A paper available as a pre-proof in the journal Science of the Total Environment demonstrated the comprehensive immune response of various organs, specifically the hematopoietic organs, in adult mice to rare earth element nanoparticle (REE NP) exposure.
Study: Inflammation and accompanied disrupted hematopoiesis in adult mouse induced by rare earth element nanoparticles. Image Credit: ImageFlow/Shutterstock.com
Link Between REE NP Exposure and Immune Response
REE NPs are used extensively in different fields such as wastewater treatment and biomedicine owing to their exceptional physicochemical properties. However, the application of REE NPs is indirectly or directly leading to significant REE contamination in water and soil, specifically around the REE mining areas, which increases the REE exposure through injection, dermal contact, and inhalation.
Several epidemiological studies indicated a link between long-term REE exposure and abnormal liver function, although the extent of damage to the liver is either negligible or mild. However, certain studies have demonstrated that occupational exposure to REE NPs is responsible for pulmonary fibrosis in REE mining workers and polishers.
The spleen and liver are rich in immune cells, such as adaptive and innate immune cells, for immune surveillance. Thus, these organs appear as more injured or inflamed sites when interacting with NPs, exogenous chemicals, and pathogens.
NPs circulating in the blood are eventually accumulated in the spleen and liver, which leads to the immune reaction. Additionally, exposure to REE NPs can also trigger immune responses in the other organs. For instance, after the exposure of REENPs through intratracheal infusion, the inflammation caused by macrophages can generate growth factors and pro-inflammatory cytokines.
The systematic inflammation can lead to abnormally accelerated hematopoiesis, facilitating blood cell generation to maintain homeostasis. Under the systematic inflammatory conditions, accelerated abnormal hematopoiesis can also lead to the generation and release of additional inflammatory cells. These inflammatory cells can adversely impact the inflamed organs by further aggravating the injury of tissues.
Toxicological studies indicated that certain REE-containing molecules or REE NPs can induce drastic immune cell or system responses, leading to adverse effects such as pro-inflammatory cell infiltration and inflammation. However, studies investigating the effect of REE exposure on toxicological mechanisms are limited, which necessitates a comprehensive and systematic investigation based on the animal model to understand the in vivo interaction between the REE NPs and the immune system.
In Vivo Study Based on Animal Model to Evaluate the Effect of REE NPs on the Immune System
In this study, researchers systematically investigated immune responses in vivo using gadolinium oxide (Gd2O3) NPs as model REE NPs. Researchers measured the changes in typical immune system components in the spleen and liver, such as bone marrow cells (B cells), thymus cells (T cells), neutrophils (NEs), myeloid-derived dendritic cells (DCs), monocytes (MOs), and monocyte-derived macrophages (MoMFs). Researchers also measured the effect of Gd2O3 NPs in the spleen and bone marrow and analyzed the peripheral blood cells to understand the overall response of various organs to Gd2O3 NPs.
All investigations were performed in two groups of adult mice, designated as the REE NP group and the control group. Mice in the REE NP group received REE NPs suspended in phosphate buffer saline (PBS) through tail vein injection, while mice in the control group received only PBS through intravenous injection. Blood samples were obtained on day two and day seven. All mice used in the study were narcotized and killed on day two and day seven, and their organs, including brain, kidneys, lungs, spleen, liver, and heart, were collected for experiments.
Researchers performed complete blood count (CBC) analysis, fluorescence-activated cell sorting (FACS) analysis, messenger ribonucleic acid (mRNA) expression level measurements, and cytokine measurement in serum to evaluate the immune responses to Gd2O3 exposure in vivo.
Research Findings
The Gd2O3 exposure induced hematopoiesis disturbance and distinct changes in immune cell types in mice at two milligrams per kilogram dose through intravenous injection. The overall accumulation of Gd2O3 in the spleen and liver collectively accounted for 65 percent of the injected Gd2O3 dose, which indicated that the liver and spleen were the major Gd2O3 deposition sites in the mouse body.
The average Gd2O3 concentration in the spleen was 4.4 times higher compared to the liver. The infiltration of inflammatory mediator NEs and monocyte-derived cells in the spleen and liver, respectively, indicated a higher risk of inflammation due to their mediation in diseases, chronic inflammatory effects, and inflammatory effects under pathological conditions.
The Gd2O3 exposure increased the number of M-DCs and MoMFs in the liver and facilitated the infiltration of B cells, M-DCs, and NEs in the spleen. The increased MoMF population in the liver can enhance damage in the liver by secreting pro-inflammatory cytokines. The secretion of pro-inflammatory mediators in injured organs disrupted the hematopoietic homeostasis.
The duration of Gd2O3 exposure played a significant role in generating the immune response in the liver and spleen. The Gd2O3 exposure for seven days increased the number of altered immune cell types in the liver and spleen and peripheral blood compared to the exposure for two days. Additionally, the hematopoiesis disturbance was more significant on day seven compared to day two.
The Gd2O3 accumulation in the spleen or liver also increased the cytokine concentration in the peripheral blood. In the peripheral blood, the monocytes decreased on day two, while the lymphocytes decreased significantly on day seven, indicating the role of exposure duration in the immune response of peripheral cells.
Gd2O3 increased the number of common lymphoid progenitors, multipotent progenitors, and hematopoietic stem cells (HSCs) in the spleen and bone marrow. On day seven, a significant hematopoietic response was observed in the spleen and bone marrow, indicating that a longer accumulation of Gd2O3 activates hematopoiesis in the spleen and bone marrow.
To summarize, the findings of this study systematically demonstrated the alterations in immune response and hematopoiesis in lymphoid and myeloid lineages induced by exposure to Gd2O3 NPs. However, more research is required to evaluate the potential long-term REE NP toxicity on the hematopoietic system and immune system.
Reference
He, B., Gao, J., Liu, Y. et al. (2022) Inflammation and accompanied disrupted hematopoiesis in adult mouse induced by rare earth element nanoparticles. Science of the Total Environment https://www.sciencedirect.com/science/article/pii/S0048969722025098?via%3Dihub
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