Adverse effects and underlying mechanism of rare earth elements

Abstract

Background

Rare earth elements (REEs) have found broad application in a range of industries, including electronics, automotive, agriculture, and healthcare. However, their widespread utilization and release into the environment pose potential risks of human exposure. Despite extensive research on REEs toxicity, the relationship between exposure and subsequent health concerns remains ambiguous. Given that the biological effects of REEs can vary based on their design and application, assessing their toxicity can be highly challenging.

Objective

This review is to offer a thorough comprehension of REEs' application and toxicity, guiding future research and policy-making to safeguard public health and environmental integrity.

Methods

A systematic search across PubMed, Web of Science, Cochrane Library, and Embase was conducted using the terms: ("rare earth" OR "lanthanoid") AND ("health hazard" OR "toxic" OR "adverse health effect"). From 5,924 initial records, 89 studies were selected through deduplication and two-stage screening to assess systemic toxicity of REEs. An additional 100 articles on REEs mechanisms and applications were incorporated via citation tracking. All selections followed PRISMA guidelines with dual-author verification to ensure rigor.

Conclusion

The review emphasizes REEs' applications in various domains and documents potential environmental pathways. Furthermore, it elaborates on current processes to assess REEs-related toxicity across different model organisms and cell lines, estimating health threats posed by REEs exposure. Finally, based on the findings of both in vivo and in vitro experiments, the potential toxic mechanisms of REEs are detailed. To guide future research and policy development to safeguard public health and environmental integrity.

Graphical Abstract

Introduction

REEs comprise the 15 lanthanides (atomic numbers 57–71), scandium (Sc, atomic number 21), and yttrium (Y, atomic number 39), due to their co-occurrence and similar chemical properties Connelly [37] (Table S1). These elements are subdivided into light rare earth elements (LREEs) and heavy rare earth elements (HREEs) based on distinctions in ionic radius, electron configuration, and coordination chemistry [60]. Major REEs mining regions around the world include the Bayan Obo mine in China, the Mountain Pass mine in the United States, the Mount Weld mine in Australia, and REEs resources in eastern Canada [114]. The proven reserves of REEs resources are 43.5 million tons, Bayan Obo mining area accounts for 83.7% of the national total and 37.8% of the global total (G). Currently, China contributes to over 60% of the world's total output [142, 146]. The REEs are categorized into light and heavy types based on atomic electron configuration and are primarily found in minerals such as phosphates, silicates, carbonates, oxides, and halides [45, 148]. Light REEs oxides and chlorides are pivotal in catalysis and coordination chemistry, utilized notably in hybrid car battery production, petroleum refining, and water treatment [100], while heavy REEs oxides and chlorides are vital for magnetic materials and high-temperature superconductors [19]. Nano oxides derived from REEs have applications in catalysis, sensing, and biomedical imaging [10]. These diverse applications drive the continuous growth in the market demand for REEs.

REEs demonstrate long-lasting presence in the human body even years after being exposed to them in a work environment [94]. As far back as 1965, Haley provided detailed insights into the pharmacological and toxicological properties of REEs [63]. The REEs can enter the human body through ingestion, inhalation, or intravenous injection, as seen in the use of pharmaceuticals and food products [82, 104]. Additionally, during the production, manufacturing, usage, fertilizers, livestock feeds, or disposal of REEs containing materials, these elements can be released into the environment through waste management processes, sewage treatment plants, and recycling systems [61, 150]. This leads to their eventual dissemination into air, soil, surface water, and sediments, posing exposure risks to humans [123, 124, 130]. Observational studies have found that workers inhaling REEs particles are more susceptible to acquiring respiratory illnesses, such as airway inflammation and fibrosis [25, 69]. Similarly, Wingard et al. report that Cerium oxide nanoparticles (CeO₂ NPs) activate mast cells, causing lung inflammation, decreased vascular relaxation, and enhanced cardiac ischemia/reperfusion damage [158]. Huang et al. reported that children living near REEs mining areas had increased levels of lead and REEs in their hair, correlating with a higher percentage of abnormal IQs [76]. REEs have been identified in many human samples, including hair, nails, urine, blood, semen, breast milk, and tissues, raising concerns about their pollution and bioaccumulation [29, 128, 182]. The US Environmental Protection Agency classifies REEs as emerging contaminants present in trace amounts [145].

According to earlier research, modest doses of REEs can have beneficial impacts on animals and plants, whereas long-term consumption of REE-contaminated food may lead to chronic poisoning, involving hormonal imbalances, carcinogenic consequences, and neurological damage [81, 189]. In contrast, Xu et al. found that early pregnancy exposure to lower levels of REEs combination was related to a higher likelihood of gestational diabetes [170]. Therefore, it is necessary to conduct long-term assessments of the health status of residents in areas with high concentrations of REEs. In recent years, numerous studies have demonstrated the toxic effects of REEs on various biological systems, encompassing the respiratory [110, 118, 126], cardiovascular [9, 51, 58], hepatic [6, 21, 109], neurological (Fig. 4a) [54], immune [155], and reproductive systems [22, 125, 129]. However, the toxicological evaluation of REEs lags significantly behind the rapidly developing rare earth field and the expanding market demand. Based on current laboratory research evidence, the health damage caused by REEs may be attributed to the migration of REEs into the systemic circulation, or secondary organ changes induced by inflammation, oxidative stress, or other factors following local tissue damage [123, 124]. Despite extensive research, current literature reveals considerable inter-study variability and contradictory findings, leaving the toxicological mechanisms inadequately understood.

Therefore, the review delves into understanding the applications, toxicity, and mechanisms of REEs. A literature search on October 30, 2023, across PubMed, Web of Science, Cochrane Library, and Embase retrieved a total of 2764, 3033, 3, and 124 articles, respectively. Search terms include: 'rare earth', 'rare earth elements', 'rare earth oxides', 'rare earth metals', 'earth metals', 'health damaged degree', 'health hazard', 'adverse health effects', 'health risks', 'health harmful'. Combine search terms using Boolean logical operators (AND, OR). We included articles related to rare earths and health damage, screened titles and abstracts to determine relevance, and duplicated articles, reviews without original data, and studies not related to REEs were excluded. We added a flowchart to illustrate the article selection process (Fig. 1). We provide detailed analysis of the toxic effects of REEs on humans, aiming to identify limitations and suggest new research directions. Additionally, we explore the release pathways and human risks of REEs, analyzing their toxicity through evidence from in vivo and in vitro experiments. By integrating these insights, we aim to comprehensively understand the applications and environmental consequences of REEs while identifying research gaps and hazards.

Fig. 1

Article screening process for scoping reviews. Created with BioRender.com

Applications

REEs have been in high demand across various industries, including electronics, military, energy, and other high-technology sectors, due to their low melting point and ductility [36, 105]. The following sections will detail the specific applications of REEs in traditional materials, new materials, agriculture, and medicine (Fig. 2).

Fig. 2

The application of REEs. a REEs in traditional materials. b REEs in new materials. c REEs in agriculture. d REEs in medicine. Created with BioRender.com

Traditional materials

REEs are increasingly crucial in traditional materials due to advanced technologies (Fig. 2a). They enhance physical properties when added to aluminum, steel, and other metals, and serve as crucial catalysts in the petroleum industry and air pollution control [27]. Additionally, rare earth glass ceramics are foundational in industry and daily life, such as CeO₂ used in cathode ray tube (CRT) glass to reduce electron emission browning and as a glass polishing compound [70]. However, rising REEs demand raises environmental concerns, with increased risks of these elements entering freshwater and marine environments [143]. Bau and Dulski [12] and studies by Khan et al. reported elevated REEs levels in aquatic environments [12, 86]. In spite of REEs contamination, heavy metal and U pollution are severe consequences of REEs mining and processing [66]. The mining process necessary for REEs has also had a negative impact on human well-being and ecosystems, resulting in geological challenges such as soil degradation, disruptions of geological structures, and alterations of hydrogeological systems [16]. Implementing effective REEs recycling and recovery techniques can reduce the ecological impact of mining and promote energy reuse, making the advancement of recovery technologies highly urgent.

New materials

Advancements in technology have significantly expanded the applications of REEs in new materials (Fig. 2b), making them indispensable in high-tech fields, particularly in the production of permanent magnets [74]. Neodymium-iron-boron magnets are crucial for military weapons systems, while samarium-cobalt magnets excel in high-temperature applications such as precision-guided missiles and smart bombs [89]. Superconducting materials made from barium base oxide modified by barium yttrium copper oxygen elements, marking a breakthrough in the development of superconducting materials [175]. Catalysis, energy materials, environmental pigments, thermoelectric materials, analytical instruments, optical materials, and magnetic materials are among the applications of rare earth sulfides [95, 169, 181]. Rare earth compounds function as corrosion inhibitors for aluminium alloys, providing significant protection and meeting military standards. Rare earth tantalates offer thermal and oxidative protection for high-temperature components in aero-engines and gas turbines. Rare earth fluorides are used in arc carbon for lighting purposes [122, 152]. Azimi et al. demonstrate that these rare earth fluoride can also be added to arc carbon as a wick, which was employed for a diverse array of illumination purposes [4]. The quick use of REEs in new materials has resulted in an increased exposure to these elements, necessitating careful consideration of their benefits and potential risks.

Agriculture

The impact of REEs in agriculture has increased substantially over the past few decades, primarily due to the use of REEs-based fertilizers to enhance crop growth and yield (Fig. 2c). The chemical characteristics of REEs are similar to those of Ca due to their similar ionic radius. For example, the addition of La could alleviate the symptoms of Ca deficiency in plants [61]. Moreover, REEs regulate plant growth and development in a dose-dependent manner. However, the long-term application of REEs-rich fertilizers and extractive mining activities release significant amounts of these elements into the environment [42]. Studies have shown that after applying rare earth fertilizers to maize, except for Sc and Lu, all other REEs demonstrated significant cumulative effects in maize roots within ten days [171]. Specifically, low concentrations of La slightly increased root and shoot biomass, but excessive La concentrations negatively affected cell division, Deoxyribonucleic acid (DNA) structure and nutrient absorption, causing toxicity symptoms [40]. For example, high La concentrations inhibited the growth of soybeans [48]. Furthermore, vegetables can accumulate REEs from the soil, and the potential toxicity of this accumulation remains unclear [13]. Given the increasing use of REEs in agriculture, it is crucial to conduct further research and monitoring to understand their long-term effects on both plant health and food safety.

Medicine

REEs have widespread applications in the medical field (Fig. 2d), including biomolecular detection, imaging, oxidant detection, and as contrast agents in magnetic resonance imaging (MRI) [17, 156]. For instance, CeO₂ NPs are used to develop fluorescent nano biosensors for rapid DNA methylation detection [3]. These nanoparticles possess antioxidant, antibacterial, anti-inflammatory, anticancer, and biocompatibility properties [8, 30, 156], and are widely applied in dental adhesives, caries prevention, and implant coatings [2, 49, 55]. They also show potential in treating cancer, eye diseases, neurodegenerative diseases, ischemic cardiomyopathy, and diabetes [121], yet their safety remains uncertain (S [80]). Gd³⁺ is crucial in medical applications, especially for light therapy in cancer treatment, where it reduces cell proliferation and induces apoptosis [144]. However, its salt form has been shown toxic in animal studies since the 1960s [38], primarily accumulating in the kidneys, skin, liver, lungs, spleen, femoral muscle, diaphragm, and heart [133]. In conclusion, while REEs offer significant medical benefits, it is vital to continue researching and monitoring their potential human toxicity.

Biological distribution of REEs

REEs can penetrate the body through multiple routes, including respiratory inhalation, digestive ingestion, and dermal contact [104, 116, 151]. The biological distribution of REEs is greatly influenced by the mode of entry, inhalation through the respiratory or dietary tract is the common route of exposure [66, 190]. For example, the daily REEs intake through inhalation ranged from 5.09 × 10⁻⁷ to 2.25 × 10⁻⁵ mg/kg/day in Baotou [96]. Inhaled REEs penetrate the alveolar epithelium, breach the alveolar air-blood barrier in the lungs, and then circulate throughout the body, reaching extra-pulmonary organs such as the heart, liver, and kidneys [123, 124]. REEs can also penetrate the human body through the food chain, as they are used as feed additives, pesticides, herbicides, and fertilizers [1]. REEs can enter the cell cytosol through various mechanisms, potentially altering the cell membrane structure and permeability upon binding [162]. Long-term exposure to low levels of REEs may affect blood pressure, blood cells, neural reflexes, and bone quality [178, 179]. Some REEs exhibit a propensity to accumulate within human bones and teeth, posing challenges in terms of excretion and potentially affecting bone health [18, 44]. In summary, the distribution and bioaccumulation of REEs can negatively impact multiple human health systems, especially with long-term exposure.

Toxicity assessment of REEs

In recent years, various model organisms have been used to study the toxic effects of REEs. For instance, research using sea urchins has demonstrated that REEs affect fertilization, embryonic development, skeletal formation, and the regulation of gene expression during embryogenesis [115]. Studies show that Ce exposure in Lake Taihu increases microcystin pollution by enhancing endocytosis in M. aeruginosa [174]. Research on zebrafish embryos has shown that exposure to high concentrations (0.46 to 1000 mg/L) of REEs such as La and Pr leads to increased DNA damage and apoptotic activity [186]. These findings highlight the developmental risks that REEs pose to aquatic ecosystems. In ecotoxicology, Caenorhabditis elegans (C. elegans) is a canonical model organism that demonstrates how REEs exposure can induce neural damage, inhibit body length, and reduce movement frequency [168]. Additionally, rodent studies provide further insights, showing detailed physiological impacts of REEs exposure. For example, He et al. reported that water contaminated with REEs such as Sc may cause significant DNA genetic damage in rats [68]. Furthermore, human health studies have indicated potential risks associated with environmental exposure to REEs, particularly in areas with elevated levels of these elements, which have been linked to abnormal blood biochemical indicators or fetal neural tube defects [157, 180]. This section summarizes the most widely available evidence regarding the health effects of REEs on various systems or organs (Fig. 3).

Fig. 3

Potential health risks associated with REEs exposure. The diagram illustrates the adverse effects of REEs on various organs and tissues, as observed in numerous laboratory studies. Created with BioRender.com

Respiratory system

In vitro models

Alveolar macrophages are primarily responsible for creating pro-inflammatory mediators and are considered one of the primary lines of protection against ingested particles [83]. Palmer et al. conducted a study using rat pulmonary alveolar macrophages to reveal the potential impacts of different REEs, such as LaCl₃, CeCl₃, and Nd₂O₃, on lung tissue. The results indicated that these REEs fumes are cytotoxic, with LaCl₃ (LC50 = 52 µM), CeCl₃ (LC50 = 29 µM), and Nd₂O₃ (LC50 = 101 µM) showing significant cytotoxicity. This suggests that these fumes could potentially be fibrogenic [125]. Similarly, Huang et al. revealed that exposure to Nd₂O₃ can cause cell damage and enhance the synthesis and release of inflammatory chemokines through experiments on rat NR8383 alveolar macrophages [77]. Furthermore, Verstraelen et al. conducted a study on the exposure of Cobalt Oxid Nanoparticles (CoO NPs) and CeO2 NPs to alveolar A549 and bronchial BEAS- 2B epithelial cells. They found that CoO NPs and CeO₂ NPs primarily induced downregulation of gene transcription, with BEAS- 2B cells being more delicate [149].

In vivo models

Haley et al. demonstrated that REEs inhalation can lead to pulmonary toxicity, with the severity of effects influenced by factors such as particle size, duration, and dose of exposure [62, 88]. Huang's study observed size-dependent toxic effects of REEs, finding that smaller CeO₂ NPs (23 nm) significantly induced more acute pro-inflammatory lung responses in mice compared to larger CeO₂ particles (88 nm) [77]. Besides, Sisler et al. demonstrate that there are indeed differences in the lung responses to CoO (72 nm) and lanthanum oxide nanoparticles (La₂O₃ NPs) (25 nm) in the induction of acute vs. long-time pulmonary responses [138]. Such discrepancies reflect unfavourable outcome pathways for these compounds [120]. Shin et al. conducted a study in which male rats were exposed to La₂O₃ and observed La₂O₃ deposition in lung tissue, alveolar proteinosis, lung inflammation, and increased total cell counts, suggesting that the target organ of lanthanum was the lung [137]. Furthermore, Ahmad et al. reported that Nd₂O₃ exhibit the capability to A549 cancer cell death via Reactive Oxygen Species (ROS) generation and genotoxicity study pathways [5]. Wu et al. reported that long-term gavage exposure to Ce(NO₃)₃ could induce the incidence of foreign body granulomatous lesions in the lungs, which may also contribute to the development of fibrosis in multiple organs [160, 161]. At the same time, the findings of Schwotzer et al. also emphasized the potential long-term health effects of CeO₂ NPs, indicating the need for further research on nanoparticle risk assessment and the establishment of safety thresholds [135]. Keller et al. exposed rats to CeO₂ NPs at concentrations of 0.5, 5, and 25 mg/m³ for 1 or 4 weeks, with observations at 24 or 129 days post-exposure. They found that higher concentrations impaired lung clearance, leading to prolonged retention and an inflammatory response whose severity was linked to the duration and dose of exposure [85]. Solid evidence has confirmed that CeO₂ exposure is associated with pulmonary phospholipid deposition, fibrosis, and sustained inflammatory responses, with the severity of inflammation in the lung tissue increasing with both the duration and concentration of exposure [59, 111]. Given that the respiratory tract is likely the primary route of human exposure to REEs, it is crucial to pay close attention to the potential lung diseases induced by REEs (Fig. 4a).

Fig. 4

REEs induced adverse effects on the respiratory, cardiovascular, and digestive systems. a Cerium oxide (CeO₂₎ exposure induced pulmonary fibrosis. Reprint from ref [110], reproduced under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). b Cardiovascular damage induced by YCl₃ exposure. The images illustrate significant myocardial hypertrophy, necrosis, and fibrosis in left ventricular tissue across different YCl₃ doses, highlighting the dose-dependent progression of cardiac injury. Reprint from ref [166]. c Ultrastructural changes in mouse liver after 60 days of CeCl₃ exposure. The TEM images reveal dose-dependent liver damage, including nuclear chromatin condensation, mitochondrial swelling, cytoplasmic lipid droplets, and nuclear vacuolization, highlighting progressive hepatic injury across varying CeCl₃ doses. Reprint from ref [183]

Cardiovascular system

In vitro models

Because of their minuscule size, the largest numbers of REEs NPs have the capability to penetrate the air-blood barrier and travel through the bloodstream. Throughout this process, they unavoidably interact with the vasculature and eventually reach the heart. Xiong et al. conducted experiments to assess the cytotoxicity of YCl₃ on rat H9c2 cardiomyocytes across various concentrations. Their findings revealed that exposure to YCl₃ resulted in DNA damage mediated by ROS and a notable increase in gamma-H2ax levels [165]. Gojova et al. reported that Y₂O₃ particles are taken up by aortic endothelial cells and enter vesicles, leading to a significant inflammatory response [57]. Moreover, Zhao et al. reported that LaCl₃ inhibits calcium deposition in vascular smooth muscle cells at low concentrations but promotes calcium deposition and induces apoptosis at high concentrations, which suggests that the use of LaCl₃ may carry a risk of toxic effects on vascular health [183, 185]. Kuruvilla et al. proved through in vitro cell experiments that Ce directly stimulated subendocardial fibroblasts could cause cardiac lesions in endocardial myocardial fibrosis [90]. While these studies reveal REEs'cardiovascular toxicity, further research is needed on interactions between different REEs, as well as protective strategies due to their persistence.

In vivo models

The cardiovascular effects of REEs have also been demonstrated in vivo studies (Fig. 4b). Minarchick et al. investigated the impact of pulmonary CeO₂ NPs exposure on microvascular function using isolated mesenteric and coronary arteries. They found that CeO₂ NPs impair endothelium-dependent and independent arteriolar dilation in a dose-dependent manner, with mesenteric microvessels being more sensitive than coronary arteries. These changes may contribute to cardiovascular dysfunction and increased mean arterial pressure in some groups [119]. Besides, Zhao et al. proved that REEs have detrimental effects on the swimming action and cardiac morphology of zebrafish, particularly in the case of La and Pr, where cardiac hypertrophy and myocardial contraction are two critical toxic pathways [186]. Chen et al. reported that neodymium sesquioxide (Nd₂O₃ NPs) disrupt early development in zebrafish embryos, leading to increased mortality, malformations, heart arrhythmias and elevated apoptosis [31]. Given the evidence from these studies, conducting long-term studies to assess the chronic effects of REEs exposure on cardiovascular health, which are currently underexplored, is crucial.

Digestive system

Studies have shown that REEs can enter the body through the digestive tract and have toxic effects on the digestive system, particularly on liver function (Fig. 4c). Subacute exposure to CeCl₃ was reported to induce liver apoptosis and alter the expression levels of genes related to metal detoxification, metabolism regulation, and radical scavenging in mice (Fig. 4b) [183, 185]. Marzi et al. demonstrated that, compared to short-term exposure, which showed minimal toxicity, long-time exposure to CeO₂ NPs led to significant toxicity in various cell lines, with HepG2 cells being especially sensitive [39]. Moreover, Cheng et al. found that long-term exposure to CeCl₃ can lead to Ce accumulation, liver inflammation, and hepatocyte necrosis, along with significant alterations in gene expression profiles related to immune response, apoptosis, and metabolic processes in the liver [33, 34]. In vivo models further investigated REEs'impact, showing irreversible accumulation of La, Ce, Pd, Nd, and Gd in the liver of SD rats, underscoring the liver as a critical organ affected by these elements [21]. For example, administration of Pr(NO₃)₃ to rats resulted in fatty liver [92]. Acute toxic effects of La on the gills and liver of the Gobiocypris rarus [75]. Furthermore, La deposition in the upper gastrointestinal tract was associated with clinical symptoms such as dysphagia, nausea, vomiting, and reflux, long-term La carbonate administration can lead to multiple forms of gastroduodenal lesions [67]. Intriguingly, Yabuki et al. revealed that oral administration of LaCl₃ (1000 mg/day) for more than 2 weeks in rats caused La deposition in the gastric mucosa and led to histological changes, including glandular atrophy, fibrosis, mucous neck cell hyperplasia, and ulcers [172]. These findings collectively underscore the significant impact of REEs on the digestive system, particularly on liver function, necessitating further research into their toxicological effects and mechanisms. (Table 1).

Table 1 Toxicological effects of REEs on respiratory, cardiovascular, and digestive systems

Nervous system

In vitro models

REEs are known to exert neurotoxic effects, impacting neuronal function and health through various mechanisms elucidated in vitro models (Fig. 5a). Gao et al. investigated the neurotoxic effects of LaCl₃ in vitro, revealing that it induces autophagy by inhibiting the Akt/mTOR signalling pathway and activating the AMPK/mTOR signalling pathway [54]. Moreover, LaCl₃ decreased the expression of VAPB-PTPP51, BAP 31-FIS 1, and MFN2-MFN1, resulting in abnormal cultured rat cortical neurons and neuronal damage [103]. Ariyani et al. recently found that gadolinium-based contrast agents (GBCAs) enhance astrocyte migration and adhesion by activating integrin αvβ3 and related signalling pathways, which may adversely affect brain development with repeated use [7]. Meanwhile, similar results were also confirmed by Sun et al., who reported that LaCl₃ inhibits lactate production and transport in astrocytes, leading to learning and memory impairment, which may be related to disruptions in lactate metabolism [141].

Fig. 5

REEs have adverse effects on the nervous system, immune system, and reproductive system. a The effects of LaCl₃ on spatial learning and memory in rats. The graphs show escape latency and total distance traveled over the first five training days, indicating a dose-dependent decline in cognitive performance with increasing LaCl₃ concentrations [53]. Reproduced under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). b Cerium nitrate (CN) exposure induces immunotoxicity in BALB/c mouse offspring. As evidenced by changes in PFC numbers and increased footpad thickness on PND 21 and PND 42. Bar graphs show mean ± SD (n = 10), with significant differences from the control group indicated. Reprint from ref [56]. c YCl₃ exhibits toxic effects on the testes of adult male mice. Reduced survival rates, weight loss, decreased testes-to-body weight ratios, and histopathological changes, including impaired varicocele function, lower sperm counts, and alterations in the expression of genes related to the blood-testes barrier, clearly demonstrate this toxicity. Reprinted from ref [73]

In vivo models

In vivo studies have shed light on the neurotoxic insults and behavioral deficits induced by REEs exposure (Table 2). Notably, chronic exposure to La may compromise learning, potentially because of disturbances in trace elements, enzymes, and neurotransmitter systems in the brain [46]. La exposure causes neurotoxic insults and behavioural deficits in C. elegans. La (NO₃) ₃ 6H₂O inhibits C. elegans growth, and also inhibits or activates neurotransmitter transporters and receptors (glutamate, serotonin, and dopamine) that regulate behavioral and motor function. In addition, ROS was significantly increased in stage L4 C. elegans exposed to La [64]. In rats, La exposure leads to excessive oxidative stress in hippocampal neurons, resulting in elevated ROS levels and increased transcription of autophagy-related genes through the JNK/c-jun and JNK/FoxOs signalling pathways [53]. Furthermore, research find that LaCl₃ administration has been found to alter TP activity and cause partial brain cell damage in Wistar rats, along with reductions in the expression levels of pCaMK IV, pMAPK, pCREB, c-fos, and egr1 in the hippocampus, potentially impairing offspring memory [173]. Moreover, adult rats exposed to La after weaning exhibit reduced plasma neurotransmitter levels of acetylcholine and norepinephrine, as well as decreased neuron numbers in the CA1 region of the hippocampus [164]. GBCAs commonly used in clinical practice, have raised concerns regarding their neurotoxicity. Intravenous exposure to GBCAs has been associated with neuronal tissue deposition, with elevated Gd levels observed in various brain regions and across the intact blood–brain barrier in patients with relatively normal renal function [117]. Furthermore, the neurotoxicity of REEs is closely related to their ability to penetrate the blood–brain barrier (BBB) and disrupt its integrity. Studies have shown that La and Gd can cross the BBB through multiple mechanisms, including direct penetration, diffusion via cerebrospinal fluid, and periarterial pathways along cortical arteries [127]. For example, LaCl₃ significantly increases BBB permeability in young rats by downregulating tight junction proteins and upregulating matrix metalloproteinase- 9 activity [160, 161].

Table 2 Damaging effects of REEs on nervous, immune and reproductive systems

In the C. elegans model, La(NO₃)₃·6H₂O crosses the BBB-like barrier and induces motor and behavioral deficits by degenerating dopaminergic and GABAergic neurons, promoting abnormal alpha-synuclein aggregation, and disrupting neurotransmitter systems [64]. Notably, the size and surface modifications of REEs nanoparticles significantly influence their BBB penetration efficiency. Smaller nanoparticles exhibit higher BBB permeability, while targeted modifications enhance intracerebral delivery, providing insights into the neurotoxicity mechanisms of REEs nanoparticles [136]. REEs cause subclinical damage to the cerebral cortex through the blood–brain barrier [188], cause depression, anxiety behavior, memory impairment and neural tube defects [101, 157]. In summary, REEs pose multiple risks of neurotoxicity by disrupting BBB integrity, activating oxidative stress and interfering with neuronal signaling pathways, and its mechanism of action is closely related to particle physicochemical properties and targeted delivery strategies. All this evidence suggests that REEs should be a novel threat to the nervous system, which should be of great concern.

Immune system

Some research shows that REEs can damage the immune system (Fig. 5b). Cheng et al. documented that exposure to lanthanoids (Ln) impacts both cellular and humoral immunity in mice [33, 34]. Moreover, Ce₂(NO₃)₃ significantly inhibits the cytotoxicity of natural killer NK cells, reduces the proportion of NK cells in peripheral blood and spleen (Fig. 5b), suppresses T/B lymphocyte proliferation, and dampens humoral and cellular immune responses [56]. Exposure to CeCl₃ is associated with notable decreases in white blood cell, lymphocyte, platelet counts, reticulum count, and neutrophil percentage, as well as in the A/G ratio. Conversely, it leads to significant increases in alkaline phosphatase, lactate dehydrogenase, and cholinesterase activity, as well as in triglyceride and total cholesterol concentrations [33, 34]. Additionally, Gd₂O₃ increases the number of monocyte-derived macrophages and myeloid-derived dendritic cells (M-DCs) in the liver. It also induces infiltration of neutrophils, M-DCs, and B cells in the spleen. Furthermore, Gd₂O₃ leads to expanded populations of hematopoietic stem cells, multipotent progenitors, and common lymphoid progenitors in both the bone marrow and spleen [52].

Reproductive system

Numerous studies have highlighted the potential reproductive system damage associated with REEs exposure [91, 97,98,99]. Once these elements enter an organism, they tend to accumulate and disrupt the normal function of the reproductive system [15]. Chen et al. reported that when the concentration of Nd₂O₃ NPs exceeded 200 μg/mL, embryonic development was adversely affected [31]. Similarly, Hou et al. confirmed that YCl₃ disrupts antioxidant stress signalling pathways and, through ROS-Ca²⁺ axis activation, causes apoptosis (Fig. 5c) and autophagy in testicular cells, leading to testicular injury as well as impaired male reproductive function [73]. Additionally, research has shown that maternal exposure to CeO₂ NPs impairs placental development, resulting in placental dysfunction, fetal loss, or growth restriction, and increases the risk of spontaneous abortion [32, 187]. Animal experiments further revealed that La₂O₃ NPs could induce apoptosis by inhibiting the Nrf- 2/ARE pathway and the expression of NQO1, HO- 1, and GSH-Px. Additionally, La₂O₃ NPs altered testicular ultrastructure, inducing oxidative stress and inflammatory responses in the testes of exposed mice [177]. Excessive exposure to REEs has thus been implicated as a risk factor for infertility or developmental abnormalities [28]. In conclusion, mounting evidence suggests that REEs may adversely affect the reproductive health of both males and females, representing a significant public health concern.

Other systems

In addition to the aforementioned systemic toxicities, REEs also exert effects on various other systems. Several studies have demonstrated that REEs bind to biofilms, altering membrane structure and permeability, thereby facilitating their entry into erythrocytes [162]. For instance, La(NO₃)₃ inhibits lipogenesis and impacts cell proliferation in 3 T3-L1 preadipocytes [167]. Additionally, CeO₂ NPs exposure has been associated with cell transformation, and the toxicity induced by Ce exposure is linked to tumorigenesis [11]. In animal models, REEs have demonstrated mild oncogenic activity, highlighting potential carcinogenic risks [134]. Long-term environmental and occupational exposure to REEs leads to their accumulation, resulting in decreased levels of iron and Ca due to competitive binding. This phenomenon collectively induces bone metabolic disorders and subsequently reduces bone mineral density [102]. Furthermore, Lutetium- 177 shows promise in the treatment of early-stage prostate cancer but may cause myelosuppression [26]. Intravascular gadolinium-based contrast is an alternative to iodinated contrast [24]. Nephrogenic systemic fibrosis can lead to severe complications and even death, and it is associated with exposure to GBCAs used in MRI [79]. In mice with normal renal function, gadolinium contrast agents have been shown to cause metabolic disorders and kidney damage, and the damaging effects of gadolinium contrast are exacerbated by obesity [43].

Essential toxicity mechanism

REEs can permeate the human body through multiple methods, associated with a variety of diseases. By inducing oxidative stress, inflammation, autophagy dysfunction, and mitochondrial dysfunction, REEs can cause health-related issues in the human body. The fate of the cell will be determined by the interaction between these subcellular effects (Fig. 6).

Fig. 6

The fundamental mechanisms underlying REEs-induced toxicity. a YCl₃ increases ROS and MDA levels in mouse testes, indicating oxidative stress. Reproduced from Hou et al. [73], reproduced under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). b Nd₂O₃ elevates inflammatory cytokine levels in NR8383 cells after 24 h of treatment. Reproduced from Huang et al. [77]. c Gd induces neuronal apoptosis by impairing mitochondrial function. Reproduced from Feng et al. [47]. d Sm₂O₃, Eu₂O₃, Gd₂O₃, and Tb₂O₃ trigger autophagy in HeLa cells. Reproduced from Yu et al. [176]

Oxidative stress

The chemical properties and biological activities of REEs depend on factors such as their valence state, structure, and environmental conditions [112]. ROS overproduction and oxidative stress are acknowledged as fundamental mechanisms driving the detrimental impacts of REEs on organisms. Mechanistically, CeO₂ can inhibit ROS production and induce cell resistance to exogenous oxidative stress [163]. However, The Gd₂O₃ and CeO₂-Gd NPs were also seen to generate ROS in U- 87 MG cells after irradiation [108]. Under other conditions, REEs may interact with oxidation–reduction reaction participants, leading to the generation of oxidative damage, but the molecular mechanisms are not clear completely. REEs exhibit dual effects, possibly influenced by their concentration, morphology, and exposure duration. Li et al. demonstrated that La(NO₃)₃ could restore the redox homeostasis that was disrupted by ethanol by provoking the Keap 1/Nrf2/p62 signalling pathway at low concentrations [97,98,99]. However, at high concentrations, they may overproduce free radicals, exceeding the antioxidant capacity of cells, leading to the occurrence of oxidative damage. Khosa et al. concluded that the accumulation of La, Ce, and Nd in the nuclei and mitochondria of hepatocytes results in oxidative stress [87]. In addition, different forms of REEs (such as nanoparticles, solutions, ions, etc.) may have different effects on their actions, affecting their oxidation status on cells. Wang et al. concluded that CeO₂ NPs with a small specific surface area induced more cell apoptosis, leading to increased mitochondrial membrane potential (MMP), ROS, and glutathione (GSH). This reflects a compensatory antioxidant response, but when oxidative stress overwhelms cellular defenses, it reduces the ability to remove hydroxyl radicals, ultimately causing toxicity in human hepatocellular carcinoma cells [153].

Additionally, the dual effects of REEs may be related to cell type and physiological state. Different cell types may respond differently to REEs, and some cells may be more susceptible to their oxidative damage, while others may be more resistant. For instance, Sun et al. have concentrated on the oxidative stress induced by La in choroid plexus epithelial cells. This stress can significantly impede the normal function of the blood-cerebrospinal fluid barrier, resulting in central nervous system dysfunction [140]. Some studies suggest that LaCl₃ exerts oxidative stress effects on the kidney, increasing the production of ROS, increasing lipid, protein, and DNA peroxidation levels, and reducing the activity of superoxide dismutase (SOD) [184]. In mice exposed to La, Ce, and Nd, the activities of hepatic nuclear SOD and catalase (CAT) were reduced, while glutathione peroxidase (GPx), GSH, and malondialdehyde (MDA) levels were increased. Notably, mitochondrial SOD, CAT, GPx, and GSH activities in hepatocytes were significantly decreased, accompanied by a marked increase in MDA levels, suggesting that La, Ce, and Nd may penetrate hepatocytes and disrupt mitochondrial function [78]. In contrast, Leite et al. observed that exposure to praseodymium in the mussel species Mytilus galloprovincialis increased SOD activity at lower concentrations (≤ 40 μg/L) and significantly enhanced glutathione reductase (GR) activity at the highest concentration (80 μg/L). These findings indicate that Pr, within a specific concentration range, may enhance cellular antioxidant capacity by activating antioxidant enzymes [93]. On the contrary, La(NO₃)₃ ameliorates atherosclerosis by regulating lipid metabolism, oxidative stress and endothelial dysfunction in mice [97,98,99]. Therefore, in the study of oxidative stress damage of REEs, the above factors should be comprehensively considered, and the mechanism of action should be further explored through systematic experimental design and analysis.

Inflammation

REEs NPs exposure can additionally stimulate inflammatory responses in target organs. When macrophages are exposed to intratracheal instillation, they can cause inflammation and produce pro-inflammatory cytokines, chemokines, and growth factors. In the liver, the increased population of monocyte-derived macrophages may enhance liver damage by secreting pro-inflammatory cytokines [52]. As an important participant in the inflammatory process, mast cells may play a key role in lung inflammation [20]. Wingard et al. showed that CeO₂ has the ability to directly stimulate mast cells, leading to the production of inflammatory cytokines and chemokines, using laboratory tests in C57BL/6 mice. Collectively, these data suggest that mast cell activation may act as a neglected inflammatory mechanism when exposed to CeO₂ [158]. Hong et al. conducted a study to assess the oxidative stress and molecular mechanism involved in pulmonary inflammation caused by long-term lung toxicity in mice. The animals were treated with injected CeCl₃ for a period of 90 consecutive days. Their experiment proved that a large number of Ce accumulation in the lung, leading to a prominent increase in lung index, inflammatory cells as well as produce lung inflammation [71]. At the same time, by comparing REEs NPs with other toxic particles, Han et al. concluded that all types of REEs NPs have higher inflammatory potential than other toxic particles [65].

Mitochondrial dysfunction

Mitochondria function as vital hubs for cellular metabolism, facilitating energy production and metabolic processes. They are renowned for their pivotal role in ATP synthesis through oxidative phosphorylation, a cornerstone of cellular catabolism [147]. Studies have revealed that the CeCl₃ efficient activation of caspase- 3 and- 9, inhibition of Bcl- 2, increased the levels of Bax and cytochrome c, and promoted the accumulation of ROS in the mouse hippocampus, implying that CeCl₃ induced apoptosis in the mouse hippocampus is triggered by a mitochondria-mediated pathway [35]. Wu et al. reported that collapse the MMP, release cytochrome c into the cytosol, and increase the activated caspase- 3 expression, triggering the mitochondrial apoptotic pathway in cortical neurons. LaCl₃ elevated intracellular Ca.²⁺ concentration, promoting the generation of ROS, up-regulates pro-apoptotic Bax, and downregulates anti-apoptotic Bcl- 2 expression, thereby changing the Bcl- 2 ratio, ultimately leading to mitochondrial apoptosis in neurons. In summary, the toxicity of La in cortical neurons may be partly attributed to enhanced mitochondrial apoptosis [159]. Besides, exposure to Gd causes disruption of the oxidative state, mitochondrial dysfunction, apoptosis, necrosis, and autophagy [47]

Autophagy

REEs have emerged as significant players in cellular responses, particularly in the induction of autophagy, a pivotal process crucial for cell survival. Autophagy is typically activated by food and ATP depletion, but ROS production and oxidative stress also play important roles in autophagy regulation [84]. rare earth oxide nanocrystals is a novel class of autophagy inducers [113]. The rare-earth Y causes cell death and autophagy in the male reproductive system via the ROS-Ca²⁺-CamkII/AMPK axis [73]. Moreover, Le et al. revealed that rare earth oxide nanocrystals activate autophagy in HeLa cells (Fig. 6d) [176]. Further elucidation of the molecular pathways involved unveils the complex mechanisms underlying REEs-induced autophagy. For instance, LaCl₃ can activation of ROS-AMPK-mTOR signaling pathway, increase the expression level of autophagy-related proteins, and lead to abnormal enhancement of autophagy [103]. Additionally, understanding the cellular uptake mechanisms and intracellular trafficking of REEs provides crucial insights into their modes of action. The interplay between REEs and cellular organelles, such as lysosomes and endoplasmic reticulum, further elucidates the multifaceted nature of REEs-induced autophagy.

DNA, RNA and Proteins Damage

REEs exhibit significant interactions with DNA, ribonucleic acid(RNA) and proteins, influencing their structural integrity and biological functions (Table S2). Ln are particularly effective catalysts for the hydrolytic cleavage of phosphate ester bonds, including those in DNA [50]. Recent studies have shown that exposure to La metal–organic frameworks can alter the expression of DNA methylation and demethylation enzymes, suggesting potential epigenetic modifications even at low concentrations [23]. Additionally, single-effect analyses indicate that Y, La, and Tb significantly elevate mitochondrial DNA copy number (MtDNACN), with Y posing the highest risk for genetic damage [72]. REEs also play a critical role in stabilizing DNA secondary structures. For instance, Satapathy et al. [132] demonstrated that low concentrations of LREEs can stabilize G-quadruplex structures in human telomere sequences, which has potential applications in the design of functional nanomaterials and molecular switches [132]. Furthermore, Bhanjadeo et al. [14] found that LaCl₃ strongly binds to the phosphate backbone of Z-DNA, suggesting its role as an inducer of left-handed DNA conformations [14]. These findings highlight the ability of REEs to modulate DNA topology, which may influence gene regulation and disease mechanisms.

Occupational and environmental exposure studies further underscore the biological impact of REEs. For example, Bai et al. [9] reported that simultaneous exposure to REEs in factory workers may synergistically enhance DNA damage, emphasizing the need for careful monitoring of mixed exposures [9]. Moreover, Ln cations have been shown to induce DNA compaction in a concentration- and force-dependent manner, which could affect chromatin organization and gene expression [131]. Population-based studies have also linked maternal REEs exposure during the third trimester to increased neonatal mitochondrial DNA content, suggesting potential transgenerational effects [106]. Mechanistically, REEs can induce DNA damage through oxidative stress pathways. Song et al. reported that LaCl₃ decreased the expression of LKB1, p-LKB1, STRAD and MO25 proteins, and directly or indirectly affected the expression of LKB1, leading to axonal abnormalities in offspring rats [139]. Xiong et al. [165] demonstrated that YCl₃ induces DNA damage by causing intracellular ROS overproduction and inhibiting antioxidant defense mechanisms [165]. These findings collectively highlight the dual role of REEs in both stabilizing DNA structures and inducing damage, depending on the context and concentration. The toxicity mechanisms of REEs are still under active investigation. Beyond the mechanisms previously discussed, epigenetic alterations have emerged as significant contributors. Wang et al. analyzed the expression profiles of miRNA, lncRNA, circRNA, and mRNA in mouse testicular tissue after exposure to Nd₂O₃ through RNA sequencing and found that the abnormal expression of these RNA molecules is closely related to reproductive damage [154].

Conclusions

Despite the notable industrial benefits of REEs, their extensive production and use have led to significant environmental contamination, creating serious risks for both human health and ecosystems. REEs can permeate the human body through various routes—such as inhalation, ingestion, dermal contact, and medical procedures—leading to their accumulation and damage across multiple organ systems. Research suggests that REEs may induce oxidative stress, disrupt mitochondrial function, and cause harmful effects on the respiratory, cardiovascular, digestive, reproductive, and nervous systems. Nonetheless, the exact link between in vivo and in vitro toxicity and the mechanisms involved remain unclear. There is a critical need for further epidemiological studies to confirm animal model findings and explore the long-term effects of REEs exposure. Key issues to address include: the functional mediators involved, their activation by REEs, their interactions, and the upstream factors that regulate relevant signaling pathways. The lack of official occupational exposure limits for REEs underscores the necessity for detailed guidelines and protective measures, to reduce worker exposure. Tackling these issues requires continued research and the establishment of effective safety standards.