Crucial components of magnets, batteries and other technologies, lanthanides disrupt important cellular pathways in yeast, but to varying degrees, according to a new study that dug into the toxicity of these widely used metals.

Researchers evaluated the effects of 13 lanthanides, also known as rare earth elements, on genetic pathways in brewer's yeast, a model organism for studying genetics. The findings, published April 26 in Proceedings of the National Academy of Sciences, are a first step toward better understanding lanthanide toxicity in people and the environment.

"The lanthanides are a series of metals. In the periodic table, it's one of the rows of metals that's at the bottom that usually gets cut off," said study senior author Rebecca Abergel, an assistant professor of nuclear engineering at the University of California, Berkeley and a faculty scientist at Lawrence Berkeley National Laboratory. "They have very interesting properties for a lot of different applications in building magnets or building optical devices and also for enhancing contrast in MRI."

These silvery white metals were once considered to be relatively non-toxic, but recent studies have linked lanthanides with kidney and respiratory diseases in people involved with metal mining or processing and MRI patients. But the picture of lanthanide toxicity is incomplete: It's unclear how they cause harm, for example. And the few studies looking at the toxicology of these metals have focused on just a handful of lanthanides, assuming that the whole group behaves similarly, according to the researchers.

Lanthanide use is on the rise, driven in part by the demand for electric vehicles and other renewable energy technologies. As a growing number of people and wildlife could be exposed to these metals, there is a need to understand their toxic effects, Abergel told The Academic Times.

As a first step toward this goal, the researchers looked to the yeast Saccharomyces cerevisiae, a favorite species of geneticists because its genome is well-mapped and it shares many genes with other creatures, including humans. The researchers screened a library of more than 4,000 yeast strains, each with a specific gene deleted. Then the team measured how well the strains grew in nutrient media spiked with each of 13 lanthanides compared with control media that had no additions. 

If the analysis found that a yeast strain was sensitive to a particular lanthanide, that implied that the strain's deleted gene was involved in tolerance to this metal. On the other hand, yeast strains that were resistant to a particular metal indicated that the strain's missing gene was targeted by this lanthanide. 

By looking at the function of genes associated with sensitivity or resistance to each of the metals, the researchers found that lanthanides often disrupt cell processes regulated by calcium, possibly by mimicking calcium and binding to or blocking its binding sites. 

Calcium is a metal with critical biological functions, including bone formation and regulating cell membrane channels. Disruption of those can cause neurological disorders, suggesting that this could be a way in which lanthanides cause toxic effects in organisms, the nuclear engineer said. 

The team also found that lanthanides disrupted so-called endocytosis pathways, which are involved in uptake of nutrients, including essential metals. According to Abergel, disruption of these pathways could also "potentially lead to serious toxicology effects."

To look for clues of the specific proteins lanthanides act upon to disrupt these processes, the researchers mapped out interactions between proteins encoded by the genes involved in sensitivity or resistance. A few dozen proteins emerged as potential candidates, 11 of which are encoded by genes that are shared by humans.

In future work, the researchers will look more closely at these proteins to see if they can identify binding sites for lanthanides and potentially look at ways to prevent binding to mitigate their toxicity.

Another key finding was that specific lanthanides had different effects.

"So it appears that we can't just say, 'OK, if we know something about one lanthanide, we can assume that all lanthanides do the same thing in a biological system,'" Abergel said. "That's really important."

Early lanthanides, those that appear earlier in the periodic table, were less toxic to yeast strains than late ones.

"That means that down the line, when we think about building a magnet or a battery or separating different lanthanides, what kind of exposure are people going to be having? Maybe we want to replace a late lanthanide with an early lanthanide," Abergel said. "Or just thinking about [lanthanides] not as a whole series, but potentially some having more environmental and toxicological impacts than others."

The researchers also plan to home in on individual metals such as gadolinium, commonly used for medical imaging. According to Abergel, the team will look for links between biological pathways and symptoms that have been associated with exposure to lanthanides, such as kidney disease and neurological disorders.

Going forward, Abergel said, it will be important to think about toxicity of these metals throughout their life cycle, from processing to production of new devices and disposal of those devices.

"There's waste from the isolation processes and waste from discarded end-of-life devices, but also we've seen, for example, in areas where you have a lot of diagnostic medicine, so a lot of MRI, you see a pretty high concentration of gadolinium in the water and the sewer system. What environmental impact does this have?" she said. "It's not only humans, but aquatic life and other animals."

The study, "Genome-wide toxicogenomic study of the lanthanides sheds light on the selective toxicity mechanisms associated with critical materials," published April 26 in Proceedings of the National Academy of Sciences, was authored by Roger M. Pallares, David Faulkner, Dahlia D. An, Solène Hébert, Jonathan A. Villalobos, Kathleen A. Bjornstad and Chris J. Rosen, Lawrence Berkeley National Laboratory; Alex Loguinov, Michael Proctor and Christopher Vulpe, University of Florida, Gainesville; and Rebecca J. Abergel, Lawrence Berkeley National Laboratory and University of California, Berkeley.