Toxicological Impact of Rare Earth Elements (REEs): Comparison
Please note this is a comparison between Version 1 by Rosaria Scudiero and Version 2 by Dean Liu.

This review focused on the impact of lanthanides in marine organisms on reproductive fitness, fertilization and embryonic development, using the sea urchin as a biological model system. Scientific evidence shows that exposure to lanthanides triggers a wide variety of toxic insults from reproductive performance to  fertilization, redox metabolism, embryogenesis and regulation of embryonic gene expression. This was thoroughly demonstrated for  gadolinium, the most widespread lanthanide widely used in diagnostic medicine,  whose uptake in sea urchin embryos occurs in a time- and concentration-dependent manner, correlates with decreased calcium absorption and primarily affects skeletal growth, with incorrect regulation of the skeletal gene regulatory network. The results collected on sea urchin embryos demonstrate a variable sensitivity of the early life stages of different species, highlighting the importance of testing the effects of pollution in different species.

  • calcium uptake
  • sea urchin embryonic development
  • gene expression
  • gadolinium
  • rare earth elements
  • lanthanoids

1. Rare Earth Elements

Among the contaminants of emerging interest, rare earth elements (REEs) play a fundamental role; they consist of a group of 15 trivalent elements of the lanthanide family with atomic numbers of 57 to 71 (IUPAC, 2005) and are used in various fields of technology such as medicine (diagnostics and drugs), electronic devices (cell phones and plasma screens), and permanent magnets. REE extraction and processing into commercial products have grown exponentially in recent years and have raised environmental concerns about their release into aquatic and terrestrial ecosystems. Increased concentrations of REEs have been reported in lakes, rivers, and marine environments, making the removal of REEs from wastewater almost impossible. The ratio of the concentration of a chemical in biota to that in ambient water is called the bioconcentration factor (BCF) and depends on many parameters; in the case of lanthanides, it depends on the type, the exposure concentration, and the microorganism considered. BCF is a very common parameter to describe the accumulation of pollutants in biota relative to water. It can be expressed as the ratio of the concentration of a chemical in an organism to the concentration of the chemical in the surrounding environment, so BCF is expressed in units of liter per kilogram. The BCF of lanthanides in algae reaches values up to 3,000,000 L/kg. The importance of the chemical mobility of a REE is its link to its bioavailability. In physiological studies, lanthanides are often used to inhibit the uptake of divalent calcium ions (Ca2+, which have a similar ionic radius but a lower charge density than the trivalent lanthanide ion. However, in addition to the health risks associated with their applications, ecotoxicological and epidemiological evidence are directly linked to environmental exposure to REEs and adverse health conditions remain weak.

2. Gadolinium

Among the lanthanides, gadolinium is widely used as a contrasting agent in the diagnostic procedures of magnetic resonance imaging (MRI) due to its paramagnetic properties. For this reason, Gd is becoming a new powerful contaminant of aquatic environments, and the most common pollutant of the lanthanide family. Gadolinium, like other REEs, is naturally occurring in the environment as a result of the dissolution of minerals. The background Gd level only minimally affects the total Gd measured in fresh and marine water, since most of the Gd+3 ions determined in aquatic environments derive from gadolinium-based contrast agents (GBCAs) excreted via the kidney by MRI patients. GBCAs are eliminated unmetabolized. Being at first generally considered safe, the use of Gd in medicine has grown exponentially in the last decades, leading to a consequent increase in its emission into the environment, although its use has later been linked to nephrogenic systemic fibrosis (NSF) disease. Indeed, in 2016, an annual emission of 4 tons of Gd has been estimated in Germany and to 19 tons in Europe. Increasing concentrations of Gd have been found in rivers, where it passed from the geogenic background of a few ng/L to about 100 µg, with peaks of 1 mg, per liter. High Gd concentrations have also been found in drinking water. An increase in Gd concentrations has also been demonstrated in coastal seawaters,  In the future, GBCA concentrations in the aquatic environment are likely to increase due to the constant use of MRI.
The presence of Gd has been confirmed in aquatic organisms, such as lichens, algae, plants, invertebrates and vertebrates. However, like other REEs, detailed studies on metabolization, bioaccumulation, and the environmental fate of Gd complexes and their toxicological effects on living organisms are lacking.
In this framework, it is important to develop appropriate methodologies to gain a deeper understanding of the impact of REEs on several important processes, including fertilization and embryonic development. In particular, the use of biological model systems should provide valuable information on this fundamental issue.

3. The Sea Urchin Embryo

The sea urchin (Echinodermata: Echinoidea) embryo has long been used as a model organism for biological developmental studies. Several factors make this system suitable for conducting a wide range of biological tests. These include low maintenance costs; a small size; high fecundity; simple artificial spawning; fertilization and rearing; rapid synchronous development; optical transparency of the embryo, allowing for direct observation of cell division and movement within the embryos and larvae; and well understood embryogenesis. Furthermore, as invertebrate species, sea urchins are not subject to animal welfare concerns. This trait satisfies the strategy for developing alternative approaches to the use of vertebrates in biological testing.
Sea urchin embryos have been used successfully to study many cellular processes, such as adhesion, differentiation, survival, and death. They are also recognized as an excellent model system for eco- and geno-toxicological studies.
Sea urchin embryos are being used as a model to elucidate the role of cellular and molecular mechanisms involved in human health and disease. This is because general cellular properties are common to many organisms. Complete sequencing of the sea urchin genome also revealed that sea urchins are more closely related to vertebrates, with which they share the superphylum group of deuterostomes, than other invertebrates that are commonly used as models of human disease, e.g., Drosophila melanogaster and Caenorhabditis elegans.

4. Rare Earth Elements and the Sea Urchin Embryo

Regarding toxicological studies, it is well documented that echinoderm early life stages exhibit a high sensitivity to several toxicants, including heavy metals, persistent organic pollutants and microplastics. The effects of lanthanides on sea urchins have also been evaluated; in particular, the potential damage of seawater contamination on gamete viability, fertilization, and larval development. In these studies, many sea urchin species are utilized, in consideration of their availability in the different areas interested in ecotoxicological studies.

Pollution due to the continuous introduction of human-derived contaminants into the marine environment poses a threat to all marine species. Chemical pollutants represent a constant source of evolutionary challenges for living organisms, strenuously eliciting their adaptive potential. A comparative investigation of the toxicity associated with REEs in the early life stages of sea urchins provided evidence for different effects of individual REEs; these effects affect processes such as fertilization, redox metabolism, embryogenesis, skeletogenesis and regulation of embryonic gene expression. Early damage in life stages, along with redox and cytogenetic anomalies and dysregulation of gene expression should be the focus of future REE toxicity studies, as these factors have a major impact on wildlife survival.

It is known that phenotypic responses to environmental changes can be a key factor in species survival, buffering developmental processes via altered morphology, gene expression or stress response mechanisms. The results demonstrating a variable sensitivity of the early life stages of different sea urchin species highlight the importance of testing the effects of pollution for risk assessment in different species, even within the same taxonomic group.

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