1. The use of human induced pluripotent stem cells to screen for developmental toxicity potential indicates reduced potential for non-combusted products, when compared to cigarettes
- Author
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Fan Yu, Roman Wieczorek, Edgar Trelles Sticken, Matthew Stevenson, Kathryn Rudd, Lukasz Czekala, Fiona Chapman, Lisa Maria Bode, Liam Simms, Tanvir Walele, and Jessica Palmer
- Subjects
Health, Toxicology and Mutagenesis ,OECD, Organisation for Economic Co-operation and Development ,Developmental toxicity ,HTP, heated tobacco product ,Pharmacology ,Toxicology ,Applied Microbiology and Biotechnology ,Nicotine ,EVP, electronic vapour product ,chemistry.chemical_compound ,HPLC-DAD, high-performance liquid chromatography with a diode-array detector ,Induced pluripotent stem cell ,Cytotoxicity ,CDC, Centers for Disease Control and Prevention ,ISO, International Organization for Standardisation ,Human induced pluripotent stem cells ,Q-TOF, Quadrupole Time-of-Flight ,EPA, United States Environmental Protection Agency ,bPBS, bubbled phosphate buffered saline ,E-cigarettes ,TT21C, toxicity testing in the 21st century ,iPS cells, induced pluripotent stem cells ,COT, United Kingdom Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment ,medicine.drug ,DART, developmental and reproductive toxicity ,NICE, National Institute for Health and Care Excellence ,NHS, United Kingdom National Health Service ,FDR, false discovery rate ,ECVAM, European Center for the Validation of Alternative Methods ,nAChRs, nicotinic acetylcholine receptors ,Article ,ROS, reactive oxygen species ,PBS, phosphate buffered saline ,lcsh:RA1190-1270 ,medicine ,devTOXqP, devTOX quickPredict ,Viability assay ,HYB, hybrid product ,o/c, ornithine/cystine ratio ,e-cigarettes, electronic cigarettes ,lcsh:Toxicology. Poisons ,ComputingMethodologies_COMPUTERGRAPHICS ,Smoke ,LOQ, limit of quantification ,PG/VG, propylene glycol/vegetable glycerine ,Cigarettes ,TP, cell viability toxicity potential concentration ,CV, coefficient of variation ,UPLC-HRMS, ultra-high performance liquid chromatography coupled high resolution mass spectrometry ,DNPH, 2,4-dinitrophenylhydrazine ,Embryonic stem cell ,In vitro reproduction assay ,POD, point of difference ,chemistry ,HPHCs, Harmful and Potentially Harmful Constituents ,ISTD, internal standard ,dTP, developmental toxicity potential concentration ,ODC, ornithine decarboxylase ,ND, No effect was detected within the exposure range tested ,ATRA, All-trans-retinoic acid ,dTT, developmental toxicity threshold ,LC-MS/MS, liquid chromatography with tandem mass spectrometry ,Toxicant - Abstract
Graphical abstract, Highlights • Effective in vitro strategies are required to predict early developmental toxicity. • devTOXqP is a metabolomics biomarker assay using iPSCs. • Sample smoke/aerosol captured in bPBS, was tested up to 10% concentration. • Cigarettes & HTP bPBS extracts were predicted as potentially developmentally toxic. • HYB & EVP aerosols were not predicted as having developmentally toxic potential in devTOXqP., devTOX quickPredict (devTOXqP) is a metabolomics biomarker-based assay that utilises human induced pluripotent stem (iPS) cells to screen for potential early stage embryonic developmental toxicity in vitro. Developmental toxicity potential is assessed based on the assay endpoint of the alteration in the ratio of key unrelated biomarkers, ornithine and cystine (o/c). This work aimed to compare the developmental toxicity potential of tobacco-containing and tobacco-free non-combustible nicotine products to cigarette smoke. Smoke and aerosol from test articles were produced using a Vitrocell VC10 smoke/aerosol exposure system and bubbled into phosphate buffered saline (bPBS). iPS cells were exposed to concentrations of up to 10% bPBS. Assay sensitivity was assessed through a spiking study with a known developmental toxicant, all-trans-retinoic acid (ATRA), in combination with cigarette smoke extract. The bPBS extracts of reference cigarettes (1R6F and 3R4F) and a heated tobacco product (HTP) were predicted to have the potential to induce developmental toxicity, in this screening assay. The bPBS concentration at which these extracts exceeded the developmental toxicity threshold was 0.6% (1R6F), 1.3% (3R4F), and 4.3% (HTP) added to the cell media. Effects from cigarette smoke and HTP aerosol were driven largely by cytotoxicity, with the cell viability and o/c ratio dose–response curves crossing the developmental toxicity thresholds at very similar concentrations of added bPBS. The hybrid product and all the electronic cigarette (e-cigarette) aerosols were not predicted to be potential early developmental toxicants, under the conditions of this screening assay.
- Published
- 2020