Oxidative stress of Cr(III) and carcinogenesis

CHAPTER

Oxidative stress of Cr(III) and carcinogenesis

10

James T.F. Wise⁎, Lei Wang†, Jie Xu†, Zhuo Zhang‡, Xianglin Shi⁎,†,‡ Division of Nutritional Sciences, Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, United States* Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY, United States† Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY, United States‡

­INTRODUCTION Trivalent chromium [Cr(III)] was previously considered an essential nutrient and is used in high concentrations by some individuals as a dietary supplement (1,2). Given, the usage of Cr(III) as a dietary supplement, its toxicity had been of previous concern; however, after extensive studies, it has been established that at dietary and supplementation exposure levels of Cr(III) are toxicologically safe (1). Cr(III) is poorly absorbed across the plasma membrane of mammalian cells and the cell wall of bacteria (1,3). Cr(III) is also poorly absorbed into the nucleus, and instead it is Cr(VI) that crosses into the nucleus and then is reduced to Cr(III) which can bind/ interact with DNA (3). Thus it is generally considered not toxic; however, hexavalent chromium [Cr(VI)] is a known human carcinogen (3). Cr(VI) is reduced to Cr(III) inside the cell, and this intracellular Cr(III) is important to Cr(VI)-induced carcinogenesis (3,4). The exact carcinogenic mechanisms of Cr(VI) remain elusive, though it is clear that DNA damage/genomic instability and reactive oxygen species are key pieces to this mechanism. It has previously been shown that both Cr(VI) and Cr(III) are able to produce reactive oxygen species (ROS), which is a major player mechanism of the Cr(VI)-induced carcinogenesis (3–10). Both Cr(VI) and Cr(III) produce ROS through a Haber–Weiss reaction which will be elaborated on in this chapter. We will also discuss Cr(III) potential toxicity and carcinogenesis and briefly the role of Cr(III) in Cr(VI)-induced carcinogenesis. Reactive oxygen species can be oxygen-containing free radicals or nonradicals; these include superoxides, peroxides, singlet oxygen, and hydroxyl radicals (11). In a normal biological system without exposure to a xenobiotic, ROS are generated in a number of reactions, as they can act as secondary messengers and activate various intercellular and intracellular pathways (12). These pathways include those involved with apoptosis, autophagy, apoptosis, inflammation, and so on (13). Yet, ROS are considered as a ‘double-edged sword’ as they can be secondary messengers but also The Nutritional Biochemistry of Chromium(III). https://doi.org/10.1016/B978-0-444-64121-2.00010-6 © 2019 Elsevier B.V. All rights reserved.

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be toxic to cells and be involved in carcinogenesis. The unpaired electrons endow the free radicals to be highly reactive, and thereby they can damage biomolecules (e.g., lipid, protein, and DNA) (14). As stated previously, the direct mechanisms of Cr(VI)-induced toxicity and carcinogenesis remain elusive, but it is well established that ROS and Cr(III) play major roles. Cr ions [(III), (IV), (V), and (VI))] are able to produce intracellular ROS through direct reactions with cellular molecules or indirect reactions through stimulation of cells (5). Cr species have been shown to produce a whole spectrum of ROS, such as the superoxide anion radical (O2•-), hydrogen peroxide (H2O2), and hydroxyl radical (•OH). Cr(III) and Cr(VI) produce •OH through a Haber–Weiss reaction. These ROS produced by chromium induce intracellular oxidative stress, lead to damaged macro-biomolecules, and eventually contribute to different diseases including cancer. Additionally, oxidative stress can directly or indirectly be involved in various mechanisms of carcinogenesis and toxicity (e.g., autophagy dysfunction, chronic inflammation, apoptosis resistance, genetic instability, epigenetic alteration, and metabolic reprogramming); most of these processes have been implicated in Cr(VI)-induced carcinogenesis and have the possibility of being induced by Cr(III) (14). In this chapter, we discuss the mechanisms of ROS generated by the major chromium species, the toxicity of Cr(III), and briefly the role of Cr(III) in Cr(VI) toxicity and carcinogenesis.

­MECHANISMS OF REACTIVE OXYGEN SPECIES In the classical reactions (Haber–Weiss and Fenton) involving iron, O2•- mediates •OH generation from H2O2 and also participates in the reduction of Fe(III) leading to the Fenton reaction (Eqs. (1)–(3), as can be seen in Fig. 1) (15). In the case of Cr(VI) and Cr(III), they replace Fe(II) to produce •OH (as can be seen in Figs. 2 and 3). In regards to Cr(VI)-induced carcinogenesis, the reactive oxygen species produced from the reduction of Cr(VI) to Cr(III) is considered to be the most important key mechanism underlying the carcinogenesis of Cr(VI) (3,6). Cr(III) from this reduction is able to interact with proteins, DNA, and other cellular components via direct interactions (electrostatic interactions, binding, etc.) (3,4,6,16,17). ROS generated by Cr(VI) and Cr(III) is from a Haber–Weiss reaction (Eqs. (7)–(11), as you can see in Fig. 2) (3,6). Fe(III) + •O2– ® Fe(II) + O2

(1)

Fe(II) + H2O2 ® Fe(III) + OH– + •OH

(2)

•

(3)

O2– + H2O2 ® •OH + OH– + O2

FIG. 1 Eqs. (1)–(3): This figure shows the Haber–Weiss reaction involving iron and the Fenton reaction.

­Mechanisms of reactive oxygen species

O2•–

O2

Cr(VI)

(4)

Cr(V)

NADPH

NADP+

2O2•– + 2H+ ® O2 + H2O2

(5)

Cr(V) + H2O2 ® Cr(VI) + •OH + OH– (e) Cr(VI) Cr(VI) (e) Cr(V) Cr(IV) (e) Cr(IV) Cr(III)

(6)

Cr(IV) + Cr(VI) ® 2Cr(V)

(10)

2Cr(IV) ® Cr(III) + Cr(V)

(11)

(7) (8) (9)

FIG. 2 Eqs. (4)–(11): This figure shows the reduction equations of Cr(VI) and the reactive oxygen species produced.

Cr(III) + O2•– ® Cr(II) + O2•–

(12)

Cr(II) + H2O2 ® Cr(III) + •OH + OH–

(13)

FIG. 3 Eqs. (12) and (13): This figure shows equations demonstrating how Cr(III) produces hydroxyl radicals through the Haber–Weiss reaction.

­CR(VI) TO CR(III) Cr(VI) is reduced to Cr(III) by a variety of mechanisms that vary depending on the reducing agents. Cr(V) and Cr(IV) are two short-lived reactive intermediates that are generated during the reduction processes (3). Reducing agents of Cr(VI) include flavoenzymes (i.e., glutathione reductase and ferredoxin NADP+ oxidoreductase), small molecules (i.e., ascorbate and glutathione), cell organelles, and other united systems; these reactions are represented in Eqs. (5)–(9) (as can be seen in Fig. 2) (3). The Haber–Weiss reaction can involve the different valence states of chromium, such as Cr(III), (IV), (V), and (VI). The Haber–Weiss-type mechanism of •OH generation is likely to be more predominant in vivo than the Fenton-type reaction (3,6).

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­CR(III) REDUCTION Once inside the cell Cr(III) can produce ROS, this Cr(III) can be from either the uptake of Cr(III) or the uptake of Cr(VI) and its reduction to Cr(III). However, given the poor absorption of Cr(III) into mammalian cells, the Cr(III) present is likely from the reduction of Cr(VI). Cr(III) is able to produce hydroxyl radicals via a Haber–Weisslike reaction (Eqs. (12) and (13), as can be seen in Fig. 3) (3). It should be noted that the overall generation of •OH from Cr(III) oxidation is lower than that of Cr(VI) (3). It is also important to note that it has been established that Cr(III) can bind to DNA and have interactions with DNA, and therefore it is possible that Cr(III) that interacts or binds to DNA may have significant site-specific • OH generation (17) and this will be elaborated on in sections later (3,6). In general, the conversion of superoxide to the hydroxyl radical is generally too slow to be of physiological significance unless a suitable metal ion [i.e., Fe(II)] is present to act as a Haber–Weiss catalyst (18). Metabolism of Cr(VI) to Cr(III) can act as a Haber– Weiss catalyst (as can be seen in Fig. 4) and provides us with evidence that molecular oxygen is critical to genotoxicity and carcinogenicity of reactions containing Cr(VI) and Cr(III) (3). This figure shows a representation of the reactive oxygen species produced by Cr(III) and Cr(VI), the intermediate chromium species produced, and the various reactive oxygen species produced (8,10).

­CR(III) TOXICITY AND CARCINOGENESIS Cr(VI) is in the form of a tetrahedral chromate anion, and this anion crosses the cell membrane via different anion transport systems (13). Cr(III) is primarily octahedral, and the Cr(III) ions typically cross the cell membrane at very slow rates via simple diffusion or phagocytosis (3). Given that Cr(III) is considered generally safe and is poorly absorbed by cells, due to the nonenvironmentally or nondietary relevant concentrations needed to induce toxicity or potentially cellular transformation and the lengthy exposure time likely required, there are limited studies on Cr(III)-induced carcinogenesis. However, based on the data available for Cr(III) toxicity, we can infer that if Cr(III) is taken into the cell it could cause ROS and DNA damage. This is discussed in more detail in the following sections; most studies have used bioavailable Cr(III) compounds due to the insolubility of inorganic Cr(III) salts in cell culture media and water (10).

­CHROMIUM(III) GENOTOXICITY Reports of tannery workers with long-term inorganic chromium exposures have shown some evidence of some genotoxic effects from Cr(III) including chromosomal aberrations, DNA breaks, and micronuclei formation (19–21). Likewise, Cr(III) epidemiological studies have shown that workers exposed to inorganic Cr(III) have

­Cr(III) toxicity and carcinogenesis

H2O2

•

(II

I)

Cr

(II

)

OH

NAD(P)H oxidase

Cr

O2

NADPH

H2O2

Cr(V)

•

Cr(VI)

OH

Cr +

NAD(P)

H2O2

(IV

•–

O2

•

)

OH

•

Cr

OH

(V

)

H2O2

FIG. 4 A scheme of Cr-mediated Haber–Weiss reactions.

an increased risk for developing cancer (22). These studies suggest that long-term exposures are important to Cr(III)-induced genotoxicity; however, more controlled animal and longer exposure duration cell culture studies are needed. Given the poor absorption of Cr(III) across cellular membranes, cell culture genotoxicity studies have proven challenging. Therefore most of the studies have been carried out with the less active inorganic salts which are poorly absorbed and use nonenvironmentally relevant concentrations, and these studies have been proven largely negative in regards to genotoxicity (10,23). The three organic Cr(III) compounds investigated for toxicity are those used as supplements (chromium(III) picolinate, Kemtrace, and chromium(III) nicotinate) (1,10). Given that Cr(III) is able to produce •OH in a similar mechanism to Cr(VI), we can speculate that if

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cells were exposed to high enough concentration of Cr(III) long enough duration, Cr(III) could likely produce similar changes as seen with Cr(VI); however, the chance of real world exposure of this magnitude is very low. Acute Cr(VI) exposure induces cellular toxicity due to high levels of ROS during the reduction of Cr(VI) to Cr(III) and play a key role in its toxicity, as well as the ability of Cr to cause DNA damage and altered repair (14). Cr(III) is a key Cr species in Cr(VI)induced carcinogenesis and toxicity (16). Numerical and structural chromosome instability have previously been established as a mechanism for Cr(VI)-induced carcinogenesis (24,25). In laboratory settings, Cr(III) has been shown to directly interact with DNA and induce DNA damage. More specifically, in cell-free systems Cr(III) was shown to bind to DNA and lead to decreases in fidelity and increasing in the processivity of DNA polymerases, both of which have the potential to lead to increased mutations (17,23,26). Similar to this, it has been surmised that in cell-free systems Cr(III) is able to produce a variety of genotoxic outcomes including mutations (23). Fang et al. reported that Cr(III) is able to interfere with base pair stacking and induce genotoxicity in yeast and in Jurkat cells (27). Additionally, in vitro studies have indicated that chromium(III) picolinate can generate high valent chromium species which lead to reactive oxygen species and oxidative DNA damage (28–31). In a test tube in the presence of ambient air with appropriate reducing agents (e.g., ascorbate, thiols) or the presence of peroxide, chromium(III) picolinate can give rise to ROS that is capable of generating oxidative damage.

­CR(III) TOXICITY OF DIETARY SUPPLEMENTS The usage of Cr(III) as a dietary substance is common thus human exposure to Cr(III) is of concern. The main dietary supplemental forms of Cr(III) that have been investigated for toxicity are chromium(III) picolinate, chromium nicotinate, and Cr3/ Kemtrace. These three forms of chromium(III) are more bioavailable than inorganic chromium(III) salts and are used in different supplements (10).

­Kemtrace/Cr3

Cr3 or Kemtrace has an LD50 of 2 g/kg body mass in male and female rats (32). Other reports have reported that Cr(III) has no significant effects on body mass, organ mass, feeding, DNA damage, or other deleterious effects in rats (32–36). Cr3 had no developmental effects on Drosophila (37). Similarly, no beneficial effects have been reported with doses as high as 1000 mg Cr/kg body mass for 24 weeks in rats (35). Cr3 has been reported to interact with hydrogen peroxide and form high valent chromium species (38,39), and its acetate analog is also able to undergo oxidation (40). Cr3, unlike chromium(III) picolinate, is poor at cleaving DNA in vitro (41), cleavage of DNA by Cr3 requires high concentrations of hydrogen peroxide (215 uM), and Cr3 cannot cleave DNA in the presence of physiological concentrations of ascorbic acid (41). Consequently, Cr3 or Kemtrace at physiological conditions is unable to produce DNA damage or ROS.

­Cr(III) toxicity and carcinogenesis

­Chromium(III) nicotinate

Chromium nicotinate has a reported acute oral LD50 of 5000 mg/kg in mice and has no effect in the Ames mutagenic assays or in gene mutation tests in mice (42). In mice, a 9-month diet containing doses up to 125 ppm chromium nicotinate had no effects on hepatic lipid peroxidation, DNA fragmentation, or on tissue mass and body mass (42). Similarly providing chromium nicotinate in food for 52 weeks at 25 ppm had no effect on hepatic lipid peroxidation or DNA fragmentation or changes to hematological or clinical chemical parameters in male and female Sprague-Dawley rats (43). Body mass gains were lower in both males and females in the chromium nicotinate, although the potential harmful or lasting impacts of this are uncertain. There were no developmental effects observed with long-term treatment studies in Sprague-Dawley rats (44,45). Likewise, in Drosophila no effects have been observed from treatment with chromium nicotinate or chromium(III) picolinate (37). Cultured macrophages treated with chromium nicotinate have shown DNA damage, but it should be noted that the extent of damage was less than that caused by similar levels of chromium(III) picolinate (46,47). These studies suggest that chromium nicotinate like Kemtrace is generally safe and does not cause toxicity.

­Chromium(III) picolinate

Chromium(III) picolinate results for the Ames assay for mutagenesis have been negative (48,49). This is most likely due to the inability of chromium(III) picolinate to penetrate the bacterial cell membrane (1). In contrast to the Ames assays, studies in mammalian cells have revealed mixed results. Here we summarize the previous toxicity studies of chromium(III) picolinate. For more details on the genotoxicity of chromium(III) cell culture and in vitro studies, a previous book chapter and reviews should be consulted (1,10,50). Stearns et al. (4) reported that chromium(III) picolinate (suspended in acetone) and mother liquid (from the synthesis of chromium(III) picolinate) are able to induce DNA damage in Chinese hamster ovary (CHO) cells, whereas picolinic acid alone had no effects. Other reports have shown that chromium(III) picolinate is mutagenic at the hprt locus in CHO cells (51) and induce apoptosis and generate mitochondrial damage (52). However, studies by another group failed to reproduce the same results as the study by Stearns (53,54). Vincent (1) discusses in his chapter on chromium(III) toxicity that the differences in results between studies are most likely due to the solvents used to dissolve chromium(III) picolinate, which can influence the reactive oxygen species produced by chromium(III) picolinate. More specifically, as Slesinki’s studies (53,54) used DMSO, which is a radical scavenger, it could lower the mutagenicity of chromium(III) picolinate, where Stearns used acetone, which is not a free radical scavenger. Coryell and Stearns (55) reported that using DMSO lowers the ROS from chromium(III) picolinate. Still, in the same investigation they reported that chromium(III) picolinate dissolved in DMSO was still mutagenic, but not as mutagenic as chromium(III) picolinate in acetone (55). These results clearly indicate that chromium(III) picolinate is mutagenic in CHO cells.

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Other reports have shown that chromium(III) picolinate is able to induce DNA damage, mutagenicity, ROS, and mitochondrial damage in murine macrophages and lymphocytes, and human macrophages, lymphocytes, and T cells (46,47,49,56–58). Likewise, as with CHO cells studies, the vehicle for dissolving chromium(III) picolinate influences its mutagenicity and genotoxicity (1,56). As discussed briefly previously and in more detail in a previous book’s chapter on chromium (III) toxicity (1), the solvent vehicle can affect the cell culture studies for chromium(III) picolinate, as DMSO and others like methanol are free radical scavengers. Cr(III) picolinate has been reported in multiple mammalian cell culture studies to induce DNA damage (47,56,59), induce mutations (55,60), and cause chromosomal aberrations (4) at physiologically relevant doses. Conversely, one study was found to be negative for induction of chromosome damage by chromium(III) picolinate; however, it is important to note that treatment times were limited to only 4 h exposures (53). Kareus et al. (61) reported on the metabolic fate of Cr(III) organic complexes and suggested the high levels of intracellular Cr(III) can accumulate leading to the formation of Cr-DNA adducts and thus potentially cause genotoxic effects. It is clear, however, that chromium(III) picolinate in mammalian cell culture can induce DNA damage and mutagenesis. It is also important to mention that more recent developments in the ability to detect chemical speciation in biological media have revealed that many Cr(III) compounds can be oxidized in extracellular fluids leading to more efficient cellular uptake and DNA damage (62). Multiple Cr(III) compounds have been investigated in Drosophila studies. Chromium(III) tris(2,2-bipyridine), [Cr(bpy)3]3+, was acutely toxic to Drosophila (28,50,63), while chromium nicotinate and chromium(III) chloride failed to produce any significant effects. However, chromium(III) picolinate and to a smaller degree picolinic acid resulted in delays in larvae development and adults and lower success rates in pupation and eclosion (this Cr(III) dosage is equivalent to a human consuming one 200 μg Cr(III)-containing supplement per day) (63). Additionally, chromium(III) picolinate and to a lesser extent picolinic acid had detrimental effects on the longevity of both male and female Drosophila at the nutritionally relevant concentrations (63). Clearly, chromium(III) picolinate and picolinic acid have detrimental effects on all stages of Drosophila. This study also reported that at the same concentrations that developmental and longevity affects were seen; chromium(III) picolinate induces one mutation per chromosome per individual and reduced sterility in females. Another study reported that in the salivary glands of Drosophila larvae that chromium(III) picolinate could produce DNA damage (37). Hepburn et  al. (64) previously reported that at nutritionally relevant concentrations chromium(III) picolinate in rats showed significant increases in urinary 8-­hydroxydeoxyguanosine (8-OHdG), a product of oxidative DNA damage. These levels were reported initially after 32 days of treatment and again at the study competition at 60 days of treatment. Levels of lipid peroxidation were all increased, which can lead to DNA damage and chromosomal damage (65). Anderson (56) reported 3 mg/kg body mass of chromium(III) picolinate to mice does not result in a change in frequency of micronucleated polychromatic erythrocytes in peripheral blood. Also in

­Cr(III) toxicity and carcinogenesis

lymphocytes or hepatocytes, there were no detectable DNA damage by Comet assay (56). However, as noted previously by Vincent (1), the validity of the chromium(III) picolinate used might be questionable for this study and would explain the conflicting results with the other studies. In general, the in vivo studies with orally administered chromium(III) picolinate have shown no detectable deleterious effects from this supplement, which does not match the in vitro studies’ results. Anderson et al. (66) reported that Cr(III) picolinate is not an acute toxin. Anderson and his coworkers used a dose that was remarkably higher than the adequate intake for Cr(III) supplementation for humans in a rodent study. Rats and mice were fed diets with chromium(III) picolinate monohydrate as high as 50,000 ppm for 13 weeks. No effects on body mass or composition were reported, nor were changes observed in hematology and clinical chemistry parameters (66). A similar report found that four-week-old rats fed diets containing up to 1000 mg of Cr as chromium(III) picolinate per kg diet for 24 weeks produced no major impacts on health. More specifically, histological evaluation of liver and kidney tissues revealed no effects (67). In a chronic dietary exposure study, male and female rats were fed diets containing up 5% chromium(III) picolinate for 2 years (68). Cr(III) picolinate had no effects on body mass, survival, food intake, or neoplastic lesions. Interestingly in male rats, a statistically significant increase in the incidence of preputial gland adenoma was observed in a diet concentration of 1%, but was considered by the researchers to be an equivocal finding (68). Another exposure reported in the same manuscript found similar results (when compared to the 2-year exposure) for effects on body mass, food intake, and survival after 3 months of Cr(III) dietary exposure (68). When examining the ROS-dependent DNA damage generated by chromium(III) picolinate supplementation in rats, no major effects on DNA damage were observed (69,70). A 56-day exposure of obese women to 400 μg of Cr(III) picolinate resulted in no changes in 5-hydroxymethyl uracil, a product of oxidative DNA damage (69). While in Zucker obese rats, it was found that chromium(III) picolinate reduced elevated urinary 8-OHdG levels and improved markers of inflammation; rats had received either 0.19 or 0.41 mg Cr(II)/kg body mass for 20 weeks (70). No effects on DNA damage in bone marrow were observed in Sprague-Dawley rats fed chromium(III) picolinate (71). While in growing finishing pigs, 200, 800, 1600, or 3200 mg Cr/kg diet as chromium(III) picolinate had increased serum superoxide dismutate and kidney catalase at the high concentrations, but there were no effects on malondialdehyde in tissues and blood serum, urinary 8-OHdG, and DNA strand breaks in liver and kidney (72). Mahmound et al. (73) found conflicting results on if Cr(III) picolinate can affect the morphology and histology of rat corneas. Studies have also investigated if chromium(III) picolinate can produce developmental effects. Developmental studies have reported no major changes from chromium(III) picolinate studies (74–77). One study, however, showed that pregnant mice fed 200 mg Cr/kg diet as chromium(III) picolinate had cervical arch defects (74). A similar study noticed the same trend but it was not statistically significant (36). No statistically significant neurological effects on offspring were reported

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in mated mice supplemented with chromium(III) picolinate or picolinic acid (75). When feeding a diet containing chromium(III) picolinate to breeding males, there were no skeletal defects seen in offspring (77). When looking at the reported isolated incidents of the deleterious effects of chromium(III) picolinate supplementation of humans, there have been reports of deleterious effects on weight loss, anemia, thrombocytopenia, liver dysfunction, and renal failure (77,78); rhabdomyolysis (79); acute, short-lasting cognitive, perceptual and motor changes (36); dermatitis (80); hypoglycemia (81); and exanthematous pustulosis (82). However as discussed previously it is difficult to understand the significance of these studies given the lack of proper notes (1). Lastly, given that chromium(III) picolinate was reported to have antidepressant pharmacotherapy for dysthymic disorder (83,84), its neurological effects have been briefly investigated but remain lacking. One study reported that chromium(III) picolinate could lower cortisol response to 5-hydroxytryptophan precursor (85). As discussed in previous reviews (1,85,86) chromium(III) picolinate may cause perceptual and motor changes that may be of concerning, but they could be due to the picolinic acid/picolinate. But, more investigation is still merited.

­Dietary supplement summary

Overall, one of the more bioavailable forms of Cr(III) (chromium(III) picolinate) is able to produce reactive oxygen species that can have profound consequences on the ability of Cr(III) to react with DNA causing mutations and chromosomal aberrations that could lead to genomic instability and potential carcinogenic effects (71,87). As discussed briefly previously and in more detail previously (1), the vehicle used to dissolved the Cr(III) compound can reduce its ROS and genotoxic effects. However, the majority of studies that do use a proper vehicle for dissolving chromium(III) picolinate have demonstrated its ability to induce ROS and cause genotoxicity. As pointed out in a previous review Cr(III) plays no role in DNA repair or its synthesis and has genotoxic potential (10). Interestingly, Cr(III) compounds are generally not toxic when given via oral or dietary exposures for rodents, pigs, and humans, which does not match the controlled laboratory studies. However, a recent NTP study suggests that chromium(III) picolinate may cause genotoxicity in rodents and suggests that more long-term Cr(III) studies looking at carcinogenesis are warranted.

­CR(III) IN DRINKING WATER Cr(III) has also been reported to be in drinking water, but its exact role in toxicity or carcinogenesis from drinking water exposure remains elusive. However, given the poor absorption of Cr(III) via the GI tract (2), Cr(III) is not considered as much of a concern in drinking water as Cr(VI) could be. There have been a limited studies investigating the toxicity of Cr(III) in drinking water. One study reported no chromosome damage found in bone marrow of rats treated with chromium(III) picolinate; however, this was in a single 24-h oral exposure tested after 18 and 42 h (88). A recent study reported that a 42-day exposure of chromium trichloride in drinking

­Cr(III) toxicity and carcinogenesis

water supplied to chickens resulted in oxidative stress and histological alterations in the chicken brains in the high dose group (50% LD50, the LD50 was 5013 mg/kg) (83). These studies suggest that Cr(III) in drinking water at low concentrations may be safe and that at higher concentrations there may be a toxicity concern; however, more studies are warranted.

­COMBINED EXPOSURE STUDIES Cobalt(II)–Chromium(III) metal on metal hip implants are a popular hip replacement for humans. Given their prevalence and the reports of Cr(III) and Co(II) ions showing up in the patients, there is concern of the combined toxicity of Cr(III) and Co(II) (84). In combination or mixture studies, it is possible for Cr(III) to have toxic side effects. Individuals with the metal on metal hip implants have shown increases in chromosome instability measured in their peripheral blood but the significance of this is unknown (84). A long-term study investigated the exposure to physiological relevant concentrations of Cr(III) found in patients with cobalt–chromium hip implants (89). Fibroblast cells were treated with Cr(III) levels that were equivalent to well functioning and worn implant levels in patients; cells exhibited both numerical and structural chromosome instability. A recent proteomic analysis reported that patients with cobalt–chromium hip implants that suffered from adverse local tissue reactions had changes to biological mechanisms associated with tissue damage, necrosis, and inflammation and that these processes may be caused by the Cr(III) and Co(II) ions (90). However, more in-depth mechanistic studies on these correlations are still required.

­CHROMIUM(III) NANOPARTICLES Chromium(III) nanoparticles are emerging Cr(III) compounds that are found occupationally and environmentally. Given the wide use in industrial applications for catalysts and pigments, there is a concern for this Cr(III) compound toxicity. Given nanoparticles do not follow the properties of the parent compounds it is possible that Cr(III) nanoparticles may be harmful while Cr(III) is generally safe (67,91,92). A nanoparticle is a particle that has a diameter of 100 nm or smaller in one of its dimensions (67). When studying the acute (24 h) cytotoxicity of Cr(III) oxide nanoparticles, it was found exposure to human lung carcinoma and human keratinocyte cells results in cytotoxicity levels comparable to hexavalent chromium (67). Chromium(III) nanoparticles were also able to induce ROS and activate antioxidant defense systems in human lung carcinoma and keratinocyte cells (67). Puerari et al. (92) reported on the chronic toxicity of Cr(III) oxide nanoparticles to both Daphnia magna and Aliivibrio fischeri. In brief, they found that Cr(III) oxide nanoparticles were acutely (15 min and 48 h) and highly toxic to both organisms. For D. magna chronic (21 days) exposure to Cr(III) oxide nanoparticles affected longevity, metabolism, reproduction, and growth (92). Another report found that hepatocytes exposed at high concentrations, 300–1000 ppb of chromium(III) picolinate nanoparticles,

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possessed no DNA damage after 30 min (67). It was also reported that 2 months of exposure to chromium(III) picolinate nanoparticles in feed results in no signs of toxicity in rats (91). These initial Cr(III) nanoparticle studies indicate that inorganic Cr(III) nanoparticles may be of concern; whereas, organic Cr(III) nanoparticle compounds have a similar toxicity profile as organic Cr(III) compounds and are possibly safe. More studies are needed on the toxicity of Cr(III) nanoparticle compounds as the literature are limited.

­ROLE OF CR(III) IN CR(VI) CARCINOGENESIS ROS has a dual role in Cr(VI)-induced carcinogenesis. It is very like that Cr(III) would follow a similar mechanism if exposure duration and level of Cr(III) were long and high enough. In brief, Cr(VI)-induced carcinogenesis can be divided into two parts early and late stage. In the early stage ROS generated by Cr(VI) reduction is high and causes a variety of issues that drive the carcinogenesis process. These include genomic instability, impaired DNA repair, epigenetic modifications, and redox imbalances (10,14). During Cr(VI)-induced carcinogenesis and after reduction of Cr(VI) to Cr(III), Cr(III) is able to interact with DNA and with proteins. These interactions have been shown to be key to Cr(VI) carcinogenic mechanism (3,5,16,17). Cr(III) can also produce ROS through the Haber–Weiss-like reaction, as discussed in more details earlier, and this ROS can produce the same dysfunctions as ROS produced by Cr(VI). Then during the late stage, the role of ROS changes and it becomes used as a survival mechanism by the cells/tumor, where ROS levels are lower and drive the survival advantages and other changes (autophagy deficiency, oncogenic protein accumulation, angiogenesis, and chronic inflammation) in the cells/ tumor (14). These outcomes clearly demonstrate a role for Cr(III) in Cr(VI)-induced carcinogenesis.

­SUMMARY To summarize Cr(III) is generally safe at dietary exposure levels and is not a carcinogen. Although it is important to clarify that the Cr(III) species is a key piece to the mechanisms of toxicity and carcinogenesis of Cr(VI). Multiple species of Cr are able to induce ROS, Cr(VI), Cr(IV), Cr(V), and Cr(III). Cr(III) by itself in the presence of hydrogen peroxide can produce ROS in a Haber–Weiss reaction. It has been shown that with a high concentration of Cr(III) it is able to cause ROS inside of mammalian cells and cause DNA damage. It is therefore possible that if a long enough exposure duration combined with a high enough concentration was used, Cr(III) may induce carcinogenesis. However, chronic Cr(III) treatment studies in vitro and in vivo would be needed to confirm these speculations. Interestingly, Cr(III) picolinate nanoparticles have failed to show the same results as Cr(III) picolinate, but more studies are warranted. Initial studies have indicated that Cr(III) oxide nanoparticles are just as genotoxic as Cr(VI) compounds, but again more studies are warranted. While Cr(III)

­References

at supplemental and dietary concentrations are toxicologically safe. Cr(III) may be safe in drinking water; as more data on Cr(VI) becomes available, this should become more clear. Lastly, the combined exposure of Co(II) and Cr(III) in hip replacement patients should still be investigated, as there is the potential for toxicity and possibly cancer for this combined exposure.

­ACKNOWLEDGMENTS We would like to thank Hong Lin for technical and administrative support.

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­FURTHER READING 93. McLeod, M. N.; Gaynes, B. N.; Golden, R. N. Chromium Potentiation of Antidepressant Pharmocotherapy for Dysthymic Disorder in 5 Patients. J. Clin. Psychiatry 1999, 60, 237–240. 94. McLeod, M. N.; Golden, R. N. Chromium Treatment of Depression. Int. J. Neuropsychopharmacol. 2000, 3, 311–314.