Chemosphere xxx (2013) xxx–xxx
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Review
Immunotoxicity of aluminum Yanzhu Zhu a,b,⇑,1, Yanfei Li b,⇑,1, Liguang Miao a, Yingping Wang a, Yanhuan Liu a, Xijun Yan a, Xuezhe Cui a, Haitao Li a a b
Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, Jilin 130112, China College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
h i g h l i g h t s This review showed that Al had immunotoxicity. The recent research of Al immunotoxicity was reviewed. The adverse effect of the Al immunotoxicity was pointed out.
a r t i c l e
i n f o
Article history: Received 14 May 2013 Received in revised form 5 October 2013 Accepted 21 October 2013 Available online xxxx Keywords: Al Immune function Lymphocytes Toxicity
a b s t r a c t Aluminum (Al) is present in the daily life of all humans. With the incidence of Al contamination increased in recent years, the toxicity of Al on the immune function has attracted more attention. Even with this increased attention, the mechanism of Al immunotoxicity still remains unclear. The mechanism of Al immunotoxicity reviewed herein focused on the effects of Al on the splenic trace elements, the status of a-naphthyl acetate esterase (ANAE) cells, cytokines, complement and immunoglobulins, as well as macrophages. The studies in the literature showed that Al decreased splenic iron (Fe) and zinc (Zn) levels, but the effects of Al on splenic copper (Cu) level was ambiguous and controversial. Al exposure inhibited levels of ANAE+ cells, the production of interleukin (IL)-2 and the functions of macrophages. With respect to other key cytokines, studies showed that Al suppressed the production of tumor necrosis factor (TNF)-a in vitro; effects of Al on TNF-a formation in vivo were less overt. Al exposure reduced complement 3 (C3) level, but effects of Al exposure on complement 4 (C4) level were not as clear-cut. Lastly, the effects of Al exposure on the IgG, IgM and IgA levels were conflicting. Taken in totality, the results of several studies in the literature demonstrated that Al could impart adverse effects on immune function. Ó 2013 Elsevier Ltd. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Effects of Al on the trace elements in the spleen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Effects of Al on the level of a-naphthyl acetate esterase (ANAE+) cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Effects of Al on the cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Effects of Al on the complement factor 3 (C3) and 4 (C4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. Effects of Al on the immunoglobulin G (IgG), M (IgM) and A (IgA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6. Effects of Al on macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7. Aluminum-induced contact dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⇑ Corresponding authors. Address: Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, Jilin 130112, China. Tel.: +86 18043213522; fax: +86 81919849 (Y.Z. Zhu). Tel.: +86 13936574268; fax: +86 45155191672 (Y.F. Li). E-mail addresses: [email protected] (Y.Z. Zhu), [email protected] (Y.F. Li). 1 Both authors contributed equally to this study, Institute of Special Economic Animal and Plant Science in Chinese Academy of Agricultural Sciences and Northeast Agricultural University contributed equally to this study. 0045-6535/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.chemosphere.2013.10.052
Please cite this article in press as: Zhu, Y., et al. Immunotoxicity of aluminum. Chemosphere (2013), http://dx.doi.org/10.1016/j.chemosphere.2013.10.052
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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction Immune function appears to be sensitive to aluminum (Al) exposure; however, this effect still seems to remain controversial. Some studies have noted that effects of Al on immune function were not evident (Gräske et al., 2000). But other studies detailed showed Al immunotoxicity (Synzynys et al., 2004; Khalaf et al., 2008). Even our own previous research showed that aluminum trichloride (AlCl3) did in fact impart immunotoxicity (Zhu et al., 2011a, 2012a). Zhu et al. (2013) had recently written a short review on the immunotoxicity of Al; however, some aspects of Al immunotoxicity were not discussed. Thus, this current paper summarizes effects of Al exposure on levels of some key trace elements in the spleen, a-naphthyl acetate esterase (ANAE+) cells, cytokines, complement and immunoglobulins, as well as upon functions of macrophages. The goal of this review was to provide a better understanding of the potential effects (in vivo and in vitro, where applicable) from Al exposure for the investigators in the field of aluminum biology/toxicology. It will be helpful to find the defect in the mechanisms of Al toxicity and choose appropriate aspect to explore the mechanisms of Al toxicity (Table 1). 1.1. Effects of Al on the trace elements in the spleen The spleen is sensitive to toxicants and other exogenous substances (Sizova et al., 2011). Zinc (Zn), iron (Fe), and copper (Cu) are important trace elements in the spleen and cooperate with each other to regulate immune function (Rink and Kirchner, 2000; Muñoz et al., 2007). It showed that Al interfered with Fe absorption and Fe transfer (Cannata et al., 1991). van Landeghem et al. (1994) pointed out that Al competed with Fe for binding to this protein. This relationship was examined later. It is known that Al is mainly transported in the plasma following enteral absorption and primarily in association with the Fe-binding protein transferrin (Harris, 1996; Yokel and McNamara, 2001). Another study confirmed that Al can be obtained by horse spleen apoferritin in vitro (Ciasca et al., 2011). These results indicated that Al could replace Fe in the proteins that normally contained Fe. On the contrast, others consider that Al did not replace Fe. Al disrupts Fe homeostasis in the brain by several mechanisms including the transferrin receptor, a nontransferrin iron transporter, and ferritin (Kim et al., 2007). A small but significant inhibition of 59Fe uptake from Fe-Tf was seen after addition of Al–Tf to the incubation medium of oligodendrocytes (Golub et al., 1999). It indicates that Al–Tf conpetes Tf receptor with Fe–Tf. But another experiment showed that Al-transferrin did not compete significantly with Fe-transferrin for transferrin receptors (McGregor et al., 1990). It is proposed that aluminum, when bound to transferrin, inhibits iron uptake partly by down-regulating transferrin-receptor expression and partly by interfering with
Table 1 Effects of Al on the immune function. Item
Yes
Immunotoxicity of Al
Synzynys et al. (2004), Khalaf et al. (2008), Zhu et al. (2011a, 2012a)
No
No evidence Gräske et al. (2000)
intracellular release of iron from transferrin. Later, It demonstrated that Al–Tf down-regulates surface Tf receptors on oligodendrocytes and can limit Fe and Mn uptake through this mechanism (Golub et al., 1996). Another study disagree this opinion and found that Al modified Fe uptake without affecting the expression of Tf receptors and induce upregulation of non-Tf bound Fe (NTBI) uptake. This modulation was not due to intracellular Fe decrease since NTBI transport proved not to be regulated by Fe depletion. Unlike its behavior in the presence of Tf, Al was unable to compete with NTBI uptake, suggesting that both metals do not share the same alternative transport pathway (Pérez et al., 2005). The mechanism of Al effects on the Fe remain unclear now. It is not surprising that Al exposure might impact on Fe level in many sites where there is significant ferritin/transferrin trafficking. This would also be an issue with other potential metals transported by such carrier proteins, including Zn and Cu. In keeping with this concept, Fe deficiency enhanced the absorption and accumulation of Al in the spleen of rats (Brown and Schwartz, 1992). Further, Nasiadek and Chmielnicka (2000) reported that Al exposure decreased Fe level in the spleen of female Wistar rats that received daily (for 35 d via gavage) 0.00111 M alone or in conjunction with Fe. Aluminum inhibits hemoglobin synthesis but enhances iron uptake in Friend erythroleukemia cells (Abreo et al., 1990). However, the Friend erythroleukemia cells were specel cell and the increase of Fe may be attributed to the increase of transferring. Aluminum enhances iron uptake and expression of neurofibrillary tangleprotein in neuroblastoma cells (Abreo et al., 1999). Neuroblastoma cells were different from immune cell, so the effects of Al on the Fe uptake may be different. Cao and Jiao (2001) later showed that levels of Zn and Cu in spleen of mice decreased with increased AlCl3 by intraperitoneal (IP) injection. However, there were no significant differences observed regarding to the decrease of Cu in mice which received AlCl3 by IP injections over a period of 2 wk. In contrast to the lack of finding with a more-prolonged exposure scenario, Liu et al. (2007a) showed that levels of Zn, Fe and Cu decreased in the spleen of chicken which were exposed daily to 0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3 for 60 d by IP injection. Clearly,
Table 2 Effects of Al on the Fe, Cu and Zn. Item
Agree
Disagree
The reduction of Fe level induced by Al Al replace Fe
Cannata et al. (1991), Kim et al. (2007), Nasiadek and Chmielnicka (2000), Liu et al. (2007a), Zhu et al. (2012b) van Landeghem et al. (1994), Yokel and McNamara (2001), Harris (1996), Ciasca et al. (2011) Golub et al. (1999)
Abreo et al. (1990), Abreo et al. (1999)
Golub et al. (1996)
Pérez et al. (2005) Zhu et al. (2012b)
Al–Tf competes the Tfreceptor with Fe–Tf Al affected the Tf-receptor Cu Zn
Cao and Jiao (2001), Liu et al. (2007a) Cao and Jiao (2001), Liu et al. (2007a), Zhu et al. (2012b)
No evidence
McGregor et al. (1990)
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because IP injection itself could induce stress (Maricchiolo et al., 2008), the outcomes of that study in regard to Al exposure were likely obscured. In a study that avoided this stress factor and also extended the timeframe of exposure, Zhu et al. (2012b) showed that Fe and Zn level decreased and Cu level increased in spleen of male Wistar rats exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d (Table 2). 1.2. Effects of Al on the level of a-naphthyl acetate esterase (ANAE+) cells T-lymphocytes play a key role in cellular immune function. Any enhancement or reduction of T-lymphocyte-dependent immune function primarily depends on the number of T-lymphocytes present overall, and ANAE+ staining serves as a useful marker for the present of active T-lymphocytes (Vishwase et al., 2003). Zhu et al. (1998) showed that the level of ANAE+ cells increased in Al factory workers that were exposed to Al for 2.4 yr (mean), but decreased in workers exposed for 16.5 yr (mean), mean concentrations of Al and fluorine (F) in the air of Al factory were 9.69 10 8 and 4.0403 10 8 mol L 1, respectively. Since F was also present in the worker environment, and the present of F would affect the levels of ANAE+ cells. Liu et al. (2007b) reported that AlCl3 decreased the level of ANAE+ cells in chickens exposed to 0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3 for 60 d via daily IP injection. In this experiment it showed that Al increased the level of ANAE+ cell. It avoided the effect of F on the level of ANAE+ cell. But IP injection was adopted for a long time. As noted above, because IP injections could induce stress, the outcomes of that study in regard to Al exposure were likely obscured (Maricchiolo et al., 2008). In a study that avoided this stress factor and also extended the timeframe of exposures, Zhu et al. (2012a) showed that the level of ANAE+ cells in AlCl3treated male Wistar rats decreased when the rats were exposed to AlCl3 (0, 0.000144 M, 0.000288 M and 0.000576 M) in drinking water for 120 d. Oral exposure was adopted in this experiment and IP injection was not used compared with the experiments before. In recent experiments, the range of Al dose was from 0 to 0.000576 M. The range of Al exposure time was from 60 d to 2.35 yr. It indicates that Al increases the level of ANAE+ cells in short exposure time. The increased levels of ANAE+ cell were compensatory to regulate the physiology condition. Then with the time increased the ANAE+ cells would be reduced by long-term Al exposure. It indicates that Al decreases the level of ANAE+ cell with long time exposure (Table 3). 1.3. Effects of Al on the cytokines Interleukin (IL)-2 and tumor necrosis factor (TNF)-a are important cytokines, and the changes of which in status can serve as indices of alterations in host immune function. IL-2 exerts both stimulatory and regulatory functions in the immune system (Krieg et al., 2010). TNF-a is a key regulator of innate immunity, and it plays an important role in the regulation of TH1 immune responses against intracellular bacteria and certain viral infections (Silva et al., 2010). The cooperation of IL-2 and TNF-a promote the
Table 3 Effects of Al on the ANAE+ cell. Item
Suppression
Enhancement
ANAE+
Liu et al. (2007b), Zhu et al. (2012a)
Zhu et al. (1998)
No evidence
Table 4 Effects of Al on the IL-2 and TNF-a. Item
Suppression
IL-2
Wei et al. (2001), Wang and Li (2008), Liu et al. (2007a), Zhu et al. (2012a) Wei et al. (2001), Wang and Li (2008), Braydich-Stolle et al. (2010), Zhu et al. (2012a)
TNF-
a
Enhancement
No evidence
Zhu et al. (1998), Liu et al. (2007a)
production of T-lymphocytes and B-lymphocytes to regulate the immune function. Wei et al. (2001) reported that in vitro AlCl3 treatment (0.01 M, 0.05 M, or 0.10 M, for 24 h and 48 h) inhibited IL-2 and TNF-a production by cultured human T-lymphocytes. Wang and Li (2008) similarly showed that AlCl3 treatment (2.996 M, 4.494 M, or 5.992 M for 24 h) inhibited IL-2 and TNF-a production by cultured chicken T-lymphocytes. These experiments focused the in vitro effect of Al on the production of IL-2 and TNF-a. The Al form and in vitro study were adopted. But the lymphocytes were from different animal and the exposure doses of Al were different. They still got the same results. Braydich-Stolle et al. (2010) showed that Al suppressed secretion of TNF-a by human alveolar macrophages (more precisely, cultured human Type II pneumocytes). A part of TNF-a is secreted by macrophages (Howard et al., 2009). And this experiment highlights the relation between Al and TNF-a in macrophages. Even though these in vitro experiments focused on effects of Al using cells from different species (mammal vs. avian), cell types (lymphocyte vs. macrophage), and doses of Al, the results were consistent overall with regard to ex vivo/in vitro effects of Al on IL-2 and TNF-a. With regard to in vivo analyses, Liu et al. (2007a) found that among chickens exposed to 0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3 for 60 d by IP (with the above-noted caveats in place here as well), the level of IL-2 decreased and that of TNF-a increased in the spleen. Zhu et al. (2012a) showed that IL-2 and TNF-a in the serum decreased when the male Wistar rats were orally exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d. The reasons for the change of TNF-a status were related to the compartment being analyzed (i.e., spleen vs. blood) or more attributable to the stressors induced by daily IP injections in the chicken models. These experiments were the in vivo studies. The same Al form and the in vivo condition were adopted. But the animal, Al dose, exposure time and exposure method were different. The results were coincidence in the reduction of IL-2 in vivo, but the effects of Al on the TNF-a in vivo were controversy. The different results may attribute to the exposure time, i.e., 60 d of Liu’s experiment (2007a) is a half of 120 d of Zhu’s experiment (2012a). The change may likely occur if the chickens were continuously exposed to Al for 120 d (Table 4). 1.4. Effects of Al on the complement factor 3 (C3) and 4 (C4) The complement system plays a crucial role in the innate defense against common pathogens and C3 and C4 are important components (Dunkelberger and Song, 2010). It has long been established that there is a relationship between the present of Al and the activation of complement (Ramanathan et al., 1979). It showed that the contact activation of coagulation and complement system were related with silicon and titanium via coagulation factor XII, but Al was not (Arvidsson et al., 2007). Few studies focused on the effects of Al on the levels of C3 and C4. Al(OH)3 is the most common adjuvant in human vaccines, and Al(OH)3 treatment of serum depletes complement components and activates the complement system (Güven et al., 2013). Liu et al. (2007a) showed that levels of C3 decreased and those of C4 increased in chickens
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Table 5 Effects of Al on the C3 and C4. Item
Suppression
C3
Güven et al. (2013), Liu et al. (2007a), Zhu et al. (2011b) Güven et al. (2013), Zhu et al. (2011b)
C4
Table 7 Effects of Al on the macrophages. Enhancement
No evidence
1.5. Effects of Al on the immunoglobulin G (IgG), M (IgM) and A (IgA) IgG, IgM, and IgA are the major immunoglobulins in the serum and their levels are used as important indexes of host humoral immune function (Zhu et al., 2011b). Some studies have focused on the relationship between Al exposure and humoral immune function, but it was unclear whether Al induced adverse effect on humoral immunity or not. Aluminum adjuvants are widely used in human and veterinary vaccines and mainly stimulate humoral immunity. They are appropriate adjuvants for vaccines that confer protection by inducing antibodies via the induction of a type 2 immune response (HogenEsch, 2002). In a study of healthy humans
Table 6 Effects of Al on the IgG, IgM, and IgA. Item
Suppression
Enhancement
No evidence
IgG
Synzynys et al. (2004), Liu et al. (2009) Synzynys et al. (2004), Liu et al. (2009), Zhu et al., (2011b) Synzynys et al. (2004), Liu et al. (2009)
Zhu et al. (2011b)
Gräske et al. (2000) Gräske et al. (2000) Gräske et al. (2000)
IgA
Suppression
Macrophages
Rimaniol et al. (2004), Tong (1990), Wagner et al. (2007), Hu et al. (2011), Goto et al. (1993)
Liu et al. (2007a)
exposed to 0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3 for 60 d by IP injection. Zhu et al. (2011b) found that AlCl3 exposure decreased levels of C3 and C4 in male Wistar rats exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d. The same Al form and the in vivo condition were adopted. But the exposure time, exposure dose, exposure method and experiment animal were different. They also got agreement in the reduction of C3, but the change of C4 induced by Al was different. This may also attributed to the exposure time, i.e., 60 d was less than 120 d. The increase of C4 may attribute to the compensation of physiology function when the experiment animals were exposed to Al. After 60 d, the C4 level would be decreased with the increased exposure time and Al dose. The compensation of the physiology function of the organism was confined. If the effects of Al on the C4 in chicken were continued to study after 120 d, the result will resolve the dispute in this field. Circulating immune complex increased when the male Wistar rats were orally exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d (Zhu et al., 2011a). The circulating immune complex activated the complement system (Zhu et al., 2011a). Therefore, complement can be activated indirectly by Al and was occupied simultaneously by circulating immune complex. C3 was the main component in the complement system and C4 was the second component in complement. C3 was consumed by the circulating immune complex at day 60 and C4 was not consumed completely at day 60. It can explain the increases of C4 in Liu’s experiment (2007a). However, with the time increased the accumulation of Al was enhanced. C4 was dramatically consumed after 120 d. So AlCl3 decreased level of C4 in Zhu’s experiment (Zhu et al., 2011b) (Table 5).
IgM
Item
Zhu et al. (2011b)
Enhancement
No evidence
Table 8 Effects of Al on the contact dermatitis. Item
Induction
Contact dermatitis
Krewski et al. (2007), Hall (1944), Netterlid et al. (2013)
No evidence
ingested with antacid (aluminum hydroxide, 756.41 M, 10 ml three times daily) for 6 wk, no variations over time were found in serum IgG, IgM and IgA levels (Gräske et al., 2000). This was a classic reference in this field though it did not find the effect of Al on the IgG, IgM and IgA. Antacid was chosen as the Al form and 6 wk was very short. The actual Al content might be very less than 22.692 mol Al d 1 for one human. The toxicology of Al did not exert during this little time. Al would be excreted in healthy human. In contrast, AlCl3 possessed marked immunotoxic properties on primary T-dependent humoral immune responses (Synzynys et al., 2004). And this finding broke the knowledge that Al did not affect the levels of IgG, IgM, and IgA. It encourages more researchers to focus this topic in this field. Liu et al. (2009) showed that levels of IgG, IgM and IgA decreased in AlCl3-treated (0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3, 60 d, IP) chickens compared with control chickens. Zhu et al. (2011b) showed that reductions of IgM and the increases of IgA and IgG occurred in male Wistar rats orally exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d. The same Al form and in vivo condition were adopted. But the Al exposure time, Al exposure dose, exposure way and animal model were different. They did not get agreement in these results. The exposure time might play important role in the results. 60 d was shorter than 120 d. IP injection was adopted in Liu’s experiment (2009). Oral exposure was adopted in Zhu’s experiment (2011b). Al will be absorbed from different position when IP injection and Oral exposure were used. This may contribute to the different results. These various studies show that with respect to effects of Al on immunoglobulins, route of exposure, form of the Al agent, and length of exposure are critical variables. Overall, it would be sufficient to state that prolonged exposure to Al affects immunoglobulin status (Table 6).
1.6. Effects of Al on macrophages Macrophages are ubiquitous mononuclear phagocytes present in mammalian tissues; peritoneal macrophages have been recognized as a form of the cells representative of many other macrophages. Al(OH)3-stimulated macrophages contain large and persistent intracellular crystalline inclusions, a characteristic property of muscle infiltrated macrophages described in animal models of vaccine injection, as well as in the recently described macrophagic myofasciitis (MMF) histological reaction in humans (Rimaniol et al., 2004). Al–gel elicited vascular permeabilityincreasing and toxic effects to macrophages (Mu), while its haemolytic effect was weak (Goto et al., 1993). Few studies focused on this field. Tong (1990) showed that in vitro exposure to 3.703 10 6 mol L 1 Al3+ ion significantly inhibited the ex vivo
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phagocytic activity of mouse macrophages. Wagner et al. (2007) found that the phagocytic ability of rat lung macrophages cultured in vitro for 24 h was significantly suppressed by Al nanoparticles at a dose of 0.000926 M. Both of these studies clearly indicated that macrophages were affected by Al. It indicates that Al inhibits the activity of macrophages in vitro. Similarly, in vivo studies by Hu et al. (2011) showed that macrophages were reduced when male Wistar rats were orally exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 kg 1 BW in drinking water for 120 d. It indicates that Al suppresses the function of macrophages both in the in vivo and in vitro experiments (Table 7). 1.7. Aluminum-induced contact dermatitis Contact dermatitis is defined as ‘‘airborne’’ when the causative factor is present in the environment and may determine irritative or allergic skin reactions. It is often work-related (Minciullo et al., 2013). The review of Krewski et al. (2007) mentioned that the occurrence of contact dermatitis and irritant dermatitis was reported in workers exposed to aluminum alloys and aluminum dust. Four cases of contact dermatitis to dural, an alloy of 95–95.5% aluminum, 3.5–4% copper, 0.5% manganese and 0.5% magnesium, and 2 cases of contact dermatitis to aluminum were seen in 202 cases of contact dermatitis among aircraft workers (Hall, 1944). Hall (1944) found the relationship between contact dermatitis and Al, though the occurrence of contact dermatitis induced by Al was low. A total of 205 individuals were invited to quantify the development of contact allergy to aluminum during allergen-specific immunotherapy, and positive test of contact allergy to aluminum during allergen-specific immunotherapy were found in 5/78 children and 3/127 adults (Netterlid et al., 2013). Netterlid et al. (2013) demonstrate that contact dermatitis could be induced by Al, but the occurrence was also very low (Table 8). 1.8. Conclusions This review summarized the recent researches about the immunotoxicity of Al. In general, Al decreased levels of Zn, but effects of Al on Fe and Cu levels was unclear. Other studies showed that Al inhibited the level of ANAE+ and suppressed production of IL-2 in in vivo and in vitro studies. While Al suppressed production of TNF-a in vitro, effects of Al on the TNF-a in vivo were elusive. In addition, Al inhibited C3 levels in vivo, but effects of Al on C4 was conflict with different exposure time. Effects of Al on IgG, IgM and IgA levels were not clear. Lastly, it appears that Al suppresses the function of macrophages both in vivo and in vitro experiments. Al induced contact dermatitis with lower occurrence. In each of the above-noted studies and associated outcomes, a major reason for differing results might be related to variations in experimental conditions. Clearly, Al form, Al dose, exposure time, exposure method and animal model are factors that could influence the effect of Al. Acknowledgments We would like to thank Dr. Mitch Cohen, Editor in Chief of Journal of Immunotoxicology, for his help in writing this paper. This study was supported by a grant from the National Science Foundation Project (31302147, 31172375, 31372496) and Science Foundation for Young Scientists of Jilin Province, China (20130522091JH). To compare the similar studies, the doses of many experiments were treated to have the same unit. If you want to cite the relevant data, please use the primary data in their papers.
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Review
Immunotoxicity of aluminum Yanzhu Zhu a,b,⇑,1, Yanfei Li b,⇑,1, Liguang Miao a, Yingping Wang a, Yanhuan Liu a, Xijun Yan a, Xuezhe Cui a, Haitao Li a a b
Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, Jilin 130112, China College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
h i g h l i g h t s This review showed that Al had immunotoxicity. The recent research of Al immunotoxicity was reviewed. The adverse effect of the Al immunotoxicity was pointed out.
a r t i c l e
i n f o
Article history: Received 14 May 2013 Received in revised form 5 October 2013 Accepted 21 October 2013 Available online xxxx Keywords: Al Immune function Lymphocytes Toxicity
a b s t r a c t Aluminum (Al) is present in the daily life of all humans. With the incidence of Al contamination increased in recent years, the toxicity of Al on the immune function has attracted more attention. Even with this increased attention, the mechanism of Al immunotoxicity still remains unclear. The mechanism of Al immunotoxicity reviewed herein focused on the effects of Al on the splenic trace elements, the status of a-naphthyl acetate esterase (ANAE) cells, cytokines, complement and immunoglobulins, as well as macrophages. The studies in the literature showed that Al decreased splenic iron (Fe) and zinc (Zn) levels, but the effects of Al on splenic copper (Cu) level was ambiguous and controversial. Al exposure inhibited levels of ANAE+ cells, the production of interleukin (IL)-2 and the functions of macrophages. With respect to other key cytokines, studies showed that Al suppressed the production of tumor necrosis factor (TNF)-a in vitro; effects of Al on TNF-a formation in vivo were less overt. Al exposure reduced complement 3 (C3) level, but effects of Al exposure on complement 4 (C4) level were not as clear-cut. Lastly, the effects of Al exposure on the IgG, IgM and IgA levels were conflicting. Taken in totality, the results of several studies in the literature demonstrated that Al could impart adverse effects on immune function. Ó 2013 Elsevier Ltd. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Effects of Al on the trace elements in the spleen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Effects of Al on the level of a-naphthyl acetate esterase (ANAE+) cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Effects of Al on the cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Effects of Al on the complement factor 3 (C3) and 4 (C4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. Effects of Al on the immunoglobulin G (IgG), M (IgM) and A (IgA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6. Effects of Al on macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7. Aluminum-induced contact dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00
⇑ Corresponding authors. Address: Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, Jilin 130112, China. Tel.: +86 18043213522; fax: +86 81919849 (Y.Z. Zhu). Tel.: +86 13936574268; fax: +86 45155191672 (Y.F. Li). E-mail addresses: [email protected] (Y.Z. Zhu), [email protected] (Y.F. Li). 1 Both authors contributed equally to this study, Institute of Special Economic Animal and Plant Science in Chinese Academy of Agricultural Sciences and Northeast Agricultural University contributed equally to this study. 0045-6535/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.chemosphere.2013.10.052
Please cite this article in press as: Zhu, Y., et al. Immunotoxicity of aluminum. Chemosphere (2013), http://dx.doi.org/10.1016/j.chemosphere.2013.10.052
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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction Immune function appears to be sensitive to aluminum (Al) exposure; however, this effect still seems to remain controversial. Some studies have noted that effects of Al on immune function were not evident (Gräske et al., 2000). But other studies detailed showed Al immunotoxicity (Synzynys et al., 2004; Khalaf et al., 2008). Even our own previous research showed that aluminum trichloride (AlCl3) did in fact impart immunotoxicity (Zhu et al., 2011a, 2012a). Zhu et al. (2013) had recently written a short review on the immunotoxicity of Al; however, some aspects of Al immunotoxicity were not discussed. Thus, this current paper summarizes effects of Al exposure on levels of some key trace elements in the spleen, a-naphthyl acetate esterase (ANAE+) cells, cytokines, complement and immunoglobulins, as well as upon functions of macrophages. The goal of this review was to provide a better understanding of the potential effects (in vivo and in vitro, where applicable) from Al exposure for the investigators in the field of aluminum biology/toxicology. It will be helpful to find the defect in the mechanisms of Al toxicity and choose appropriate aspect to explore the mechanisms of Al toxicity (Table 1). 1.1. Effects of Al on the trace elements in the spleen The spleen is sensitive to toxicants and other exogenous substances (Sizova et al., 2011). Zinc (Zn), iron (Fe), and copper (Cu) are important trace elements in the spleen and cooperate with each other to regulate immune function (Rink and Kirchner, 2000; Muñoz et al., 2007). It showed that Al interfered with Fe absorption and Fe transfer (Cannata et al., 1991). van Landeghem et al. (1994) pointed out that Al competed with Fe for binding to this protein. This relationship was examined later. It is known that Al is mainly transported in the plasma following enteral absorption and primarily in association with the Fe-binding protein transferrin (Harris, 1996; Yokel and McNamara, 2001). Another study confirmed that Al can be obtained by horse spleen apoferritin in vitro (Ciasca et al., 2011). These results indicated that Al could replace Fe in the proteins that normally contained Fe. On the contrast, others consider that Al did not replace Fe. Al disrupts Fe homeostasis in the brain by several mechanisms including the transferrin receptor, a nontransferrin iron transporter, and ferritin (Kim et al., 2007). A small but significant inhibition of 59Fe uptake from Fe-Tf was seen after addition of Al–Tf to the incubation medium of oligodendrocytes (Golub et al., 1999). It indicates that Al–Tf conpetes Tf receptor with Fe–Tf. But another experiment showed that Al-transferrin did not compete significantly with Fe-transferrin for transferrin receptors (McGregor et al., 1990). It is proposed that aluminum, when bound to transferrin, inhibits iron uptake partly by down-regulating transferrin-receptor expression and partly by interfering with
Table 1 Effects of Al on the immune function. Item
Yes
Immunotoxicity of Al
Synzynys et al. (2004), Khalaf et al. (2008), Zhu et al. (2011a, 2012a)
No
No evidence Gräske et al. (2000)
intracellular release of iron from transferrin. Later, It demonstrated that Al–Tf down-regulates surface Tf receptors on oligodendrocytes and can limit Fe and Mn uptake through this mechanism (Golub et al., 1996). Another study disagree this opinion and found that Al modified Fe uptake without affecting the expression of Tf receptors and induce upregulation of non-Tf bound Fe (NTBI) uptake. This modulation was not due to intracellular Fe decrease since NTBI transport proved not to be regulated by Fe depletion. Unlike its behavior in the presence of Tf, Al was unable to compete with NTBI uptake, suggesting that both metals do not share the same alternative transport pathway (Pérez et al., 2005). The mechanism of Al effects on the Fe remain unclear now. It is not surprising that Al exposure might impact on Fe level in many sites where there is significant ferritin/transferrin trafficking. This would also be an issue with other potential metals transported by such carrier proteins, including Zn and Cu. In keeping with this concept, Fe deficiency enhanced the absorption and accumulation of Al in the spleen of rats (Brown and Schwartz, 1992). Further, Nasiadek and Chmielnicka (2000) reported that Al exposure decreased Fe level in the spleen of female Wistar rats that received daily (for 35 d via gavage) 0.00111 M alone or in conjunction with Fe. Aluminum inhibits hemoglobin synthesis but enhances iron uptake in Friend erythroleukemia cells (Abreo et al., 1990). However, the Friend erythroleukemia cells were specel cell and the increase of Fe may be attributed to the increase of transferring. Aluminum enhances iron uptake and expression of neurofibrillary tangleprotein in neuroblastoma cells (Abreo et al., 1999). Neuroblastoma cells were different from immune cell, so the effects of Al on the Fe uptake may be different. Cao and Jiao (2001) later showed that levels of Zn and Cu in spleen of mice decreased with increased AlCl3 by intraperitoneal (IP) injection. However, there were no significant differences observed regarding to the decrease of Cu in mice which received AlCl3 by IP injections over a period of 2 wk. In contrast to the lack of finding with a more-prolonged exposure scenario, Liu et al. (2007a) showed that levels of Zn, Fe and Cu decreased in the spleen of chicken which were exposed daily to 0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3 for 60 d by IP injection. Clearly,
Table 2 Effects of Al on the Fe, Cu and Zn. Item
Agree
Disagree
The reduction of Fe level induced by Al Al replace Fe
Cannata et al. (1991), Kim et al. (2007), Nasiadek and Chmielnicka (2000), Liu et al. (2007a), Zhu et al. (2012b) van Landeghem et al. (1994), Yokel and McNamara (2001), Harris (1996), Ciasca et al. (2011) Golub et al. (1999)
Abreo et al. (1990), Abreo et al. (1999)
Golub et al. (1996)
Pérez et al. (2005) Zhu et al. (2012b)
Al–Tf competes the Tfreceptor with Fe–Tf Al affected the Tf-receptor Cu Zn
Cao and Jiao (2001), Liu et al. (2007a) Cao and Jiao (2001), Liu et al. (2007a), Zhu et al. (2012b)
No evidence
McGregor et al. (1990)
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because IP injection itself could induce stress (Maricchiolo et al., 2008), the outcomes of that study in regard to Al exposure were likely obscured. In a study that avoided this stress factor and also extended the timeframe of exposure, Zhu et al. (2012b) showed that Fe and Zn level decreased and Cu level increased in spleen of male Wistar rats exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d (Table 2). 1.2. Effects of Al on the level of a-naphthyl acetate esterase (ANAE+) cells T-lymphocytes play a key role in cellular immune function. Any enhancement or reduction of T-lymphocyte-dependent immune function primarily depends on the number of T-lymphocytes present overall, and ANAE+ staining serves as a useful marker for the present of active T-lymphocytes (Vishwase et al., 2003). Zhu et al. (1998) showed that the level of ANAE+ cells increased in Al factory workers that were exposed to Al for 2.4 yr (mean), but decreased in workers exposed for 16.5 yr (mean), mean concentrations of Al and fluorine (F) in the air of Al factory were 9.69 10 8 and 4.0403 10 8 mol L 1, respectively. Since F was also present in the worker environment, and the present of F would affect the levels of ANAE+ cells. Liu et al. (2007b) reported that AlCl3 decreased the level of ANAE+ cells in chickens exposed to 0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3 for 60 d via daily IP injection. In this experiment it showed that Al increased the level of ANAE+ cell. It avoided the effect of F on the level of ANAE+ cell. But IP injection was adopted for a long time. As noted above, because IP injections could induce stress, the outcomes of that study in regard to Al exposure were likely obscured (Maricchiolo et al., 2008). In a study that avoided this stress factor and also extended the timeframe of exposures, Zhu et al. (2012a) showed that the level of ANAE+ cells in AlCl3treated male Wistar rats decreased when the rats were exposed to AlCl3 (0, 0.000144 M, 0.000288 M and 0.000576 M) in drinking water for 120 d. Oral exposure was adopted in this experiment and IP injection was not used compared with the experiments before. In recent experiments, the range of Al dose was from 0 to 0.000576 M. The range of Al exposure time was from 60 d to 2.35 yr. It indicates that Al increases the level of ANAE+ cells in short exposure time. The increased levels of ANAE+ cell were compensatory to regulate the physiology condition. Then with the time increased the ANAE+ cells would be reduced by long-term Al exposure. It indicates that Al decreases the level of ANAE+ cell with long time exposure (Table 3). 1.3. Effects of Al on the cytokines Interleukin (IL)-2 and tumor necrosis factor (TNF)-a are important cytokines, and the changes of which in status can serve as indices of alterations in host immune function. IL-2 exerts both stimulatory and regulatory functions in the immune system (Krieg et al., 2010). TNF-a is a key regulator of innate immunity, and it plays an important role in the regulation of TH1 immune responses against intracellular bacteria and certain viral infections (Silva et al., 2010). The cooperation of IL-2 and TNF-a promote the
Table 3 Effects of Al on the ANAE+ cell. Item
Suppression
Enhancement
ANAE+
Liu et al. (2007b), Zhu et al. (2012a)
Zhu et al. (1998)
No evidence
Table 4 Effects of Al on the IL-2 and TNF-a. Item
Suppression
IL-2
Wei et al. (2001), Wang and Li (2008), Liu et al. (2007a), Zhu et al. (2012a) Wei et al. (2001), Wang and Li (2008), Braydich-Stolle et al. (2010), Zhu et al. (2012a)
TNF-
a
Enhancement
No evidence
Zhu et al. (1998), Liu et al. (2007a)
production of T-lymphocytes and B-lymphocytes to regulate the immune function. Wei et al. (2001) reported that in vitro AlCl3 treatment (0.01 M, 0.05 M, or 0.10 M, for 24 h and 48 h) inhibited IL-2 and TNF-a production by cultured human T-lymphocytes. Wang and Li (2008) similarly showed that AlCl3 treatment (2.996 M, 4.494 M, or 5.992 M for 24 h) inhibited IL-2 and TNF-a production by cultured chicken T-lymphocytes. These experiments focused the in vitro effect of Al on the production of IL-2 and TNF-a. The Al form and in vitro study were adopted. But the lymphocytes were from different animal and the exposure doses of Al were different. They still got the same results. Braydich-Stolle et al. (2010) showed that Al suppressed secretion of TNF-a by human alveolar macrophages (more precisely, cultured human Type II pneumocytes). A part of TNF-a is secreted by macrophages (Howard et al., 2009). And this experiment highlights the relation between Al and TNF-a in macrophages. Even though these in vitro experiments focused on effects of Al using cells from different species (mammal vs. avian), cell types (lymphocyte vs. macrophage), and doses of Al, the results were consistent overall with regard to ex vivo/in vitro effects of Al on IL-2 and TNF-a. With regard to in vivo analyses, Liu et al. (2007a) found that among chickens exposed to 0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3 for 60 d by IP (with the above-noted caveats in place here as well), the level of IL-2 decreased and that of TNF-a increased in the spleen. Zhu et al. (2012a) showed that IL-2 and TNF-a in the serum decreased when the male Wistar rats were orally exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d. The reasons for the change of TNF-a status were related to the compartment being analyzed (i.e., spleen vs. blood) or more attributable to the stressors induced by daily IP injections in the chicken models. These experiments were the in vivo studies. The same Al form and the in vivo condition were adopted. But the animal, Al dose, exposure time and exposure method were different. The results were coincidence in the reduction of IL-2 in vivo, but the effects of Al on the TNF-a in vivo were controversy. The different results may attribute to the exposure time, i.e., 60 d of Liu’s experiment (2007a) is a half of 120 d of Zhu’s experiment (2012a). The change may likely occur if the chickens were continuously exposed to Al for 120 d (Table 4). 1.4. Effects of Al on the complement factor 3 (C3) and 4 (C4) The complement system plays a crucial role in the innate defense against common pathogens and C3 and C4 are important components (Dunkelberger and Song, 2010). It has long been established that there is a relationship between the present of Al and the activation of complement (Ramanathan et al., 1979). It showed that the contact activation of coagulation and complement system were related with silicon and titanium via coagulation factor XII, but Al was not (Arvidsson et al., 2007). Few studies focused on the effects of Al on the levels of C3 and C4. Al(OH)3 is the most common adjuvant in human vaccines, and Al(OH)3 treatment of serum depletes complement components and activates the complement system (Güven et al., 2013). Liu et al. (2007a) showed that levels of C3 decreased and those of C4 increased in chickens
Please cite this article in press as: Zhu, Y., et al. Immunotoxicity of aluminum. Chemosphere (2013), http://dx.doi.org/10.1016/j.chemosphere.2013.10.052
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Table 5 Effects of Al on the C3 and C4. Item
Suppression
C3
Güven et al. (2013), Liu et al. (2007a), Zhu et al. (2011b) Güven et al. (2013), Zhu et al. (2011b)
C4
Table 7 Effects of Al on the macrophages. Enhancement
No evidence
1.5. Effects of Al on the immunoglobulin G (IgG), M (IgM) and A (IgA) IgG, IgM, and IgA are the major immunoglobulins in the serum and their levels are used as important indexes of host humoral immune function (Zhu et al., 2011b). Some studies have focused on the relationship between Al exposure and humoral immune function, but it was unclear whether Al induced adverse effect on humoral immunity or not. Aluminum adjuvants are widely used in human and veterinary vaccines and mainly stimulate humoral immunity. They are appropriate adjuvants for vaccines that confer protection by inducing antibodies via the induction of a type 2 immune response (HogenEsch, 2002). In a study of healthy humans
Table 6 Effects of Al on the IgG, IgM, and IgA. Item
Suppression
Enhancement
No evidence
IgG
Synzynys et al. (2004), Liu et al. (2009) Synzynys et al. (2004), Liu et al. (2009), Zhu et al., (2011b) Synzynys et al. (2004), Liu et al. (2009)
Zhu et al. (2011b)
Gräske et al. (2000) Gräske et al. (2000) Gräske et al. (2000)
IgA
Suppression
Macrophages
Rimaniol et al. (2004), Tong (1990), Wagner et al. (2007), Hu et al. (2011), Goto et al. (1993)
Liu et al. (2007a)
exposed to 0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3 for 60 d by IP injection. Zhu et al. (2011b) found that AlCl3 exposure decreased levels of C3 and C4 in male Wistar rats exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d. The same Al form and the in vivo condition were adopted. But the exposure time, exposure dose, exposure method and experiment animal were different. They also got agreement in the reduction of C3, but the change of C4 induced by Al was different. This may also attributed to the exposure time, i.e., 60 d was less than 120 d. The increase of C4 may attribute to the compensation of physiology function when the experiment animals were exposed to Al. After 60 d, the C4 level would be decreased with the increased exposure time and Al dose. The compensation of the physiology function of the organism was confined. If the effects of Al on the C4 in chicken were continued to study after 120 d, the result will resolve the dispute in this field. Circulating immune complex increased when the male Wistar rats were orally exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d (Zhu et al., 2011a). The circulating immune complex activated the complement system (Zhu et al., 2011a). Therefore, complement can be activated indirectly by Al and was occupied simultaneously by circulating immune complex. C3 was the main component in the complement system and C4 was the second component in complement. C3 was consumed by the circulating immune complex at day 60 and C4 was not consumed completely at day 60. It can explain the increases of C4 in Liu’s experiment (2007a). However, with the time increased the accumulation of Al was enhanced. C4 was dramatically consumed after 120 d. So AlCl3 decreased level of C4 in Zhu’s experiment (Zhu et al., 2011b) (Table 5).
IgM
Item
Zhu et al. (2011b)
Enhancement
No evidence
Table 8 Effects of Al on the contact dermatitis. Item
Induction
Contact dermatitis
Krewski et al. (2007), Hall (1944), Netterlid et al. (2013)
No evidence
ingested with antacid (aluminum hydroxide, 756.41 M, 10 ml three times daily) for 6 wk, no variations over time were found in serum IgG, IgM and IgA levels (Gräske et al., 2000). This was a classic reference in this field though it did not find the effect of Al on the IgG, IgM and IgA. Antacid was chosen as the Al form and 6 wk was very short. The actual Al content might be very less than 22.692 mol Al d 1 for one human. The toxicology of Al did not exert during this little time. Al would be excreted in healthy human. In contrast, AlCl3 possessed marked immunotoxic properties on primary T-dependent humoral immune responses (Synzynys et al., 2004). And this finding broke the knowledge that Al did not affect the levels of IgG, IgM, and IgA. It encourages more researchers to focus this topic in this field. Liu et al. (2009) showed that levels of IgG, IgM and IgA decreased in AlCl3-treated (0, 0.0000411, 0.0000617 and 0.0000822 M AlCl3, 60 d, IP) chickens compared with control chickens. Zhu et al. (2011b) showed that reductions of IgM and the increases of IgA and IgG occurred in male Wistar rats orally exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 in drinking water for 120 d. The same Al form and in vivo condition were adopted. But the Al exposure time, Al exposure dose, exposure way and animal model were different. They did not get agreement in these results. The exposure time might play important role in the results. 60 d was shorter than 120 d. IP injection was adopted in Liu’s experiment (2009). Oral exposure was adopted in Zhu’s experiment (2011b). Al will be absorbed from different position when IP injection and Oral exposure were used. This may contribute to the different results. These various studies show that with respect to effects of Al on immunoglobulins, route of exposure, form of the Al agent, and length of exposure are critical variables. Overall, it would be sufficient to state that prolonged exposure to Al affects immunoglobulin status (Table 6).
1.6. Effects of Al on macrophages Macrophages are ubiquitous mononuclear phagocytes present in mammalian tissues; peritoneal macrophages have been recognized as a form of the cells representative of many other macrophages. Al(OH)3-stimulated macrophages contain large and persistent intracellular crystalline inclusions, a characteristic property of muscle infiltrated macrophages described in animal models of vaccine injection, as well as in the recently described macrophagic myofasciitis (MMF) histological reaction in humans (Rimaniol et al., 2004). Al–gel elicited vascular permeabilityincreasing and toxic effects to macrophages (Mu), while its haemolytic effect was weak (Goto et al., 1993). Few studies focused on this field. Tong (1990) showed that in vitro exposure to 3.703 10 6 mol L 1 Al3+ ion significantly inhibited the ex vivo
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Y. Zhu et al. / Chemosphere xxx (2013) xxx–xxx
phagocytic activity of mouse macrophages. Wagner et al. (2007) found that the phagocytic ability of rat lung macrophages cultured in vitro for 24 h was significantly suppressed by Al nanoparticles at a dose of 0.000926 M. Both of these studies clearly indicated that macrophages were affected by Al. It indicates that Al inhibits the activity of macrophages in vitro. Similarly, in vivo studies by Hu et al. (2011) showed that macrophages were reduced when male Wistar rats were orally exposed to 0, 0.000144 M, 0.000288 M and 0.000576 M AlCl3 kg 1 BW in drinking water for 120 d. It indicates that Al suppresses the function of macrophages both in the in vivo and in vitro experiments (Table 7). 1.7. Aluminum-induced contact dermatitis Contact dermatitis is defined as ‘‘airborne’’ when the causative factor is present in the environment and may determine irritative or allergic skin reactions. It is often work-related (Minciullo et al., 2013). The review of Krewski et al. (2007) mentioned that the occurrence of contact dermatitis and irritant dermatitis was reported in workers exposed to aluminum alloys and aluminum dust. Four cases of contact dermatitis to dural, an alloy of 95–95.5% aluminum, 3.5–4% copper, 0.5% manganese and 0.5% magnesium, and 2 cases of contact dermatitis to aluminum were seen in 202 cases of contact dermatitis among aircraft workers (Hall, 1944). Hall (1944) found the relationship between contact dermatitis and Al, though the occurrence of contact dermatitis induced by Al was low. A total of 205 individuals were invited to quantify the development of contact allergy to aluminum during allergen-specific immunotherapy, and positive test of contact allergy to aluminum during allergen-specific immunotherapy were found in 5/78 children and 3/127 adults (Netterlid et al., 2013). Netterlid et al. (2013) demonstrate that contact dermatitis could be induced by Al, but the occurrence was also very low (Table 8). 1.8. Conclusions This review summarized the recent researches about the immunotoxicity of Al. In general, Al decreased levels of Zn, but effects of Al on Fe and Cu levels was unclear. Other studies showed that Al inhibited the level of ANAE+ and suppressed production of IL-2 in in vivo and in vitro studies. While Al suppressed production of TNF-a in vitro, effects of Al on the TNF-a in vivo were elusive. In addition, Al inhibited C3 levels in vivo, but effects of Al on C4 was conflict with different exposure time. Effects of Al on IgG, IgM and IgA levels were not clear. Lastly, it appears that Al suppresses the function of macrophages both in vivo and in vitro experiments. Al induced contact dermatitis with lower occurrence. In each of the above-noted studies and associated outcomes, a major reason for differing results might be related to variations in experimental conditions. Clearly, Al form, Al dose, exposure time, exposure method and animal model are factors that could influence the effect of Al. Acknowledgments We would like to thank Dr. Mitch Cohen, Editor in Chief of Journal of Immunotoxicology, for his help in writing this paper. This study was supported by a grant from the National Science Foundation Project (31302147, 31172375, 31372496) and Science Foundation for Young Scientists of Jilin Province, China (20130522091JH). To compare the similar studies, the doses of many experiments were treated to have the same unit. If you want to cite the relevant data, please use the primary data in their papers.
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