Role of calcium ion channels and cytoskeletal proteins in Thorium-232 induced toxicity in normal human liver cells (WRL 68) and its validation in swiss mice


Posted: 2021-10-15 19:00:00
Chemosphere . 2021 Oct 12;132557. doi: 10.1016/j.chemosphere.2021.132557. Online ahead of print. Affiliations Expand Affiliations 1 Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India. 2 Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India. 3 Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India. Electronic address: amitk@barc.gov.in. Item in Clipboard Rakhee Yadav et al. Chemosphere. 2021. Show details Display options Display options Format Chemosphere . 2021 Oct 12;132557. doi: 10.1016/j.chemosphere.2021.132557. Online ahead of print. Affiliations 1 Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India. 2 Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India. 3 Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, India. Electronic address: amitk@barc.gov.in. Item in Clipboard CiteDisplay options Display options Format Abstract Hepatic disorders reported in humans exposed to Thorium-232 (Th-232) rationalizes the present study investigating the toxicological response of normal human liver cells (WRL 68) and its validation in Swiss mice. Cell count analysis of WRL 68 cells-treated with Th-nitrate (1-200 μM) estimated IC50 of ∼24 μM (at 24 h) and 35 μM (at 48 h). Analysis of cell viability (trypan blue assay) showed the IC50 of ∼172 μM. Phase contrast bright-field microscopy revealed Th-induced morphological changes and cell-released microvesicle-like structures in extracellular space. Th-estimation by ICP-MS (Inductively-coupled plasma mass-spectrometry) showed uptake of Th by cells as a function of concentration and incubation time. Employing DTPA as a chelating agent in cell harvesting solution, cell-internalized/strongly-bound Th was estimated to be ∼42% of total incubated Th. Th-uptake studies in the presence of ion-channel specific inhibitors (e.g. nifedipine, thapsigargin) revealed the role of plasma membrane calcium channels and cytoplasmic calcium in modulating the Th-uptake. Transmission electron microscopy of Th-treated cells showed cell-derived extracellular vesicles, alterations in the shape and size of nucleus and mitochondria as well as cytoplasmic inclusions. The order of Th accumulation in various sub-cellular protein fractions was found to be as cytoskeleton (43%) > cytoplasmic (15%) > chromatin (7%) > nuclear (5%) & membrane (5%). Immunofluorescence analysis of WRL 68 cells showed that Th significantly altered the expression of cytoskeleton proteins (F-actin and keratin), which was further validated in liver tissues of Swiss mice administered with Th-232. Findings herein highlight the role of calcium channels and cytoskeleton in Th-induced toxicity. Keywords: Thorium toxicity; Liver cells; Calcium channels; Sub-cellular targets, Cytoskeleton; Swiss Mice. Keywords: Calcium channels; Cytoskeleton; Liver cells; Sub-cellular targets; Swiss mice; Thorium toxicity. Copyright © 2021. Published by Elsevier Ltd. Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. [x] Cite Copy Format: Send To [x]

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