Dataset Information

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites.

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-100?M) 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.

SUBMITTER: Grimm FA

PROVIDER: S-EPMC7377239 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites.

Grimm Fabian A FA Klaren William D WD Li Xueshu X Lehmler Hans-Joachim HJ Karmakar Moumita M Robertson Larry W LW Chiu Weihsueh A WA Rusyn Ivan I

Environmental health perspectives 20200723 7

<h4>Background</h4>Xenobiotic metabolism is complex, and accounting for bioactivation and detoxification processes of chemicals remains among the most challenging aspects for decision making with <i>in vitro</i> new approach methods data.<h4>Objectives</h4>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 sens ...[more]

PMID: 32701041

Similar Datasets

Project description:Hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) have been found to be ubiquitous in the environment due to the oxidative metabolism of their parent PCBs. With more polarity, OH-PCBs may be more toxic and mobile than their parent compounds. However, the behavior and fate of OH-PCBs have been neglected in the environment because they are not the original contaminants. Some of these hydroxylated metabolites are chiral, and chiral compounds can be used to probe biological metabolic processes. Therefore, chiral OH-PCBs were selected to study their uptake, translocation, transformation, and enantioselectivity in plants in this work. Poplars (Populus deltoides × nigra, DN34), a model plant with complete genomic sequence, were hydroponically exposed to 5-hydroxy-2,2',3,4',6-pentachlorobiphenyl (5-OH-PCB91) and 5-hydroxy-2,2',3,5',6-pentachlorobiphenyl (5-OH-PCB95) for 10 days. Chiral 5-OH-PCB91 and 5-OH-PCB95 were clearly shown to be sorbed, taken up, and translocated in whole poplars, and they were detected in various tissues of whole poplars. However, the enantioselectivity of poplar for 5-OH-PCB91 and 5-OH-PCB95 proved to be quite different. The second-eluting enantiomer of OH-PCB95, separated on a chiral column (Phenomenex Lux Cellulose-1), was enantioselectively removed in whole poplar. Enantiomeric fractions in the middle xylem, top bark, top xylem, and stem, reached 0.803 ± 0.022, 0.643 ± 0.110, 0.835 ± 0.087, and 0.830 ± 0.029, respectively. Therefore, 5-OH-PCB95 was significantly enantioselectively biotransformed inside poplar tissues, in contrast to nearly racemic mixtures of 5-OH-PCB95 remaining in hydroponic solutions. Unlike 5-OH-PCB95, 5-OH-PCB91 remained nearly racemic in most tissues of whole poplars during 10 day exposure, suggesting the enantiomers of 5-OH-PCB91 were equally transported and metabolized in whole poplars. This is the first evidence of enantioselectivity of chiral OH-PCBs and suggests that poplars can enantioselectively biotransform at least one chiral OH-PCB: namely, 5-OH-PCB95.

Dataset Information

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites.

Publications

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets