Informing Hazard Identification and Risk Characterization of Environmental Chemicals by Combining Transcriptomic and Functional Data from Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes

Environmental chemicals may contribute
to the global burden of
cardiovascular disease, but experimental data are lacking to determine
which substances pose the greatest risk. Human-induced pluripotent
stem cell (iPSC)-derived cardiomyocytes are a high-throughput cardiotoxicity
model that is widely used to test drugs and chemicals; however, most
studies focus on exploring electro-physiological readouts. Gene expression
data may provide additional molecular insights to be used for both
mechanistic interpretation and dose–response analyses. Therefore,
we hypothesized that both transcriptomic and functional data in human
iPSC-derived cardiomyocytes may be used as a comprehensive screening
tool to identify potential cardiotoxicity hazards and risks of the
chemicals. To test this hypothesis, we performed concentration–response
analysis of 464 chemicals from 12 classes, including both pharmaceuticals
and nonpharmaceutical substances. Functional effects (beat frequency,
QT prolongation, and asystole), cytotoxicity, and whole transcriptome
response were evaluated. Points of departure were derived from phenotypic
and transcriptomic data, and risk characterization was performed.
Overall, 244 (53%) substances were active in at least one phenotype;
as expected, pharmaceuticals with known cardiac liabilities were the
most active. Positive chronotropy was the functional phenotype activated
by the largest number of tested chemicals. No chemical class was particularly
prone to pose a potential hazard to cardiomyocytes; a varying proportion
(10–44%) of substances in each class had effects on cardiomyocytes.
Transcriptomic data showed that 69 (15%) substances elicited significant
gene expression changes; most perturbed pathways were highly relevant
to known key characteristics of human cardiotoxicants. The bioactivity-to-exposure
ratios showed that phenotypic- and transcriptomic-based POD led to
similar results for risk characterization. Overall, our findings demonstrate
how the integrative use of in vitro transcriptomic and phenotypic
data from iPSC-derived cardiomyocytes not only offers a complementary
approach for hazard and risk prioritization, but also enables mechanistic
interpretation of the in vitro test results to increase confidence
in decision-making.