Delineating toxicity mechanisms associated with MRI contrast enhancement through a multidimensional toxicogenomic profiling of gadolinium

Abstract

Although gadolinium is widely used for magnetic resonance imaging in clinical settings, many concerns regarding its toxicity and bioaccumulation after gadolinium-based contrast agent (GBCA) administration have been raised and published...

Identifying Toxicity Mechanisms Associated with Early Lanthanide Exposure through Multidimensional Genome-Wide Screening

“…These results agreed with the previous literature, which reported that heavy metals disrupt the biological functions of proteins and enzymes as well as the processes that these biomolecules regulate. 56 It is worth noting that these results are substantially different from what was observed and previously reported with later lanthanides for which a similar analysis was performed: neither europium 43 nor gadolinium 46 displayed such significant metal-induced toxicity even under the greater IC 10 exposure conditions at 15 generations.…”

“…These different times of exposure are commonly used in toxicogenomics because they allow determination of time-dependent responses and delayed onset effects. 40 , 41 Sensitive and resistant mutants to the metal treatments were identified by DSSA, 46 with their growth variations reported in the log 2 scale in Dataset S1 and the total number of mutants affected under each treatment plotted ( Figure 1 a). The growth of only a few mutants (between 1 and 40) was disturbed at low lanthanide concentrations (IC 5 ) or low exposure time (10 generations).…”

“…The La­(III) and Pr­(III) concentrations that resulted in 5% (IC 5 ) and 10% (IC 10 ) growth inhibition of the wild-type strain were determined (Table S1) as these concentrations allow identification of specific toxicological responses to chemicals rather than overall non-specific cytotoxic effects. , Next, a pool of 4291 homozygous diploid deletion strains were grown in the presence of IC 5 or IC 10 concentrations of La­(III) or Pr­(III) for 10 or 15 generations, yielding eight experimental conditions in total. These different times of exposure are commonly used in toxicogenomics because they allow determination of time-dependent responses and delayed onset effects. , Sensitive and resistant mutants to the metal treatments were identified by DSSA, with their growth variations reported in the log 2 scale in Dataset S1 and the total number of mutants affected under each treatment plotted (Figure a). The growth of only a few mutants (between 1 and 40) was disturbed at low lanthanide concentrations (IC 5 ) or low exposure time (10 generations).…”

“…It is worth noting that the results obtained by the genome-wide screening based on the automated liquid dispensing system built in-house had been previously validated via non-competitive assays. , For the validation tests, the growth of the strains with the largest log 2 ratio variations was compared under competitive and non-competitive conditions.…”

Development of radiopharmaceuticals for targeted alpha therapy: Where do we stand?

“…Free radioisotopes and metals, particularly f-block elements, have high binding affinities for biological receptors (30,31), resulting in their endogenous chelation and subsequent deposition in tissues (32,33). Internal contamination with radiometals (and their decay products) cause metal-and radiotoxicity, as multiple biological processes get disrupted (34)(35)(36)(37)(38)(39). Therefore, minimizing daughter release is a fundamental step to extend the use of targeted alpha therapy beyond metastatic non-responding patients (28).…”