High-Throughput Screening to Identify Chemical Cardiotoxic Potential

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.