Review
Immunotoxicity of nickel: Pathological and toxicological effects

https://doi.org/10.1016/j.ecoenv.2020.111006Get rights and content

Highlights

  • Ni inhibits immune organ development.

  • Ni inhibits cytokines and immunoglobulins production.

  • Ni impair NK cells and macrophages activity.

  • Ni induces allergic contact dermatitis.

Abstract

Nickel (Ni) is a widely distributed metal in the environment and an important pollutant because of its many industrial applications. With increasing incidences of Ni contamination, Ni toxicity has become a global public health concern and recent evidence suggests that Ni adversely affects the immune system. Hence, this paper reviews the literature on immune-related effects of Ni exposure, the immunotoxicological effects of Ni, and the underlying mechanism of Ni immunotoxicity. The main focus was on the effect of Ni on the development of organs of immune system, lymphocyte subpopulations, cytokines, immunoglobulins, natural killer (NK) cells, and macrophages. Moreover, Ni toxicity also induces inflammation and several studies demonstrated that Ni could induce immunotoxicity. Excessive Ni exposure can inhibit the development of immune organs by excessively inducing apoptosis and inhibiting proliferation. Furthermore, Ni can decrease T and B lymphocytes, the specific mechanism of which requires further research. The effects of Ni on immunoglobulin A (IgA), IgG, and IgM remain unknown and while Ni inhibited IgA, IgG, and IgM levels in an animal experiment, the opposite result was found in research on humans. Ni inhibits the production of cytokines in non-inflammatory responses. Cytokine levels increased in Ni-induced inflammation responses, and Ni activates inflammation through toll like (TL)4-mediated nuclear factor-κB (NF-κB) and signal transduction cascades mitogen-activated protein kinase (MAPK) pathways. Ni has been indicated to inactivate NK cells and macrophages both in vitro and in vivo. Identifying the mechanisms underlying the Ni-induced immunotoxicity may help to explain the growing risk of infections and cancers in human populations that have been exposed to Ni for a long time. Such knowledge may also help to prevent and treat Ni-related carcinogenicity and toxicology.

Introduction

Nickel (Ni) is an abundant metal in the Earth's crust and is the 24th most abundant element. Also, Ni is nutritionally regarded as an essential trace element for many animal species, plants, and microorganisms (Chivers, 2015; Genchi et al., 2020; Shahzad et al., 2018; Zambelli and Ciurli, 2013). Because of its unique chemical properties, Ni has extensive applications in various modern industrial fields, such as refining, electroplating, welding, electroforming, and the production of nickel-cadmium batteries (Binet et al., 2018; Schaumloffel, 2012). The consumption of products containing Ni has resulted in environmental pollution by Ni and its compounds. With increasing incidences of Ni contamination over recent years, the toxicity of Ni has also attracted more attention (Filatova and Cherpak, 2020; Lyu et al., 2019; Zambelli et al., 2016; Zhang et al., 2019). Many studies have suggested that Ni exposure can result in various adverse health effects, such as developmental toxicity, genotoxicity, immunotoxicity, haematotoxicity, reproductive toxicity, and neurotoxicity (Denkhaus and Salnikow, 2002; Doll, 1984; Dumala et al., 2019b; Guo et al., 2016b, 2016c; Rizvi et al., 2020; Zhang et al., 2019, 2020). Furthermore, oxidative stress, apoptosis, and DNA damage are important molecular mechanism underlying Ni toxicology (Guo et al., 2016a, 2019b). In 1950, the carcinogenic effects of Ni and its compounds have been recognized and reported (Bidstrup, 1950). Several epidemiological reports showed that Ni exposure because of occupational needs results in a higher prevalence of nasal and lung cancers in humans (Cempel and Nikel, 2006; Das et al., 2008; Kalagbor et al., 2019). In 1990, Ni and its compounds have been classified as group 1 carcinogens (i.e., confirmed carcinogen) to humans by the International Agency for Research on Cancer (IARC) (Scarselli et al., 2018).

Until now, a large body of scientific evidence summarizes the deleterious effect of Ni on the immune system (Petersen et al., 2019; Singh et al., 2019). Ni immunotoxicity potentially forms a significant part of Ni carcinogenesis in various tissues since it decreases immune surveillance. Previous research showed that nickel chloride (NiCl2) impairs the immune system of broiler chickens (Huang et al., 2014; Tang et al., 2015; Wu et al., 2013, 2014a; Yin et al., 2016a). NiCl2 has been shown to inhibit the development of immune organs and increase lymphocyte apoptosis (Huang et al., 2013; Tang et al., 2014, 2015; Wu et al., 2014a; Yin et al., 2016a). It has also been shown that Ni exerts toxic effects on the growth of macrophages and B cells in vitro (Guo et al., 2019a; Lou et al., 2013; Sunderman et al., 1989; Taira et al., 2008; Volke et al., 2013). While many studies have shown that Ni in fact imparted immunotoxicity, the underlying mechanism still remains unclear, and no evidence is available on the effect of Ni on bone marrow and complement systems. The goal of this review therefore is to summarize recent research about the immunotoxicity of Ni, including the development of organs of immune system, lymphocyte subpopulations, cytokines, immunoglobulins, natural killer (NK) cells, and macrophages, and also allergic contact dermatitis. This review will be helpful for the identification of defects in the mechanisms underlying Ni toxicity, and will provide a theoretical basis for the prevention and treatment of Ni-related carcinogenicity and toxicology.

Section snippets

Source of Ni exposure

Ni belongs to group VIII B in the periodic table (Cempel and Nikel, 2006), is widely distributed, and is released from both natural and anthropogenic sources. Ni can occur in the water, air, soil, and biological materials. In the atmosphere, Ni originates from dust blown by wind, volcanic emissions, weathering products of soils and rocks, wild fires, and vegetation (Das et al., 2018). Ni exists in nature either in insoluble particles, such as nickel sulfides (e.g., NiS and Ni3S2), oxides (NiO),

Effect of Ni on the organs of immune system

The immune system comprises of organs that control the production and maturation of lymphocytes. Over recent decades, great attention has been paid on the roles of Ni in the modulation of immune system. Previous works have confirmed that Ni and its compounds can impair immune organs, such as thymus, spleen, bursa of Fabricius and cecal tonsil (Supplemental Table 1).

Effect of Ni on lymphocyte subpopulations

Immunophenotyping of the lymphocytes of the blood serves as a key instrument for the diagnosis of immunologic and hematologic disorders (Deneys et al., 2001). Evidence from recent past indicates that Ni greatly influences many subpopulations of immune cells (Salsano et al., 2004). The population of T lymphocytes is a crucial decisive factor for cellular immunity (Zuluaga et al., 2016). As an essential component of cell-mediated immunity, T lymphocytes can be further categorized into many

Effect of Ni on cytokines

The immune system is a complex network consisting of single cells, lymphoid tissues and organs, and cell aggregations. To achieve a coordinated immune response, effective communication within the network is needed, which is accomplished by cytokines (Brodin and Davis, 2017). Cytokines regulate lymphocyte proliferation and differentiation, cell trafficking and inflammation, and lymphoid development (Huang et al., 2005). Th1 helper cells increase the responses mediated by cells, particularly to

Effect of Ni on immunoglobulins

Recent studies that evaluated antibody levels of Ni-exposed individuals reported conflicting results (Table 3). Singh et al. (2019) reported no changes in serum total immunoglobulin (Ig) and IgG concentrations in female hariana heifers in response to exposure to 3.0 mg of Ni/kg. However, another study reported that ingestion of NiSO4 could depress the responses of IgG and IgM antibodies against keyhole limpet hemocyanin (KLH) injection in mice (Schiffer et al., 1991). A previous study also

Effect of Ni on NK cells and macrophages

Macrophages and NK cells exert a significant function in immunity and immune responses (Gordon, 2003; Vivier et al., 2008). They assume a defensive role in the phagocytosis of parasites and microbes. It has been shown that Ni can affect the activity and survival of macrophages and NK cells (see supplementary Table 2). Mice injected with NiCl2 showed suppressed activities of splenic NK cells and phagocytic activities of resident peritoneal macrophages (Smialowicz et al., 1984, 1985). Systemic

Conclusions

This review summarizes recent research on Ni immunotoxicity. Excessive Ni exposure can inhibit immune organ development by inducing excessive apoptosis and proliferation inhibition. Moreover, while Ni can decrease T and B lymphocytes, the specific underlying mechanism requires further research. Effects of Ni on IgA, IgG, and IgM were elusive. Ni inhibited IgA, IgG, and IgM levels in animal experiments but the opposite result was found in human research. Also, Ni inhibited the production of

Declaration of competing interest

The authors declare that there are no conflicts of interest.

Acknowledgment

This research was supported by the program for Changjiang scholars and the university innovative research team (IRT 0848), and the Shuangzhi project of Sichuan Agricultural University (03572437; 03573050).

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