4.5 Article

Potential toxicity evaluation and comparison within multiple mice organs after repeat injections of linear versus macrocyclic gadolinium-based contrast agents: A comprehensive and time course study

Journal

TOXICOLOGY LETTERS
Volume 350, Issue -, Pages 152-161

Publisher

ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2021.07.016

Keywords

Gadolinium-based contrast agents; Multiple-organ; tissue; Toxicity evaluation; Time course

Categories

Funding

  1. China International Medical Foundation [Z-2014-07-1912-24]

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The study found that exposure to gadolinium-based contrast agents may cause adverse effects including changes in renal tubular epithelial cells, skin lesions, abnormal pain sensation, and elevated white blood cell levels. Different types of GBCAs showed varying rates of accumulation and regression in multi-organ/tissue toxicity evaluation.
As nephrogenic systemic fibrosis (NSF) and increased signal intensities in deep cerebellar nuclei (DCN) were successively discovered in renal insufficiency patients and healthy persons after gadolinium-based contrast agents (GBCAs) exposure, an awareness of potential toxicity with GBCAs exposure has been heightening. Herein, we performed a multi-organ/tissue toxicity assessment after different GBCAs administration with a large number of samples, and long-term, time-course schedule investigation. ICR mice were randomized to five exposure groups (n = 42/group) and received intravenous injection of GBCAs (2.5 mmol Gd/kg) or saline four time a week for 5 consecutive weeks. Gadolinium concentration detection, sensory tests, histological and hematological analyses were performed at corresponding timepoints (4th or 6th or 10th week). Our results showed that (i) gadodiamide could cause reversible vacuolar changes in the renal tubular epithelial cells, which appeared at 6th week and recovered at 10th week, and severe skin lesion in mice tail with consecutive injection for 10 weeks, that (ii) linear GBCAs (gadodiamide and gadopentetate dimeglumine) markedly elevated heat hyperalgesia and white blood cells of mice at 6th week and most of these changes could recovery at 10th week, and that (iii) linear GBCAs exhibited more gadolinium retention in multi-organ/tissue versus macrocyclic GBCAs and in most case, linear GBCAs showed faster accumulation and regression speed in examined tissues than macrocyclic GBCAs excepting gadodiamide in skin which showed slowest regression speed. Collectively, macrocyclic GBCAs presents more stable, lower propensity to release Gd and safer profiles versus linear GBCAs. (c) 2021 Elsevier B.V. All rights reserved.

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