Nickel Abstracts 2

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Cancer

 

The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not
            (Aquino et al., 2012) Download
During the past half-century, incidences of breast cancer have increased globally. Various factors--genetic and environmental--have been implicated in the initiation and progression of this disease. One potential environmental risk factor that has not received a lot of attention is the exposure to heavy metals. While several mechanisms have been put forth describing how high concentrations of heavy metals play a role in carcinogenesis, it is unclear whether chronic, low-level exposure to certain heavy metals (i.e., cadmium and nickel) can directly result in the development and progression of cancer. Cadmium and nickel have been hypothesized to play a role in breast cancer development by acting as metalloestrogens--metals that bind to estrogen receptors and mimic the actions of estrogen. Since the lifetime exposure to estrogen is a well-established risk factor for breast cancer, anything that mimics its activity will likely contribute to the etiology of the disease. However, heavy metals, depending on their concentration, are capable of binding to a variety of proteins and may exert their toxicities by disrupting multiple cellular functions, complicating the analysis of whether heavy metal-induced carcinogenesis is mediated by the estrogen receptor. The purpose of this review is to discuss the various epidemiological, in vivo, and in vitro studies that show a link between the heavy metals, cadmium and nickel, and breast cancer development. We will particularly focus on the studies that test whether these two metals act as metalloestrogens in order to assess the strength of the data supporting this hypothesis.

Nickel carcinogenesis.
            (Kasprzak et al., 2003) Download
Human exposure to highly nickel-polluted environments, such as those associated with nickel refining, electroplating, and welding, has the potential to produce a variety of pathologic effects. Among them are skin allergies, lung fibrosis, and cancer of the respiratory tract. The exact mechanisms of nickel-induced carcinogenesis are not known and have been the subject of numerous epidemiologic and experimental investigations. These mechanisms are likely to involve genetic and epigenetic routes. The present review provides evidence for the genotoxic and mutagenic activity of Ni(II) particularly at high doses. Such doses are best delivered into the cells by phagocytosis of sparingly soluble nickel-containing dust particles. Ni(II) genotoxicity may be aggravated through the generation of DNA-damaging reactive oxygen species (ROS) and the inhibition of DNA repair by this metal. Broad spectrum of epigenetic effects of nickel includes alteration in gene expression resulting from DNA hypermethylation and histone hypoacetylation, as well as activation or silencing of certain genes and transcription factors, especially those involved in cellular response to hypoxia. The investigations of the pathogenic effects of nickel greatly benefit from the understanding of the chemical basis of Ni(II) interactions with intracellular targets/ligands and oxidants. Many pathogenic effects of nickel are due to the interference with the metabolism of essential metals such as Fe(II), Mn(II), Ca(II), Zn(II), or Mg(II). Research in this field allows for identification of putative Ni(II) targets relevant to carcinogenesis and prediction of pathogenic effects caused by exposure to nickel. Ultimately, the investigations of nickel carcinogenesis should be aimed at the development of treatments that would inhibit or prevent Ni(II) interactions with critical target molecules and ions, Fe(II) in particular, and thus avert the respiratory tract cancer and other adverse health effects in nickel workers.

Cobalt and nickel stabilize stem cell transcription factor OCT4 through modulating its sumoylation and ubiquitination.
            (Yao et al., 2014) Download
Stem cell research can lead to the development of treatments for a wide range of ailments including diabetes, heart disease, aging, neurodegenerative diseases, spinal cord injury, and cancer. OCT4 is a master regulator of self-renewal of undifferentiated embryonic stem cells. OCT4 also plays a crucial role in reprogramming of somatic cells into induced pluripotent stem (iPS) cells. Given known vivo reproductive toxicity of cobalt and nickel metals, we examined the effect of these metals on expression of several stem cell factors in embryonic Tera-1 cells, as well as stem cells. Cobalt and nickel induced a concentration-dependent increase of OCT4 and HIF-1α, but not NANOG or KLF4. OCT4 induced by cobalt and nickel was due primarily to protein stabilization because MG132 stabilized OCT4 in cells treated with either metals and because neither nickel nor cobalt significantly modulated its steady-state mRNA level. OCT4 stabilization by cobalt and nickel was mediated largely through reactive oxygen species (ROS) as co-treatment with ascorbic acid abolished OCT4 increase. Moreover, nickel and cobalt treatment increased sumoylation and mono-ubiquitination of OCT4 and K123 was crucial for mediating these modifications. Combined, our observations suggest that nickel and cobalt may exert their reproductive toxicity through perturbing OCT4 activity in the stem cell compartment.

 

Hormones

Hormonal Perturbations in Occupationally Exposed Nickel Workers.
            (Beshir et al., 2016) Download
BACKGROUND:  Nickel exposure is recognized as an endocrine disruptor because of its adverse effects on reproduction. AIM:  This study was designed to investigate the possible testiculo-hormonal perturbations on workers occupationally exposed to nickel and to assess its effects on human male sexual function. METHODS:  Cross-sectional comparative study, comprising 105 electroplating male non-smoker, non-alcoholic workers exposed to soluble nickel and 60 controls was done. Serum luteinizing hormone, follicle stimulating hormone, testosterone levels and urinary nickel concentrations were determined for the studied groups. RESULTS:  Serum luteinizing hormone, follicle stimulating hormone, urinary nickel and the simultaneous incidence of more than one sexual disorder were significantly higher in the exposed workers compared to controls. The occurrence of various types of sexual disorders (decreased libido, impotence and premature ejaculation) in the exposed workers was 9.5, 5.1 and 4.4 folds respectively than the controls. CONCLUSIONS:  Exposure to nickel produces possible testiculo-hormonal perturbations in those exposed workers.

Nickel contact allergy and menstrual cycle.
            (Bonamonte et al., 2005) Download
According to some reports in the literature, the hormonal fluctuations which occur during the menstrual cycle may affect the clinical expression of contact allergy to a greater or lesser degree. In clinical practice, too, patient history often shows exacerbation of the contact dermatitis during the days immediately preceding menstruation. On the contrary, the follicular phase of the cycle seems to have a temporary protective role in inhibiting the eliciting phase of allergic contact dermatitis. One possible explanation for this phenomenon is of immunological type: it has been demonstrated that oestradiol induces inhibition of delayed hypersensitivity type reactions, probably by acting indirectly on cells having a regulatory function in cell-mediated immunity. To investigate any inhibitory effect of the ovulatory phase of the menstrual cycle on contact sensitization, 30 selected fertile women, allergic to nickel sulfate and with a regular menstrual cycle lasting between 25 and 32 days, were enrolled. Patch tests were performed with a series of 10 serial aqueous dilutions of nickel sulfate, from 5% to 0.0013%. The 30 women were tested at 2 different times, in the ovulatory phase (demonstrated by transvaginal ultrasound) and the progestinic phase; they were subdivided into 2 groups of 15 women: in one group, the tests were made first in the ovulatory phase, and in the other, first in the progestinic phase of the menstrual cycle. There was a minimum interval of 5 weeks between the 2 test phases. The study shows that during ovulation the patch tests elicited significantly less intense responses than in the progestinic phase. These data therefore suggest that the ovulatory phase of the cycle has a significant inhibitory role on delayed hypersensitivity type reactions. For this reason, negative responses to patch tests executed in this phase could likely be false-negatives, and after careful evaluation of the phenomenon and of the clinical condition and patient history, it may be considered advisable to repeat the tests during the progestinic phase of the menstrual cycle.

Effect of nickel sulfate on testicular steroidogenesis in rats during protein restriction
            (Das and Dasgupta, 2002) Download
Nickel, a widely used heavy metal, exerts potent toxic effects on peripheral tissues as well as on the reproductive system. Low dietary protein coupled with exposure to this metal induces more severe changes, including biochemical defects, structural disorders, and altered physiologic functions. This study was designed to assess the effects of nickel sulfate on testicular steroidogenesis and to ascertain whether such alterations are reversible with normal protein and protein-restricted dietary regime. Nickel sulfate [2 mg/100 g body weight (bw)] dissolved in double-distilled water was administered on alternate days for 10 doses in a normal protein diet (18% casein) and a protein-restricted diet (5% casein) to Wistar male albino rats (bw 160 +/- 5 g). Two groups, one with a normal protein diet and the other with a protein-restricted diet, served as controls. Twenty-four hours after the last treatment, all the animals except those in withdrawal groups were sacrificed by decapitation. We observed a significant reduction in the activities of the testicular steroidogenic enzymes and plasma testosterone concentration accompanied by a significant elevation in cholesterol and ascorbic acid level in both dietary groups. After 15 days of withdrawal from the nickel sulfate treatment, the testicular steroidogenic enzymes, along with plasma testosterone level, improved significantly in both normal protein-fed and protein-restricted dietary groups. The effects of nickel on testicular cholesterol and ascorbic acid concentration were also reduced after withdrawal. Our results indicate that nickel sulfate affects the steroidogenic enzymes, causing alteration in the formation of testosterone in both dietary groups, which was manifested in the elevated cholesterol and ascorbic acid level with decreased activities of steroidogenic enzymes in adult rats testes. However, these alterations were reversible in both groups of animals fed normal protein diets and protein-restricted diets.


 

Effects of topical testosterone propionate on the positive nickel patch test.
            (Galasso et al., 1996) Download
In a group of nickel sensitized women, we investigated the effects of topical application of testosterone propionate on the epidermic density of CD1 + dendritic cells and on the response to patch tests performed with scaled nickel concentrations. In a significant number of examined subjects, treatment with testosterone propionate induced an increase of the minimum eliciting dose of nickel and an evident reduction of CD1 + dendritic cell epidermic density. In those subjects in which the minimum eliciting dose resulted unmodified, the epidermic density of CD1 + dendritic cells also did not undergo significant variations following treatment with testosterone propionate. This parallelism between the behaviour of the responses to patch tests and the epidermic density of CD1 + dendritic cells induces us to think it possible that testosterone propionate is able to increase the tolerance to contact with allergen by interfering with the activity of Langerhans cells. The possible mechanisms of testosterone action on Langerhans cells remain to be elucidated.

Correlation between urinary nickel and testosterone plasma values in workers occupationally exposed to urban stressors.
            (Sancini et al., 2014) Download
BACKGROUND:  The purpose of this study is to assess whether occupational exposure to low doses of nickel (Ni) present in urban air can cause alterations in the concentration of plasma testosterone in workers of the Municipal Police of a large Italian city assigned to different types of outdoor tasks. METHODS:  359 male subjects were included in the study and divided on the basis of job, age, length of service and smoking habits. The dosage of the atmospheric Ni was performed by personal dosimetries on a sample of the workers included in the study. For each worker included in the study the dosage of whole blood Ni and of the plasma testosterone was carried out. The total sample was subjected to the independent-samples T-test and the Mann-Whitney U test for variables with 2 modes (smoking cigarette) and the ANOVA test and the Kruskal Wallis test for variables with more than 2 modes (age, length of service and job function). The correlation of Pearson with p at 2 wings between the variables was evaluated in the total sample and after subdivision on the basis of smoking and on the basis of the job. After taking into account the major confounding factors the multiple linear regression was performed on the total sample and after breakdown by tasks. RESULTS:  The correlation between the values of urinary Ni and the values of plasma testosterone on the total sample and for all classes of subdivision was found constantly negative. These results were confirmed by multiple linear regression, which indicated the Ni as the only significant variable that can contribute to the alterations of the testosterone. CONCLUSIONS:  Based on the results, the Authors suggest that occupational exposure to low doses of Ni present in the urban environment is able to influence some lines of the hypothalamic-pituitary-gonadal axis in exposed workers.

Therapies

 

The inhibitory effects of topical chelating agents and antioxidants on nickel-induced hypersensitivity reactions.
            (Memon et al., 1994) Download
BACKGROUND:  Nickel sensitivity is a common problem, often causing significant morbidity from chronic eczematous dermatitis. The main treatment, topical steroids, usually is unable to suppress the dermatitis completely. OBJECTIVE:  Our purpose was to study the effects of "barrier" ointments containing either chelating agents (clioquinol or ethylenediaminetetraacetic acid [EDTA]) or antioxidants (ascorbic acid or alpha-tocopherol) and 1% hydrocortisone on nickel-induced hypersensitivity reactions. METHODS:  Nickel-sensitive subjects were challenged with nickel-containing coins coated with the desired barrier ointment and their inhibitory effects observed. Patients with bilateral hand or earring dermatitis explored the efficacy of these agents in clinical use. RESULTS:  Clioquinol (3%) completely abolished the allergic reaction in all 29 subjects tested. EDTA (15%), ascorbic acid (20%), and alpha-tocopherol (10%) were less effective, and 1% hydrocortisone had no significant effect. In clinical use sites treated with a commercially available preparation containing 3% clioquinol and 1% hydrocortisone showed marked clinical improvement in all 10 subjects. CONCLUSION:  Clioquinol is a potent inhibitor of nickel-induced hypersensitivity reactions and is feasible to use as a barrier ointment to block the allergenic effects of nickel in sensitive patients.

Melatonin protects against Nickel-induced neurotoxicity in vitro by reducing oxidative stress and maintaining mitochondrial function.
            (Xu et al., 2010) Download
Nickel is a potential neurotoxic pollutant. Oxidative stress is supposed to be involved in the mechanism underlying nickel-induced neurotoxicity. Melatonin has efficient protective effects against various oxidative damages in nervous system. The purpose of this study was to investigate whether melatonin could efficiently protect against neurotoxicity induced by nickel. Here, we exposed primary cultured cortical neurons and mouse neuroblastoma cell lines (neuro2a) to different concentrations of nickel chloride (NiCl(2)) (0.125, 0.25, 0.5, and 1 mm) for 12 hr or 0.5 mm NiCl(2) for various periods (0, 3, 6, 12, and 24 hr). We found that nickel significantly increased reactive oxygen species production and caused the loss of cell viability both in cortical neurons and neuro2a cells. In addition, nickel exposure obviously inhibited the mitochondrial function, disrupted the mitochondrial membrane potential (DeltaPsim), reduced ATP production, and decreased mitochondrial DNA (mtDNA) content. However, each of these oxidative damages was efficiently attenuated by melatonin pretreatment. These protective effects of melatonin may be attributable to its roles in reducing oxidative stress and improving mitochondrial function in nickel-treated nerve cells. Our results suggested that melatonin may have great pharmacological potential in protecting against the adverse effects of nickel in the nervous system.

Nickel exposure induces oxidative damage to mitochondrial DNA in Neuro2a cells: the neuroprotective roles of melatonin.
            (Xu et al., 2011) Download
Recent studies suggest that oxidative stress and mitochondrial dysfunction play important roles in the neurotoxicity of nickel. Because mitochondrial DNA (mtDNA) is highly vulnerable to oxidative stress and melatonin can efficiently protect mtDNA against oxidative damage in various pathological conditions, the aims of this study were to determine whether mtDNA oxidative damage was involved in the neurotoxicity of nickel and to assay the neuroprotective effects of melatonin in mtDNA. In this study, we exposed mouse neuroblastoma cell lines (Neuro2a) to different concentrations of nickel chloride (NiCl(2), 0.125, 0.25, and 0.5 mm) for 24 hr. We found that nickel significantly increased reactive oxygen species (ROS) production and mitochondrial superoxide levels. In addition, nickel exposure increased mitochondrial 8-hydroxyguanine (8-OHdG) content and reduced mtDNA content and mtDNA transcript levels. Consistent with this finding, nickel was found to destroy mtDNA nucleoid structure and decrease protein levels of Tfam, a key protein component for nucleoid organization. However, all the oxidative damage to mtDNA induced by nickel was efficiently attenuated by melatonin pretreatment. Our results suggest that oxidative damage to mtDNA may account for the neurotoxicity of nickel. Melatonin has great pharmacological potential in protecting mtDNA against the adverse effects of nickel in the nervous system.

 


References

Aquino, NB, et al. (2012), ‘The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not’, J Environ Sci Health C Environ Carcinog Ecotoxicol Rev, 30 (3), 189-224. PubMed: 22970719
Beshir, S, et al. (2016), ‘Hormonal Perturbations in Occupationally Exposed Nickel Workers.’, Open Access Maced J Med Sci, 4 (2), 307-11. PubMed: 27335607
Bonamonte, D, et al. (2005), ‘Nickel contact allergy and menstrual cycle.’, Contact Dermatitis, 52 (6), 309-13. PubMed: 15932580
Das, K. K. and S. Dasgupta (2002), ‘Effect of nickel sulfate on testicular steroidogenesis in rats during protein restriction’, Environ Health Perspect, 110 (9), 923-26. PubMed: 12204828
Galasso, F, V Altamura, and E Sbano (1996), ‘Effects of topical testosterone propionate on the positive nickel patch test.’, J Dermatol Sci, 13 (1), 76-82. PubMed: 8902657
Kasprzak, KS, FW Sunderman, and K Salnikow (2003), ‘Nickel carcinogenesis.’, Mutat Res, 533 (1-2), 67-97. PubMed: 14643413
Memon, AA, MM Molokhia, and PS Friedmann (1994), ‘The inhibitory effects of topical chelating agents and antioxidants on nickel-induced hypersensitivity reactions.’, J Am Acad Dermatol, 30 (4), 560-65. PubMed: 8157781
Sancini, A, et al. (2014), ‘Correlation between urinary nickel and testosterone plasma values in workers occupationally exposed to urban stressors.’, Ann Ig, 26 (3), 237-54. PubMed: 24998215
Xu, SC, et al. (2010), ‘Melatonin protects against Nickel-induced neurotoxicity in vitro by reducing oxidative stress and maintaining mitochondrial function.’, J Pineal Res, 49 (1), 86-94. PubMed: 20536687
Xu, SC, et al. (2011), ‘Nickel exposure induces oxidative damage to mitochondrial DNA in Neuro2a cells: the neuroprotective roles of melatonin.’, J Pineal Res, 51 (4), 426-33. PubMed: 21797922
Yao, Y, et al. (2014), ‘Cobalt and nickel stabilize stem cell transcription factor OCT4 through modulating its sumoylation and ubiquitination.’, PLoS One, 9 (1), e86620. PubMed: 24497960