Much of the work carried out by DTT is in support of the National Toxicology Program (NTP), an interagency partnership of the Food and Drug Administration, National Institute for Occupational Safety and Health, and NIEHS.
Public Health Significance
Chronic progressive cardiovascular (CV) disease, in all its clinical manifestations, is the most significant cause of morbidity and mortality in many developed countries and, increasingly, in countries experiencing economic growth and prosperity. Lifestyle choices and genetics have clearly been demonstrated to be significant contributors but cannot alone or even in combination account for all the risk of developing CV disease, or the individual variability in which people experience the condition.
Environmental exposures are presumed to contribute to the risk of developing CV disease and, in some cases such as air pollution, there is compelling evidence to support that likelihood. However, current approaches to environmental hazard assessment do not specifically address CV bioactivity and hazards, despite growing evidence that environmental exposures contribute to the onset, risk, or progression of chronic CV disease.
Current hazard assessment paradigms are better designed to identify overt injury or dysfunction in normal biology than exacerbation of a comorbidity. Additionally, there is no defined approach to identify agents that may contribute to contemporary and common CV diseases.
To help bolster research into the environment’s role in CV disease, the Cardiovascular Health Effects Innovation Program is structured around the following three objectives:
- Leverage existing knowledge to define key CV “failure modes” as a framework for modeling, link those modes to mediators of mechanistic bioactivity, and screen existing databases to identify putative CV hazards.
- Develop a suite of assay, testing, modeling, and knowledge management capabilities that aligns with the current NIEHS Division of Translational Toxicology (DTT) Pipeline. In an integrated fashion, use those capabilities to provide an evidence-based approach to assessing CV bioactivity of environmental substances.
- Develop and implement an innovative capability for identifying potential environmental contributors to specific and contemporary clinical CV diseases.
The Translational Toxicology Pipeline provides an iterative approach for integrating modeling systems into the toxicological evaluation of environmental exposures. An evidence-based capability for identifying CV bioactivity that aligns with the pipeline will provide better insights into the potential for environmental exposures to contribute to human disease burden. Also, designing an innovative approach to modeling fundamental CV disease biology, by connecting key molecular and cellular events with mechanistic failure modes and adverse outcomes, will support DTT’s ability to identify contemporary environmental contributors to diseases with high prevalence in society.
The program will take advantage of the full complement of modeling systems in the Translational Toxicology Pipeline, beginning with in silico systems. Existing knowledge and medium- to high- throughput bioactivity screening will be leveraged to provide insights into CV-relevant biological activities that may represent hazards to the CV system. Subsequent assessments in more complex and in vivo-relevant cell and tissue-based modeling systems are followed by in vivo studies that characterize both morphologic and functional changes associated with environmental chemical exposures.
Early predictions informed by in silico models and in vitro bioactivity are qualified in progressively complex assay systems to build confidence in the predictivity of early pipeline steps, assess model applicability, and identify capability needs. The assay systems used are aligned to known human CV failure modes and reflect human biology as much as the complexity of the system permits, with a goal of optimizing the translational relevance of the outcomes.
DTT is defining a novel paradigm for environmental hazard assessment, working collaboratively with government, academic, and industry colleagues through the Health and Environmental Safety Institute (HESI) Cardiac Safety Technical Committee. Postdoctoral trainees contribute to key projects. The program is defining and testing a full pipeline of capabilities. The outcomes of these efforts are communicated through usual scientific communications (abstracts, presentations, peer-reviewed manuscripts), National Institute of Environmental Health Sciences media platforms, and, when appropriate, National Toxicology Program publications.
|Focus Area||Projects||Description||Projected Completion/Status|
|Defining the testing framework (CV failure modes)||
High-throughput bioactivity assessment via CardioToxPi
|Map Tox21 high-throughput screening (HTS) assays to CV failure modes and develop signatures of cardiotoxicity-relevant bioactivity (CardioToxPi). Use to further develop QSAR models for in silico CardioToxPi.||
Year 1; CompleteKrishna S, Berridge B, Kleinstreuer N. 2021. High-throughput screening to identify chemical cardiotoxic potential. Chem Res Toxicol 34(2):566–583.
|In silico model of hERG inhibition||Use Tox21 HTS data and curated literature results to build QSAR model predicting chemical hERG inhibitory potential.||Year 1; Ongoing|
Systematic evidence map of environmental chemical contributions to CV disease
|Create an evidence map of published literature relevant to environmental chemicals associated with CV toxicity/effects, organized by CV failure modes.||Year 1; Ongoing|
In vitro assessment of cardiovascular toxicant mechanisms
|Identify mechanisms of CV toxicity associated with environmental chemical exposures using advanced cardiac in vitro models.||Year 1; Initiated|
|Utilization of microphysiological systems to incorporate xenobiotic metabolism in cardiovascular toxicity screening||Utilize innovative flow-based 3D co-culture model including primary human hepatocytes, endothelial, fibroblast and cardiomyocyte cells to identify environmental agents that may cause metabolism-associated CV injury and disease.||Year 1; Ongoing|
Characterization of the gene coexpression landscape of the rat heart
|Perform cartography of the rat heart gene coexpression landscape and characterize modules as to their molecular and cellular biology function. Changes in coexpression modules will be linked to cardiac failure modes in order to determine key underlying processes of response to cardiotoxicity following specific perturbations and serve as a point of reference/validation for determining whether in vitro systems can recapitulate in vivo-like patterns of gene expression.||Year 1; Reporting|
|Structural and functional in vivo assessment of environmental agent CV toxicity||Evaluate the acute CV hazard potential of select environmental agents via morphological, biochemical, transcriptional, and functional endpoints.||Year 2; Ongoing|
In vitro assessment of vascular toxicant mechanisms
|Identify mechanisms of CV toxicity associated with environmental chemical exposures using advanced endothelial in vitro models.||Year 2; Initiated|
In vitro assessment of per- and polyfluoroalkyl substances (PFAS) on cardiomyocyte health
|Screen PFAS for their effects on structural and functional and gene expression changes of human-induced pluripotent stem cell derived cardiomyocytes (iPSCC) to identify potential mechanisms of PFAS-induced cardiotoxicity.||Year 2; Initiated|
|Defining approaches to understand CV diseases||
Scoping report and evidence map to identify biomarkers of hypertensive disorders of pregnancy (HDP)
|Characterize biomarkers of HDP in women, the extent to which biomarkers have been evaluated in animal models, and whether those biomarkers have been evaluated in the context of environmental exposures to inform future studies on environmental contributions of HDP.||Year 1; Ongoing|
Scoping report to characterize cardiovascular disease in underserved, understudied, and underrepresented populations
|Characterize the epidemiological literature evaluating cardiovascular disease in underserved, understudied, and underrepresented populations to identify research gaps and explore innovative approaches to consider chemical and psychosocial stressors contributing to CV disease.||Year 1; Ongoing|