Bioactivation of trichloroethylene to three regioisomeric glutathione conjugates by liver fractions and recombinant human glutathione transferases: Species differences and implications for human risk assessment

Capinha, Liliana; Jennings, Paul; Commandeur, Jan N. M.

doi:10.1016/j.toxlet.2021.01.021

Cited by 9 publications

(7 citation statements)

References 39 publications

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“…The synthesis, purification and characterization of the used regioisomers of GSH S-conjugates (1,2-DCVG, 2,2-DCVG) and cysteine S-conjugates (1,2-DCVC, 2,2-DCVC) are described in detail in our recent study (Capinha et al 2021 ). Each laboratory involved in this study received crystals from the same batches of the four regioisomers (purity > 98% based on HPLC-analysis).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we demonstrated that 2,2-DCVG was the major GSH-conjugate formed in incubations of TCE with human liver fractions (Capinha et al 2021). Therefore, a contribution of the 2,2-regioisomers to adverse effects in human tissues should be considered.…”

Section: Comparison Of Effects Of Regioisomers Of Dcvc and Dcvgmentioning

confidence: 99%

“…Biotransformation of TCE occurs mainly by oxidation by hepatic cytochrome P450s and, to lesser extent, via GSH-conjugation, also known as mercapturic acid pathway. GSH conjugation of TCE by human glutathione-S-transferases (GSTs) can lead to the formation of three regioisomeric GSH products (Capinha et al 2021 ). Two regioisomers S-(1,2- trans -dichlorovinyl)-glutathione (1,2-DCVG) and S-(2,2-dichlorovinyl)-glutathione (2,2-DCVG) appeared to be the major regioisomers formed by human hepatic GSTs (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Most of the mechanistic in vitro studies regarding the cytotoxicity of the S-conjugates of TCE have been focused on 1,2-DCVC and to lesser extent on its corresponding GSH-conjugate 1,2-DCVG. However, a recent study has demonstrated that 2,2-DCVG is the major GSH-conjugate formed in incubations of TCE with human liver fractions, formed at seven fold higher amounts than 1,2-DCVG (Capinha et al 2021 ). In contrast to 1,2-DCVG, 2,2-DCVG has not yet been tested in in vitro studies.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models

Capinha

Zhang²,

Holzer³

et al. 2022

Arch Toxicol

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Environmental or occupational exposure of humans to trichloroethylene (TCE) has been associated with different extrahepatic toxic effects, including nephrotoxicity and neurotoxicity. Bioactivation of TCE via the glutathione (GSH) conjugation pathway has been proposed as underlying mechanism, although only few mechanistic studies have used cell models of human origin. In this study, six human derived cell models were evaluated as in vitro models representing potential target tissues of TCE-conjugates: RPTEC/TERT1 (kidney), HepaRG (liver), HUVEC/TERT2 (vascular endothelial), LUHMES (neuronal, dopaminergic), human induced pluripotent stem cells (hiPSC) derived peripheral neurons (UKN5) and hiPSC-derived differentiated brain cortical cultures containing all subtypes of neurons and astrocytes (BCC42). A high throughput transcriptomic screening, utilizing mRNA templated oligo-sequencing (TempO-Seq), was used to study transcriptomic effects after exposure to TCE-conjugates. Cells were exposed to a wide range of concentrations of S-(1,2-trans-dichlorovinyl)glutathione (1,2-DCVG), S-(1,2-trans-dichlorovinyl)-L-cysteine (1,2-DCVC), S-(2,2-dichlorovinyl)glutathione (2,2-DCVG), and S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCVC). 1,2-DCVC caused stress responses belonging to the Nrf2 pathway and Unfolded protein response in all the tested models but to different extents. The renal model was the most sensitive model to both 1,2-DCVC and 1,2-DCVG, with an early Nrf2-response at 3 µM and hundreds of differentially expressed genes at higher concentrations. Exposure to 2,2-DCVG and 2,2-DCVC also resulted in the upregulation of Nrf2 pathway genes in RPTEC/TERT1 although at higher concentrations. Of the three neuronal models, both the LUHMES and BCC42 showed significant Nrf2-responses and at higher concentration UPR-responses, supporting recent hypotheses that 1,2-DCVC may be involved in neurotoxic effects of TCE. The cell models with the highest expression of γ-glutamyltransferase (GGT) enzymes, showed cellular responses to both 1,2-DCVG and 1,2-DCVC. Little to no effects were found in the neuronal models from 1,2-DCVG exposure due to their low GGT-expression. This study expands our knowledge on tissue specificity of TCE S-conjugates and emphasizes the value of human cell models together with transcriptomics for such mechanistic studies.

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Section: Methodsmentioning

confidence: 99%

Section: Comparison Of Effects Of Regioisomers Of Dcvc and Dcvgmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models

Capinha

Zhang²,

Holzer³

et al. 2022

Arch Toxicol

Self Cite

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“…On the contrary, several in vitro studies have been performed to validate the carcinogenic initiation and promotional effects of power‐frequency MFs based on existing mechanisms; however, data supporting the correlation between MFs and childhood leukemia provided by epidemiological studies are limited [SCENIHR, 2015 ]. It is known that in various aspects, from gene expression pattern to sensitivity, cells exhibit differences in inter‐biological and cellular species and their stage of differentiation [Doseth et al, 2011 ; Ichii et al, 2014 ; Capinha et al, 2021 ; Luo et al, 2021 ; Magee and Signer, 2021 ], and it is considered that evaluation focused on the human hematopoietic system is important in in vitro risk assessment of childhood leukemia. Although human hematopoietic stem cells and lineage‐committed progenitors are specifically the most suitable subjects, the difficulty in the acquisition and handling of these cells prevents their application in the risk assessment of MFs.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Effects of Exposure to Power‐Frequency Magnetic Fields on the Differentiation of Hematopoietic Stem/Progenitor Cells Using Human‐Induced Pluripotent Stem Cells

Takahashi

Furuya²

2022

Bioelectromagnetics

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The causal association between exposure to power‐frequency magnetic fields (MFs) and childhood leukemia has been under discussion. Although evidence from experimental studies is required for a conclusion to be reached, only a few studies have focused on the effects of MF exposure on the human hematopoietic system directly related to leukemogenesis. Here, we established an in vitro protocol to simulate the differentiation of human mesodermal cells to hematopoietic stem progenitor cells (HSPCs) using human‐induced pluripotent stem cells. Furthermore, we introduced MF in the protocol to study the effects of exposure. After a continuous exposure to 0–300 mT of 50‐Hz MFs during the differentiation process, the efficiency of differentiation of mesodermal cells into HSPCs was analyzed in a single‐blinded manner. The percentage of emerged HSPCs from mesodermal cells in groups exposed to 50‐Hz MFs indicated a lack of significant changes compared with those in the sham‐exposed group. These results suggest that exposure to 50‐Hz MFs up to 300 mT does not affect the differentiation of human mesodermal cells to HSPCs, which may be involved in the initial process of leukemogenesis. © 2022 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.

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G × E interactions as a basis for toxicological uncertainty

et al. 2023

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To transfer toxicological findings from model systems, e.g. animals, to humans, standardized safety factors are applied to account for intra-species and inter-species variabilities. An alternative approach would be to measure and model the actual compound-specific uncertainties. This biological concept assumes that all observed toxicities depend not only on the exposure situation (environment = E), but also on the genetic (G) background of the model (G × E). As a quantitative discipline, toxicology needs to move beyond merely qualitative G × E concepts. Research programs are required that determine the major biological variabilities affecting toxicity and categorize their relative weights and contributions. In a complementary approach, detailed case studies need to explore the role of genetic backgrounds in the adverse effects of defined chemicals. In addition, current understanding of the selection and propagation of adverse outcome pathways (AOP) in different biological environments is very limited. To improve understanding, a particular focus is required on modulatory and counter-regulatory steps. For quantitative approaches to address uncertainties, the concept of “genetic” influence needs a more precise definition. What is usually meant by this term in the context of G × E are the protein functions encoded by the genes. Besides the gene sequence, the regulation of the gene expression and function should also be accounted for. The widened concept of past and present “gene expression” influences is summarized here as Ge. Also, the concept of “environment” needs some re-consideration in situations where exposure timing (Et) is pivotal: prolonged or repeated exposure to the insult (chemical, physical, life style) affects Ge. This implies that it changes the model system. The interaction of Ge with Et might be denoted as Ge × Et. We provide here general explanations and specific examples for this concept and show how it could be applied in the context of New Approach Methodologies (NAM).

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Bioactivation of trichloroethylene to three regioisomeric glutathione conjugates by liver fractions and recombinant human glutathione transferases: Species differences and implications for human risk assessment

Cited by 9 publications

References 39 publications

Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models

Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models

Evaluation of the Effects of Exposure to Power‐Frequency Magnetic Fields on the Differentiation of Hematopoietic Stem/Progenitor Cells Using Human‐Induced Pluripotent Stem Cells

G × E interactions as a basis for toxicological uncertainty

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