High-Throughput Screening to Identify Chemical Cardiotoxic Potential
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.
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NICEATM and NTP staff used Sysrev.com to conduct literature searches to identify in vitro methods with mechanistic targets that can be mapped to one of six identified cardiotoxicity failure modes.
“NICEATM and NTP staff used Sysrev.com to conduct literature searches to identify in vitro methods with mechanistic targets that can be mapped to one of six identified cardiotoxicity “failure modes” (Krishna et al., 2020).”
From Sysrev: A FAIR Platform for Data Curation and Systematic Evidence Review (2021) · cites this paper as Krishna et al., 2020
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Sysrev: A FAIR Platform for Data Curation and Systematic Evidence Review
Bozada, T., Borden, J., Workman, J., Del Cid, M., Malinowski, J., & Luechtefeld, T. (2021) · Frontiers in Artificial Intelligence · doi:10.3389/frai.2021.685298 · Cited by 118 · see citing works
- Authors
- Krishna, S., Berridge, B., & Kleinstreuer, N.
- Affiliations
- National Institute of Environmental Health Sciences (US)
- Corresponding author
- Kleinstreuer, Nicole
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-12-21
- Volume
- 34
- Issue
- 2
- Pages
- 566-583
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- OpenAlex
- W3117032441
- Cited by
- 52
- References
- 105
- Citations by year
- 2026: 11 · 2025: 6 · 2024: 13 · 2023: 7 · 2022: 10 · 2021: 5
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Environmental Toxicology and Ecotoxicology
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- cardiotoxicity, environmental chemicals, cardiovascular disease, high-throughput screening, ToxPi, chemical prioritization, ion channels, vascular tissue, organotin compounds, bisphenols, pesticides, quaternary ammonium compounds, clomiphene citrate, raloxifene, amiodarone, haloperidol, chlorpromazine, drug-induced cardiotoxicity
- MeSH terms
- Cardiovascular Diseases, Environmental Pollutants, Humans, Molecular Structure, High-Throughput Screening Assays
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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