Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites
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.
| Errataetall: |
CommentIn: Environ Health Perspect. 2020 Nov;128(11):114003. - PMID 33200950 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:128 |
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| Enthalten in: |
Environmental health perspectives - 128(2020), 7 vom: 02. Juli, Seite 77008 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Grimm, Fabian A [VerfasserIn] |
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| Links: |
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| Themen: |
DFC2HB4I0K |
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| Anmerkungen: |
Date Completed 09.12.2020 Date Revised 27.01.2021 published: Print-Electronic CommentIn: Environ Health Perspect. 2020 Nov;128(11):114003. - PMID 33200950 Citation Status MEDLINE |
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| doi: |
10.1289/EHP7030 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM312771347 |
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| 500 | |a CommentIn: Environ Health Perspect. 2020 Nov;128(11):114003. - PMID 33200950 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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| 650 | 7 | |a Polychlorinated Biphenyls |2 NLM | |
| 650 | 7 | |a DFC2HB4I0K |2 NLM | |
| 700 | 1 | |a Klaren, William D |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xueshu |e verfasserin |4 aut | |
| 700 | 1 | |a Lehmler, Hans-Joachim |e verfasserin |4 aut | |
| 700 | 1 | |a Karmakar, Moumita |e verfasserin |4 aut | |
| 700 | 1 | |a Robertson, Larry W |e verfasserin |4 aut | |
| 700 | 1 | |a Chiu, Weihsueh A |e verfasserin |4 aut | |
| 700 | 1 | |a Rusyn, Ivan |e verfasserin |4 aut | |
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