Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites

Overview

Journal Environ Health Perspect

Date 2020 Jul 24

PMID 32701041

Citations 16

Authors

Fabian A Grimm

William D Klaren

Xueshu Li

Hans-Joachim Lehmler

Moumita Karmakar

Larry W Robertson

Weihsueh A Chiu

Ivan Rusyn

Affiliations

Soon will be listed here.

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 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 .

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 () 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 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 phenotypes revealed that chlorination status and metabolite class are strong predictors of the 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 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 data can be used to characterize human health risks from PCBs and their metabolites. https://doi.org/10.1289/EHP7030.

Citing Articles

Characterizing PFAS hazards and risks: a human population-based in vitro cardiotoxicity assessment strategy.

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Loss of flavin-containing monooxygenase 3 modulates dioxin-like polychlorinated biphenyl 126-induced oxidative stress and hepatotoxicity.

Agarwal M, Roth K, Yang Z, Sharma R, Maddipati K, Westrick J Environ Res. 2024; 250:118492.

PMID: 38373550 PMC: 11102846. DOI: 10.1016/j.envres.2024.118492.

Complex roles for sulfation in the toxicities of polychlorinated biphenyls.

Duffel M, Lehmler H Crit Rev Toxicol. 2024; 54(2):92-122.

PMID: 38363552 PMC: 11067068. DOI: 10.1080/10408444.2024.2311270.

Assessing proarrhythmic potential of environmental chemicals using a high throughput in vitro-in silico model with human induced pluripotent stem cell-derived cardiomyocytes.

Lin H, Rusyn I, Chiu W ALTEX. 2023; 41(1):37-49.

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Maternal polychlorinated biphenyl 126 (PCB 126) exposure modulates offspring gut microbiota irrespective of diet and exercise.

Agarwal M, Hoffman J, Ngo Tenlep S, Santarossa S, Pearson K, Sitarik A Reprod Toxicol. 2023; 118:108384.

PMID: 37061048 PMC: 10257154. DOI: 10.1016/j.reprotox.2023.108384.

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