Assessing teratogenic risks of gadolinium in freshwater environments: Implications for environmental health.

Gadolinium (Gd) is among the rare earth elements extensively utilized in both industrial and medical applications. The latter application appears to contribute to the rise in Gd levels in aquatic ecosystems, as it is excreted via urine from patients undergoing MRI scans and often not captured by wastewater treatment systems. The potential environmental and biological hazards posed by gadolinium exposure are still under investigation. This study aimed to assess the teratogenic risk posed by a gadolinium chelate on the freshwater cnidarian Hydra vulgaris. The experimental design evaluated the impact of pure Gadodiamide (25 µg/l, 50 µg/l, 100 µg/l, 500 µg/l) and its commercial counterpart compound (Omniscan®; 100 µg/l, 500 µg/l, 782.7 mg/l) at varying concentrations using the Teratogenic Risk Index (TRI). Here we showed a moderate risk (Class III of TRI) following exposure to both tested formulations at concentrations ≥ 100 µg/l. Given the potential for similar concentrations in aquatic environments, particularly near wastewater discharge points, a teratogenic risk assessment using the Hydra regeneration assay was conducted on environmental samples collected from three rivers (Tiber, Almone, and Sacco) in Central Italy. Additionally, chemical analysis of field samples was performed using ICP-MS. Analysis of freshwater samples revealed low Gd concentrations (≤ 0.1 µg/l), despite localized increases near domestic and/or industrial wastewater discharge sites. Although teratogenic risk in environmental samples ranged from high (Class IV of TRI) to negligible (Class I of TRI), the low Gd concentrations, particularly when compared to higher levels of other contaminants like arsenic and heavy metals, preclude establishing a direct cause-effect relationship between Gd and observed teratogenic risks in environmental samples. Nevertheless, the teratogenic risks observed in laboratory tests warrant further investigation.

Toxicity Mechanisms of Gadolinium and Gadolinium-Based Contrast Agents-A Review.

Gadolinium-based contrast agents (GBCAs) have been used for more than 30 years to improve magnetic resonance imaging, a crucial tool for medical diagnosis and treatment monitoring across multiple clinical settings. Studies have shown that exposure to GBCAs is associated with gadolinium release and tissue deposition that may cause short- and long-term toxicity in several organs, including the kidney, the main excretion organ of most GBCAs. Considering the increasing prevalence of chronic kidney disease worldwide and that most of the complications following GBCA exposure are associated with renal dysfunction, the mechanisms underlying GBCA toxicity, especially renal toxicity, are particularly important. A better understanding of the gadolinium mechanisms of toxicity may contribute to clarify the safety and/or potential risks associated with the use of GBCAs. In this work, a review of the recent literature concerning gadolinium and GBCA mechanisms of toxicity was performed.

Comparison of the biological effects of gadodiamide (Omniscan) and gadoteridol (ProHance) by means of multi-organ and plasma metabolomics.

Gadolinium-based contrast agents (GBCAs) are massively employed in radiology to increase the diagnostic power of MRI. However, investigations aiming at detecting possible metabolic perturbations or adverse health effects due to gadolinium deposition are still lacking. In this work, aqueous organs extract and plasma samples were analyzed by GC-MS and 1H-NMR, respectively, to investigate the effects of multiple administrations of one linear (Omniscan) and one macrocyclic (ProHance) GBCA, on the main metabolic pathways in healthy mice. Multivariate analysis revealed that plasma metabolome was not differently perturbed by the two GBCAs, while, the multiorgan analysis displayed a clear separation of the Omniscan-treated from the control and the ProHance-treated groups. Interestingly, the most affected organs were the brain, cerebellum and liver. Thus, this work paves the way to both the safest use of the commercially available GBCAs and the development of new GBCAs characterized by lower general toxicity.

Cellular toxicities of gadolinium-based contrast agents used in magnetic resonance imaging.

Contrast agents have been used in magnetic resonance imaging (MRI) as a radiological method. Gadolinium-based contrast agents (GBCAs), because of their paramagnetic characteristics, are the ones mostly used in MRI to increase signal intensity. However, the use of contrast media has raised concerns on cellular toxic risks of these agents. Studies showed the accumulation of gadolinium after injection to humans with or without renal impairment. Also, there are findings obtained under in vitro and/or in vivo conditions that revealed conflicting results for their cytotoxic and genotoxic effects. Some of them declared damage in cells and genetic material; some others did not. Abnormal cell growth and genetic aberration are critical because they may lead to carcinogenesis in somatic cells or may be transferred to the next generations through germ cells. Therefore, understanding the effect of GBCAs on cells is important for their safer usage in clinical administrations to generate high-quality contrast-enhanced magnetic resonance images. Because of all these reasons, cellular toxicities-mainly genotoxic and cytotoxic effects-of GBCAs were reviewed in this paper.

Potential Ecological Risk Assessment of Critical Raw Materials: Gallium, Gadolinium, and Germanium.

In recent years, the demand for critical raw materials such as gallium, gadolinium and germanium (G(s)) has steadily increased in various industries. However, treatment or recycling rates of these elements are extremely low, which can lead to environmental pollution. An assessment of the ecological risks was also not possible until now, as there were no calculated toxicity coefficients for G(s). In this study, a well-known method, the so-called potential ecological risk index (PERI), was used for the first time to calculate the toxicity coefficients of these elements using data from recent literature studies on G(s) elements. The toxicity coefficient of each of the three elements was determined as five (5). The results show that G(s) have the same toxicity coefficient as Cu and Pb and are higher than that of Cr. The ecological risk index results varied from 4 to 414, 0.98 to 25.98 and 2.50 to 284.64 for Ga, Gd and Ge, respectively. The results show that Ga and Ge pose high ecological risk while the Eri of Gd is low. The toxicity coefficients of these elements have been calculated for the first time in the literature and provide a practical use for calculating the potential ecological risk index.

In Vivo and In Vitro Analysis of Toxicity of a Prospective Magnetic Resonance Contrast Agent Based on Arabinogalactan and Gadolinium Nanocomposite.

We studied the cytotoxic effect of gadolinium nanocomposite on cultured mouse fibroblasts 3T3-SV40 and histological changes in the liver tissue of albino rats after its administration. For in vitro experiment, gadolinium nanocomposite on the natural matrix of arabinogalactan (nGd-AG) was dissolved in DMEM nutrient medium to concentrations of 0.005, 0.02, 0.5, 2, and 5 mM. In in vivo experiment, a nGd-AG solution was orally administered to rats through a tube in a dose of 500 µg Gd/kg in 1 ml of 0.9% NaCl for 10 days. The pattern and degree of influence of the gadolinium nanocomposite on the studied cell culture depended on the concentration and duration of exposure. IC50 of nGd-AG determined after cell incubation for 24, 48, and 72 h were 616 µg/kg (3.9 mM), 302 µg/kg (1.9 mM), and 222 µg/kg (1.4 mM), respectively. Histological changes in the liver of white rats induced by exposure to nanocomposite attested to the development of a compensatory reaction of the organ.

Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration.

Gadolinium-based contrast agents (GBCAs) have transformed magnetic resonance imaging (MRI) by facilitating the use of contrast-enhanced MRI to allow vital clinical diagnosis in a plethora of disease that would otherwise remain undetected. Although over 500 million doses have been administered worldwide, scientific research has documented the retention of gadolinium in tissues, long after exposure, and the discovery of a GBCA-associated disease termed nephrogenic systemic fibrosis, found in patients with impaired renal function. An understanding of the pharmacokinetics in humans and animals alike are pivotal to the understanding of the distribution and excretion of gadolinium and GBCAs, and ultimately their potential retention. This has been well studied in humans and more so in animals, and recently there has been a particular focus on potential toxicities associated with multiple GBCA administration. The purpose of this review is to highlight what is currently known in the literature regarding the pharmacokinetics of gadolinium in humans and animals, and any toxicity associated with GBCA use.

Gadolinium Accumulation and Toxicity on In Vitro Grown Stevia rebaudiana: A Case-Study on Gadobutrol.

Gadolinium-based contrast agents are molecular complexes which are extensively used for diagnostic purposes. Apart from their tremendous contribution to disease diagnostics, there are several issues related to their use. They are extremely stable complexes and potential contaminants of surface and ground waters, an issue which is documented worldwide. The irrigation of fields with contaminated surface waters or their fertilization with sludge from wastewater treatment plants can lead to the introduction of Gd into the human food supply chain. Thus, this study focused on the potential toxicity of Gd on plants. For this purpose, we have studied the molecular effects of gadobutrol (a well-known MRI contrast agent) exposure on in vitro-grown Stevia rebaudiana. The effects of gadobutrol on plant morphology, on relevant plant metabolites such as chlorophylls, carotenoids, ascorbic acids (HPLC), minerals (ICP-OES), and on the generation of free radical species (MDA assay and EPR) were assessed. Exposures of 0.01, 0.05, 0.1, 1, and 3 mM gadobutrol were used. We found a correlation between the gadobutrol dose and the plant growth and concentration of metabolites. Above the 0.1. mM dose of gadobutrol, the toxic effects of Gd+3 ions became significant.

Evaluation of toxicity of gadolinium-based contrast agents on neuronal cells.

BACKGROUND: Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI). Recently, increased signal intensity has been reported in specific brain areas after repeated administrations of GBCAs. PURPOSE: To investigate the toxic effects of GBCAs on neuronal cells by using SH-SY5Y neuroblastoma cell cultures. MATERIAL AND METHODS: For toxicity assays, SH-SY5Y cells were incubated with different doses (0-1000 µM) of several macrocyclic (gadoterate meglumine and gadobutrol) and linear GBCAs (gadoversetamide, gadopentetate dimeglumine, gadodiamide, and gadoxetate disodium) for 48 h. Cell viability and proliferation capacity were evaluated by using MTS assay, LDH assay, and colony-forming assay. In addition, Western blotting of Bcl-2 and Bax proteins and nuclear Hoechst 33258 staining were performed to evaluate apoptotic cell death. The results were expressed as mean ± SEM. The data were analyzed using Student's t-test. A P value < 0.05 was accepted as statistically significant. RESULTS: Both macrocyclic and linear GBCAs significantly and dose-dependently reduced cell viability in neuronal cells compared to control. Cell viability was measured between 89.5% ± 4% and 61% ± 0.7% in GBCA-treated groups. In addition, neurotoxicity was more prominent in linear GBCA-treated cultures (P < 0.0005). Bax protein levels were increased in GBCA-treated cells particularly with linear agents whereas Bcl-2 expression was decreased concomitantly. CONCLUSION: The results of the present study indicated that exposure to specific GBCAs, even at low micro-molar concentrations, may have detrimental effects on neuronal survival. Further investigations are required to clarify the molecular mechanism underlying GBCA-induced cell death.

The exposure of gadolinium at environmental relevant levels induced genotoxic effects in Arabidopsis thaliana (L.).

Rare Earth Elements (REEs) are increasingly being used in agriculture and are also used to produce high end technological devices, thereby increasing their anthropogenic presence in the environment. However, the ecotoxicological mechanism of REEs on organisms is not fully understood. In this study, the effects of gadolinium (Gd) addition on Arabidopsis thaliana (L.) were investigated at both physiological and molecular levels. Four treatments (0, 10, 50 and 200 µmol·L-1 Gd) were used in the exposure tests. Biomass, root length and chlorophyll content in shoots/roots were measured to investigate the plant's physiological response to Gd stress. Random amplified polymorphic (RAPD)-Polymerase Chain Reaction (PCR) and methylation sensitive arbitrarily primed (MSAP)-PCR were used to investigate changes in genetic variation and DNA methylation of A. thaliana when exposed to Gd. At the physiological level, it was found that low concentration of Gd (10 µmol·L-1) could significantly increase the plant biomass and root length, while the growth of A. thaliana was significantly inhibited when exposed to 200 µmol·L-1 of Gd, yet the total soluble protein content in aerial plant parts increased significantly by 24.2% when compared to the control group. Among the 12 primers considered in the RAPD assessment, at the molecular level, only four primers revealed different patterns in their genomic DNA. Compared to the control group, the treatment with 50 µmol·L-1 of Gd was associated with lower polymorphism, while the treatment with 200 µmol·L-1 of Gd was associated with higher polymorphism. The polymorphism frequencies for the 50 µmol·L-1 of Gd and the 200 µmol·L-1 of Gd were 4.67% and 20.33%, respectively. The MSAP analysis revealed that the demethylation (D) type of Arabidopsis genomic DNA increased significantly under 10 and 50 µmol·L-1 of Gd, while the methylation (M) type was also significantly increased under 200 µmol·L-1 of Gd. Generally, the total methylation polymorphism (D+M) increased with an increase of Gd concentration. It was found that high concentrations of Gd appeared to cause DNA damage, but low concentrations of Gd (as low as 10 µmol·L-1) were associated with DNA methylation change. Further, it was verified by Real time Reverse Transcription PCR (RT-PCR) on the bands detected by the MSAP analysis, that the genes relative to processes including cell cycle, oxidative stress and apoptosis, appeared to be regulated by methylation under Gd stress. These findings reveal new insight regarding ecotoxicity mechanisms of REEs on plants.

Significant contribution of autophagy in mitigating cytotoxicity of gadolinium ions.

Gadolinium-based contrast agents (GBCAs) are widely used in clinical magnetic resonance imaging (MRI). Free gadolinium ions (Gd3+) released from GBCAs potentially increase the risk of GBCA-related toxicity. However, the cellular responses to Gd3+ and the underlying mechanisms responsible for protection against Gd3+ remain poorly understood. Recently, autophagy has been considered a cell survival mechanism against various toxic metals. Here, we investigated the relationship between Gd3+ and autophagy, as well as the effect of autophagy inhibition on the survival of cells exposed to Gd3+. We found that the increased expression of microtubule-associated protein 1 light chain 3 (LC3)-II, a marker protein of autophagy, in Gd3+-exposed human embryonic kidney 293 (HEK293) cells. Moreover, we found a greater accumulation of LC3-II after exposure to an autophagy inhibitor, chloroquine (CQ), combined with Gd3+ than that after exposure to CQ alone, suggesting that Gd3+ activated autophagy in HEK293 cells. Furthermore, we found that Gd3+ reduced cell viability, which was more pronounced after CQ treatment. Our findings indicated that autophagy exerted a cytoprotective effect against Gd3+ toxicity, suggesting a potential link between autophagy and GBCA-associated adverse events.

Highly Stable Lanthanide Metal-Organic Framework as an Internal Calibrated Luminescent Sensor for Glutamic Acid, a Neuropathy Biomarker.

Glutamic acid (Glu) is the most abundant excitatory neurotransmitter in the central nervous system, and an elevated level of Glu may indicate some neuropathological diseases. Herein, three isomorphic microporous lanthanide metal-organic frameworks (MOFs) [(CH3)2NH2]2[Ln6(µ3-OH)8(BDC-OH)6(H2O)6]·(solv)x (ZJU-168; ZJU = Zhejiang University, H2BDC-OH = 2-hydroxyterephthalic acid, Ln = Eu, Tb, Gd) were designed for the detection of Glu. ZJU-168(Eu) and ZJU-168(Tb) suspensions simultaneously produce the characteristic emission bands of both lanthanide ions and ligands. When ZJU-168(Eu) and ZJU-168(Tb) suspensions exposed to Glu, the fluorescence intensity of ligands increases while the emission of lanthanide ions is almost unchanged. By utilizing the emission of ligands as the detected signal and the emission of lanthanide ions as the internal reference, an internal calibrated fluorescence sensor for Glu was obtained. There is a good linear relationship between fluorescence intensity ratio and Glu concentration in a wide range with the detection limit of 3.6 µM for ZJU-168(Tb) and 4.3 µM for ZJU-168(Eu). Major compounds present in blood plasma have no interference for the detection of Glu. Furthermore, a convenient analytical device based on a one-to-two logic gate was constructed for monitoring Glu. These establish ZJU-168(Tb) as a potential turn-on, ratiometric, and colorimetric fluorescent sensor for practical detection of Glu.

Exposure to gadolinium and neurotoxicity: current status of preclinical and clinical studies.

PURPOSE: Gadolinium is a rare-earth lanthanide metal that is known to have a direct neurotoxic effect. The scope of the present review is to summarize the current preclinical and clinical evidence on the association between exposure to gadolinium of the central nervous system and neurotoxicity. METHODS: A literature review was performed by searching for original research papers investigating on gadolinium exposure and neurotoxicity. RESULTS: Gadolinium is neurotoxic through multiple mechanisms, mainly involving Ca++ homeostasis and mitochondrial functions, as shown by preclinical in vitro studies. The available evidence related to the four different classes of gadolinium-based contrast agents commonly applied in clinical practice (i.e., linear and macrocyclic based on ligand structure, and ionic and non-ionic based on their net molecular charge) suggests that serial intravenous injections of gadolinium-based contrast agents and gadolinium brain depositions are not associated to histological changes, as confirmed by preclinical animal and human (MR imaging and autopsy) studies. CONCLUSION: To date, no cause-effect relationship has been demonstrated in patients between brain gadolinium exposure and clinical consequences specific to neurological toxicity.

Cumulative administrations of gadolinium-based contrast agents: risks of accumulation and toxicity of linear vs macrocyclic agents.

Ever since gadolinium was found to deposit in the brain of patients with normal kidney function by Kanda et al. in 2014, several studies have been conducted to evaluate its effect on the patients' health. However, conflicting results were obtained regarding imaging in gadolinium retention. These finding were attributed to the chelating structure of the administered gadolinium-based contrast agent (GBCA): linear agents were found to accumulate in the dentate nucleus (DN) and the globus pallidus (GP) of subjects even after one dose. There are some contradictory results when assessing macrocyclic agents. In the following article, we review the basis of GBCAs characteristics and their side effects, as well as, the MRI studies that assessed the accumulation of gadolinium in the brain. Based on the results of several studies, in 2017, the European Medicine Agency requested the suspension of the marketing authorizations for three linear GBCAs: gadodiamide (Omniscan®), gadoversetamide (Optimark®) and gadopentate dimeglimine (Magnevist®) and limited the use of gadoxetate disodium (Primovist/Eovist®) and gadobenate dimeglumine (MultiHance®) to hepatic uptake for imaging poorly vascularized hepatic lesions. Accordingly, the FDA did not restrict GBCA use, but will continue to study their safety and urged clinicians to use these agents sparingly. All macrocyclic GBCAs continued however to be used as no available valid evidence linked them to brain gadolinium retention. Regardless of possible accumulation in the brain, there is no evidence to-date that gadolinium retention leads to any disease or disorders in subjects with normal renal function. Further investigations with long-term follow-up are needed.

Absence of potential gadolinium toxicity symptoms following 22,897 gadoteric acid (Dotarem®) examinations, including 3,209 performed on renally insufficient individuals.

OBJECTIVES: Recent safety concerns regarding gadolinium-based contrast agents (GdCAs) concluded with the suspension of some agents from the European market, yet a clinical consequence remains unknown. We used electronic health records to investigate the incidence of potential toxicity to gadoteric acid (Dotarem®) within our local population, including those with renal insufficiency (RI). METHODS: Data for patients who underwent contrast-enhanced MRI were identified, stratified by renal function at time of scan and retrospectively followed using routinely collected health data. Searches performed were: records of hypersensitivity reactions; diagnoses of nephrogenic systemic fibrosis (NSF); onset of chronic pain, a symptom that has been associated with NSF and the theorised gadolinium deposition disease (GDD); and post-contrast acute kidney injury (PC-AKI). Comparisons were made between patients and controls (those who underwent non-contrast scans) via chi-square and ANOVA statistical tests. RESULTS: Of the 22,897 contrast-enhanced MRI scans performed locally from 2004-2016 (adult, n = 22,325 and paediatric, n = 572), 14% were performed on patients with RI (30 ≤ eGFR < 60, n = 2,622; 15 ≤ eGFR < 30, n = 464; eGFR < 15, n = 123). Two adult patients (0.01%) suffered hypersensitivity reactions. Zero cases of NSF were reported, with an average follow-up time of 6.0 ± 2.5 years (range, 8 months-15 years). Analysis failed to highlight statistically higher rates of chronic pain onset post-MRI (adult: p = 0.777, paediatric: p = 0.578), or PC-AKI (adult: p = 0.566, paediatric: p = 0.841), in the patient groups compared to controls. CONCLUSIONS: These data indicate that administration of gadoteric acid to RI patients does not result in a higher rate of signs or symptoms that may be associated with gadolinium toxicity when compared to controls. KEY POINTS: • Following 22,897 administrations of gadoteric acid to a local population, there was no association with symptoms that may be associated with gadolinium toxicity. • Zero cases of nephrogenic systemic fibrosis were reported following 3,209 gadoteric acid administrations to a cohort of renally insufficient patients. • A low number of hypersensitivity reactions were observed (0.01%) and no higher rate of chronic pain or post-contrast acute kidney injury were noted when compared with a control cohort of non-contrast-enhanced examinations.

Gadolinium accumulation, distribution, chemical forms, and influence on the growth of rice seedlings.

The content of gadolinium (Gd) is continuously increased in environment, which potentially threatens human health and ecological equilibrium. However, the phytotoxicity of Gd on plants remains unknown until now. In this study, the accumulation, distribution, and chemical forms of Gd as well as its influence on growth and nutrient balance were systematically studied in rice seedlings after the treatments of different concentrations of Gd (0, 1, 10, 100, and 1000 µM) for 10 days. The results showed that most Gd was accumulated in the roots and only a little percentage of Gd was transported to shoots. The accumulation of Gd was increased in a dose-dependent manner in various chemical forms and subcellular fractions. More than 80% of Gd was in the forms of insoluble oxalates and phosphates. Gd was mainly compartmentalized in the cell wall, and the content of Gd was increased with increasing concentrations of Gd. In addition, hormetic effects of Gd were found on rice growth. The growth of rice was induced by the lower concentration of Gd, but inhibited by the higher concentration of Gd. The results indicated that rice seedlings could cope with Gd toxicity through cell wall compartmentalization as well as forming of precipitates with oxalate and phosphate.

Comparative toxicity and contrast enhancing assessments of Gd2O3@BSA and MnO2@BSA nanoparticles for MR imaging of brain glioma.

The albumin-templated Gd2O3 and MnO2 nanoparticles (NPs) have been developed as a new type of magnetic resonance (MR) T1 contrast agents. However, their potential toxicity and applicability for MR imaging of brain gliomas has not been fully explored so far. In this study, we prepared Gd2O3@BSA and MnO2@BSA nanoparticles (NPs) and investigated their toxicity comprehensively and comparatively by H&E staining, blood biochemical analysis, and adverse outcome pathways testing. It is revealed that both Gd2O3@BSA and MnO2@BSA NPs are biocompatible at a rational dose level. Although the relaxivity of MnO2@BSA NPs is less than that of Gd2O3@BSA NPs, the MnO2@BSA NPs lead to a greater contrast enhancement in the brain glioma due to the controlled release of Mn ions under the acidic tumor microenvironmental conditions. These comparative toxicity and contrast enhancement data are of fundamental importance for the clinical translation of Gd2O3@BSA and MnO2@BSA NPs as MR contrast agents for brain glioma diagnosis.

The Effects of Gadolinium-Based Contrast Agents on the Cerebellum: from Basic Research to Neurological Practice and from Pregnancy to Adulthood.

Gadolinium (Gd)-based contrast agents (GBCAs) are used in magnetic resonance imaging (MRI) to increase the diagnostic yield. Current reports using animal models or human subjects have shown that GBCAs may be deposited in brain including the cerebellum. Although further studies may be required to clarify the toxicity of GBCAs, we should be more cautious to use these agents particularly in patients who more likely to have repeated enhanced MRI along their lifespan. In this editorial, current studies to clarify the toxicity of GBCAs in the cerebellum are introduced.

Structural, Mechanical, Imaging and in Vitro Evaluation of the Combined Effect of Gd3+ and Dy3+ in the ZrO2-SiO2 Binary System.

Mechanical strength and biocompatibility are considered the main prerequisites for materials in total hip replacement or joint prosthesis. Noninvasive surgical procedures are necessary to monitor the performance of a medical device in vivo after implantation. To this aim, simultaneous Gd3+ and Dy3+ additions to the ZrO2-SiO2 binary system were investigated. The results demonstrate the effective role of Gd3+ and Dy3+ to maintain the structural and mechanical stability of cubic zirconia ( c-ZrO2) up to 1400 °C, through their occupancy of ZrO2 lattice sites. A gradual tetragonal to cubic zirconia ( t-ZrO2 → c-ZrO2) phase transition is also observed that is dependent on the Gd3+ and Dy3+ content in the ZrO2-SiO2. The crystallization of either ZrSiO4 or SiO2 at elevated temperatures is delayed by the enhanced thermal energy consumed by the excess inclusion of Gd3+ and Dy3+ at c-ZrO2 lattice. The addition of Gd3+ and Dy3+ leads to an increase in the density, elastic modulus, hardness, and toughness above that of unmodified ZrO2-SiO2. The multimodal imaging contrast enhancement of the Gd3+ and Dy3+ combinations were revealed through magnetic resonance imaging and computed tomography contrast imaging tests. Biocompatibility of the Gd3+ and Dy3+ dual-doped ZrO2-SiO2 systems was verified through in vitro biological studies.

In vivo assay of the potential gadolinium-induced toxicity for sensory hair cells using a zebrafish animal model.

Recently, intratympanic injection of gadolinium-based contrast agent (GdC) is growing in use to visualize the endolymphatic hydrops. Although GdC has been quite safely used over 20 years through intravenous injection, the biological influence of GdC on sensory hair cells needs to be thoroughly assessed for wider clinical application of it through intratympanic injection. In this in vivo experimental study, the summated number of sensory hair cells (SO1, SO2, O1 and OC1 neuromasts) showed a steep decrease in the group exposed to 10% and 20% GdC (35.7 ± 7.3, 15.09 ± 10.82, respectively, P < .01) compared with the control group (47.18 ± 2.30). An increase in apoptosis was also observed in the group exposed to 20% gadolinium (7.20 ± 5.56), as compared with the control group (0.08 ± 0.72) or the group exposed to 10% gadolinium (3.48 ± 3.32). A significant reduction in the viable cytoplasmic mitochondria was observed in embryos exposed to 20% GdC (369 ± 124 µm2 , P = .01) as compared with control embryos (447 ± 118 µm2 ) or embryos exposed to 10% GdC (420 ± 108 µm2 ). GdC administration did not impact peripheral neural structures. GdC caused a significant reduction in sensory hair cell counts in response to high concentrations along with increased apoptosis and mitochondrial damage. However, it may not be likely that GdC will lead to hair cell toxicity, as the estimated concentration in the inner ear after clinically tried intratympanic injection is far more diluted than the non-toxic concentration (0.625%) that was tested in this study.