program, National Institute of Environmental Health Sciences, 530 Davis Drive, Research Triangle Park, North Carolina 27560, United States.
Abstract:
Cardiovascular (CV) disease is one of the most prevalent public health concerns, and mounting evidence supports the contribution of environmental chemicals to CV disease burden. In this study, we performed cardiotoxicity profiling for the Tox21 chemical library by focusing on high-throughput screening (HTS) assays whose targets are associated with adverse events related to CV failure modes. Our objective was to develop new hypotheses around environmental chemicals of potential interest for adverse CV outcomes using Tox21/ToxCast HTS data. Molecular and cellular events linked to six failure modes of CV toxicity were cross-referenced with 1399 Tox21/ToxCast assays to identify cardio-relevant bioactivity signatures. The resulting 40 targets, measured in 314 assays, were integrated via a ToxPi visualization tool and ranking system to prioritize 1138 chemicals based upon formal integration across multiple domains of information. Filtering was performed based on cytotoxicity and generalized cell stress endpoints to try and isolate chemicals with effects specific to CV biology, and bioactivity- and structure-based clustering identified subgroups of chemicals preferentially affecting targets such as ion channels and vascular tissue biology. Our approach identified drugs with known cardiotoxic effects, such as estrogenic modulators like clomiphene and raloxifene, anti-arrhythmic drugs like amiodarone and haloperidol, and antipsychotic drugs like chlorpromazine. Several classes of environmental chemicals such as organotins, bisphenol-like chemicals, pesticides, and quaternary ammonium compounds demonstrated strong bioactivity against CV targets; these were compared to existing data in the literature (e.g., from cardiomyocytes, animal data, or human epidemiological studies) and prioritized for further testing.
Insights
Environmental chemicals contribute to cardiovascular disease. This study used high-throughput screening data to identify chemicals, including pesticides and bisphenols, that may pose risks to heart health.
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.
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