Journal article
Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites
Environmental health perspectives, Vol.128(7), pp.77008-77008
07/2020
DOI: 10.1289/EHP7030
PMID: 32701041
Abstract
Background: Xenobiotic metabolism is complex, and accounting for bioactivation and detoxification processes of chemicals remains among the most challenging aspects for decision making with in vitro new approach methods data.
Objectives:
Considering the physiological relevance of human organotypic culture models and their utility for high-throughput screening, we hypothesized that multidimensional chemical-biological profiling of chemicals and their major metabolites is a sensible alternative for the toxicological characterization of parent molecules vs. metabolites in vitro.
Methods:
In this study, we tested 25 polychlorinated biphenyls (PCBs) [PCB 3, 11, 52, 126, 136, and 153 and their relevant metabolites (hydroxylated, methoxylated, sulfated, and quinone)] in concentration–response (10 nM–100μM) for effects in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) (iPSC-derived and HUVECs). Functional phenotypic end points included effects on beating parameters and intracellular Ca2+ flux in CMs and inhibition of tubulogenesis in ECs. High-content imaging was used to evaluate cytotoxicity, mitochondrial integrity, and oxidative stress.
Results:
Data integration of a total of 19 physicochemical descriptors and 36 in vitro phenotypes revealed that chlorination status and metabolite class are strong predictors of the in vitro cardiovascular effects of PCBs. Oxidation of PCBs, especially to di-hydroxylated and quinone metabolites, was associated with the most pronounced effects, whereas sulfation and methoxylation of PCBs resulted in diminished bioactivity.
Discussion:
Risk characterization analysis showed that although in vitro derived effective concentrations exceeded the levels measured in the general population, risks cannot be ruled out due to the potential for population variability in susceptibility and the need to fill data gaps using read-across approaches. This study demonstrated a strategy for how in vitro data can be used to characterize human health risks from PCBs and their metabolites. https://doi.org/10.1289/EHP7030
Details
- Title: Subtitle
- Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites
- Creators
- Fabian A Grimm - Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USAWilliam D Klaren - Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USAXueshu Li - Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, Iowa City, Iowa, USAHans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, Iowa City, Iowa, USAMoumita Karmakar - Department of Statistics, College of Science, Texas A&M University, College Station, Texas, USALarry W Robertson - Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, Iowa City, Iowa, USAWeihsueh A Chiu - Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USAIvan Rusyn - Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
- Resource Type
- Journal article
- Publication Details
- Environmental health perspectives, Vol.128(7), pp.77008-77008
- DOI
- 10.1289/EHP7030
- PMID
- 32701041
- NLM abbreviation
- Environ Health Perspect
- ISSN
- 0091-6765
- eISSN
- 1552-9924
- Language
- English
- Date published
- 07/2020
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984001090402771
Metrics
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