FutureTox: Building the Road for 21st Century Toxicology and Risk Assessment Practices

Rowlands, J. Craig; Sander, Miriam; Bus, James S.

doi:10.1093/toxsci/kft252

Cited by 41 publications

(18 citation statements)

References 20 publications

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“…The liver is highly vascularized, delivering oxygen at high rates while protecting hepatocytes from the negative effects of shear (14,15). The gradients that develop along the sinusoid induce a demarcation of function, termed metabolic zonation.…”

Section: Resultsmentioning

confidence: 99%

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Bavli

Prill

Tsur

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

250

292

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Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liveron-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology.microfluidics | liver tissue engineering | toxicology | organ-on-a-chip

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Section: Resultsmentioning

confidence: 99%

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Bavli

Prill

Tsur

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

250

292

View full text Add to dashboard Cite

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“…The NRC issued a report, ''Toxicity Testing in the 21st Century: A Vision and a Strategy,'' which provided a strategy for incorporating cell lines and human cells in concert with high-throughput screening of toxicity pathways into routine toxicity testing to evaluate the health risks of potentially toxic chemicals. [1][2][3][4][5][6][7] Similarly, the Institute of Medicine report on guidance for testing modified risk tobacco products (MRTPs) suggests that molecular and toxicological tools can be used to assess the impact of smoke on inflammation, oxidative stress, and DNA damage, as well as other cellular and molecular changes. Such molecular changes are proposed to be the hallmark of disease mechanisms and may provide biomarkers to assess the effect/harm of various exposures, including tobacco product-related exposures.…”

Section: Introductionmentioning

confidence: 99%

Characterization and Application of the VITROCELL VC1 Smoke Exposure System and 3D EpiAirway Models for Toxicological and e-Cigarette Evaluations

FieldsWanda

MaioneAnna

KeyserBrian

et al. 2017

Applied In Vitro Toxicology

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The VITROCELL VC1 Ò smoke exposure machine is an aerosol exposure system that has been used to conduct toxicological assessments with cigarettes and e-cigarettes and can be used with the human 3D EpiAirwayÔ tissue model (MatTek Corporation). The goals of this study were to assess exposure parameters of the VC1, and evaluate donor-to-donor variability of three EpiAirway tissue donors with the following endpoints: viability, barrier integrity, and gene promoter/expression regulation. Additionally, we applied the EpiAirway model to assess the effects of aerosol from two reference combustible cigarettes and two e-cigarettes. Whole smoke (WS) exposures with Kentucky Reference 3R4F cigarettes and Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) Monitor were conducted under International Organization for Standardization or Health Canada Intense (HCI) conditions, and e-cigarette exposures were conducted under modified HCI conditions. Particulate deposition and collection were consistent across independent assessments. A decrease in barrier function was accompanied with a dose-dependent decrease in viability for all donors. IC 50 values were reproducible (coefficient of variations, CVs <20%) for all donors with both assays. Under HCI conditions, tissue viability and barrier integrity declined rapidly following 3R4F exposures, while no decline in either endpoint was observed with either e-cigarette. Increases in nuclear factor erythroid 2-related factor 2 (Nrf2) promoter activation through the antioxidant response element and gene expression associated with oxidative stress, inflammation, and metabolism were observed following 3R4F WS exposures, and the Nrf2 promoter was differentially regulated by 3R4F WS compared with gas-vapor-phase exposures. No activation in the Nrf2 promoter was observed for e-cigarette exposures. Collectively, the consistency of the VC1 system and EpiAirway model supports the use of these systems in respiratory toxicological assessments. Furthermore, these systems effectively discriminate the toxic impact of smoke from a combustible cigarette on cell viability and oxidative stress while showing no impact of e-cigarettes in these experiments.

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“…During the last years, the need for large-scale tools in risk assessment of chemicals has been increasingly recognized (Rowlands et al 2014 ; Thomas et al 2013 ). Particularly, chemical carcinogens give rise to major concern.…”

Section: Introductionmentioning

confidence: 99%

Use of high-throughput RT-qPCR to assess modulations of gene expression profiles related to genomic stability and interactions by cadmium

et al. 2015

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Predictive test systems to assess the mode of action of chemical carcinogens are urgently required. Within the present study, we applied the Fluidigm dynamic array on the BioMark™ HD System for quantitative high-throughput RT-qPCR analysis of 95 genes and 96 samples in parallel, selecting genes crucial for maintaining genomic stability, including stress response as well as DNA repair, cell cycle control, apoptosis and mitotic signaling. The specificity of each individually designed sequence-specific primer pair and their respective target amplicons were evaluated via melting curve analysis as part of qPCR and size verification via agarose gel electrophoresis. For each gene, calibration curves displayed high efficiencies and correlation coefficients in the identified linear dynamic range as well as low intra-assay variations. Data were processed via Fluidigm real-time PCR analysis and GenEx software, and results were depicted as relative gene expression according to the ΔΔC q method. Subsequently, gene expression analyses were conducted in cadmium-treated adenocarcinoma A549 and epithelial bronchial BEAS-2B cells. They revealed distinct dose- and time-dependent and also cell-type-specific gene expression patterns, including the induction of genes coding for metallothioneins, the oxidative stress response, cell cycle control, mitotic signaling and apoptosis. Interestingly, while genes coding for the DNA damage response were induced, distinct DNA repair genes were down-regulated at the transcriptional level. Thus, this approach provided a comprehensive overview on the interaction by cadmium with distinct signaling pathways, also reflecting molecular modes of action in cadmium-induced carcinogenicity. Therefore, the test system appears to be a promising tool for toxicological risk assessment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1621-7) contains supplementary material, which is available to authorized users.

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FutureTox: Building the Road for 21st Century Toxicology and Risk Assessment Practices

Cited by 41 publications

References 20 publications

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Characterization and Application of the VITROCELL VC1 Smoke Exposure System and 3D EpiAirway Models for Toxicological and e-Cigarette Evaluations

Use of high-throughput RT-qPCR to assess modulations of gene expression profiles related to genomic stability and interactions by cadmium

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