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Rapid hazard characterization of environmental chemicals using a compendium of human cell lines from different organs

ABSTRACT: The lack of adequate toxicity data for the vast majority of chemicals in the environment has spurred the development of new approach methodologies (NAMs). This study aimed to develop a practical high-throughput in vitro model for rapidly evaluating potential hazards of chemicals using a small number of human cells. Forty-two compounds were tested using human induced pluripotent stem cell (iPSC)-derived cells (hepatocytes, neurons, cardiomyocytes and endothelial cells), and a primary endothelial cell line. Both functional and cytotoxicity endpoints were evaluated using high-content imaging. Concentration-response was used to derive points-of-departure (POD). PODs were integrated with ToxPi and used as surrogate NAM-based PODs for risk characterization. We found chemical class-specific similarity among the chemicals tested; metal salts exhibited the highest overall bioactivity. We also observed cell type-specific patterns among classes of chemicals, indicating the ability of the proposed in vitro model to recognize effects on different cell types. Compared to available NAM datasets, such as ToxCast/Tox21 and chemical structure-based descriptors, we found that the data from the five-cell-type model was as good or even better in assigning compounds to chemical classes. Additionally, the PODs from this model performed well as a conservative surrogate for regulatory in vivo PODs and were less likely to underestimate in vivo potency and potential risk compared to other NAM-based PODs. In summary, we demonstrate the potential of this in vitro screening model to inform rapid risk-based decision-making through ranking, clustering, and assessment of both hazard and risks of diverse environmental chemicals.

SUBMITTER: Chen Z

PROVIDER: S-EPMC7941183 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cardiovascular disease remains a significant global health concern, yet the cardiotoxic effects of environmental chemicals are largely unexplored. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-Cardiomyocytes) are well-established as valuable high-throughput cardiotoxicity testing model based on the analysis of various beating parameters; however, additional adverse effects that may not be directly related to ion channel activity are difficult to ascertain from traditional assays. Transcriptomic data may provide a more comprehensive assessment for additional molecular responses and serve as a basis for dose-response analysis. We hypothesized that transcriptomic data and functional phenotypic measurements in iPSC-Cardiomyocytes could be used to effectively screen for both hazard and risk associated with chemical exposures. To test this hypothesis, we performed concentration-response analysis of 464 chemicals from 12 diverse chemical classes. Functional effects (beat frequency, QT-prolongation, and asystole) and cytotoxicity were measured. In addition, whole transcriptome RNA-seq was used to investigate global gene expression profiles. Points of departure (PODs) were derived from both phenotypic endpoints and transcriptomic data. Margin of safety (MOS) for drugs and margin of exposure (MOE) for non-drug chemicals were calculated using PODs and the exposure estimates. The phenotypic assays revealed that a varying proportion (10% to 44%) of chemicals in each class had effects on iPSC-Cardiomyocytes; positive chronotrope was the most sensitive phenotype. Overall, 244 (53%) chemicals were active in at least one functional phenotype. As expected, drugs with known adverse effects on the heart were most active. Transcriptomic data showed 69 (15%) had significant effects on the biological pathways, the pathways that were significantly affected by some tested compounds were highly relevant to cardiomyocyte function. Specifically, the enriched pathways aligned well with key characteristics of known cardiovascular toxicants, with mitochondrial dysfunction being the most affected key characteristic. Using exposure and hazard (transcriptomic and phenotypic PODs from this study), we derived MOS and MOE and found that drugs tend to have lower MOS than MOE for the environmental chemicals. Thirteen and 10 drugs had MOS < 1 using phenotypic and transcriptomic data, respectively, suggesting that further investigation may be needed for these substances to test for potential cardiovascular risk. Overall, our findings demonstrate how the integrative use of in vitro transcriptomic data and phenotypic assays in iPSC-Cardiomyocytes not only offers a unique and complementary approach for hazard and risk prioritization, but also offers comprehensive mechanistic support for in vitro test results.

Project description:Heart disease remains a significant human health burden worldwide with a significant fraction of morbidity attributable to environmental exposures. However, the extent to which the thousands of chemicals in commerce and the environment may contribute to heart disease morbidity is largely unknown, because in contrast to pharmaceuticals, environmental chemicals are seldom tested for potential cardiotoxicity. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes have become an informative in vitro model for cardiotoxicity testing of drugs with the availability of cells from multiple individuals allowing in vitro testing of population variability. In this study, we hypothesized that a panel of iPSC-derived cardiomyocytes from healthy human donors can be used to screen for the potential cardiotoxicity hazard and risk of environmental chemicals. We conducted concentration-response testing of 1029 chemicals (drugs, pesticides, flame retardants, polycyclic aromatic hydrocarbons (PAHs), plasticizers, industrial chemicals, food/flavor/fragrance agents, etc.) in iPSC-derived cardiomyocytes from 5 donors. We used kinetic calcium flux and high-content imaging to derive quantitative measures as inputs into Bayesian population concentration-response modeling of the effects of each chemical. We found that many environmental chemicals pose a hazard to human cardiomyocytes in vitro with more than half of all chemicals eliciting positive or negative chronotropic or arrhythmogenic effects. However, most of the tested environmental chemicals for which human exposure and high-throughput toxicokinetics data were available had wide margins of exposure and, thus, do not appear to pose a significant human health risk in a general population. Still, relatively narrow margins of exposure (<100) were estimated for some perfuoroalkyl substances and phthalates, raising concerns that cumulative exposures may pose a cardiotoxicity risk. Collectively, this study demonstrated the value of using a population-based human in vitro model for rapid, high-throughput hazard and risk characterization of chemicals for which little to no cardiotoxicity data are available from guideline studies in animals.

Project description:Many studies have reported perturbations of mollusc reproduction following exposure to low concentrations (ng/L range) of endocrine disrupting chemicals (EDCs). However, the mechanisms of action of these molecules on molluscs are still poorly understood. Investigation of the modifications of protein expression in organisms exposed to chemicals using proteomic methods can provide a broader and more comprehensive understanding of adverse impacts of pollution on organisms than conventional biochemical biomarkers (e.g., heat-shock proteins, metallothioneins, GST, EROD). In this study we have investigated the impacts of four chemicals, which exhibit different endocrine disrupting properties in vertebrates, on the proteome of the hermaphroditic freshwater pulmonate gastropod Lymnaea stagnalis after 21 days of exposure. Testosterone, tributyltin, chlordecone and cyproterone acetate were chosen as tested compounds as they can induce adverse effects on the reproduction of this snail. The 2D-DIGE method was used to identify proteins whose expression was affected by these compounds. In addition to modifying the expression of proteins involved in the structure and function of the cytoskeleton, chemicals had impacts on the expression of proteins involved in the reproduction of L. stagnalis. Exposure to 19.2 µg/L of chlordecone increased the abundance of ovipostatin, a peptide transmitted during mating through seminal fluid, which reduces oviposition in this species. The expression of yolk ferritin, the vitellogenin equivalent in L. stagnalis, was reduced after exposure to 94.2 ng Sn/L of tributyltin. The identification of yolk ferritin and the modification of its expression in snails exposed to chemicals were refined using western blot analysis. Our results showed that the tested compounds influenced the abundance of yolk ferritin in the reproductive organs. Alteration in proteins involved in reproductive pathways (e.g., ovipostatin and yolk ferritin) could constitute relevant evidence of interaction of EDCs with reproductive pathways that are under the control of the endocrine system of L. stagnalis.

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Rapid hazard characterization of environmental chemicals using a compendium of human cell lines from different organs

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