Attributes of oxidative stress in the reproductive toxicity of nickel oxide nanoparticles in male rats.

The nanoparticles of nickel are now being widely used in industrial, commercial, and biomedical applications. In recent years, health safety issues posed by them have aroused concerns among health scientists. The aim of the present study was to investigate the role of oxidative stress in male reproductive toxicity induced by nickel oxide nanoparticles in rats. Male Wistar rats (140-170 g) were administered with nickel oxide nanoparticles (NiONPs) (particles size <30 nm) (5 mg/kg body weight) by gavage for 30 days. Its effects on different parameters, viz., sperm count, motility, and morphology, were investigated. DNA damage in sperms was monitored through comet assay. All these observations indicated a spermicidal effect of NiONPs. Results on lipid peroxidation (MDA, H2O2, and NO) and oxidative stress (GSH, GPx, and catalase) thus studied in testes exhibited adverse effects of NiONPs. Histopathological results on male reproductive organs, viz., testis, epididymis, vas deferens, seminal vesicles, and prostate also demonstrated moderate to severe toxicity. A comparison of these results with those obtained on nickel oxide microparticle (NiOMP)-treated rats showed that NiONPs are more toxic than NiOMPs. Furthermore, NiONPs could create an imbalance between oxidants and antioxidants in the testes. It is concluded that redox imbalance in testes constitutes a major mechanism of NiONP-induced reproductive toxicity.

Distinctive fingerprints of genotoxicity induced by As, Cr, Cd, and Ni in a freshwater fish.

Genotoxicity of three toxic elements (chromium, cadmium, nickel) and a metalloid (arsenic) has been studied in a freshwater fish, Channa punctatus using micronuclei (MN) test, comet assay, and erythrocyte nuclear alterations (ENAs) as fingerprints of genotoxicity. These tests yielded different results suggesting involvement of different mechanisms for their genotoxicity. While highest frequency of blebbed nuclei was observed in chromium-treated fish (6.5 ± 0.76), lowest was observed in cadmium-treated fish (4.0 ± 1.0). Maximum number of notched nuclei was recorded in arsenic-treated fish (5.5 ± 1.15) whereas highest numbers of lobed nuclei were found in cadmium-treated fish (4.5 ± 0.13). These differences might be attributed to selective bioaccumulation and chemodynamics of each element. Other parameters used to determine genotoxicity viz.: lipid peroxidation and DNA damage also suggested different mechanisms of their genotoxicity. It is suggested that an integrative approach, using a battery of tests for determining genotoxicity, should be made while making environmental health risk assessment and ecotoxicological studies of these toxic elements.

Renal toxicity of nanoparticles of cadmium sulphide in rat.

During present investigations, renal toxicity of CdSNPs (cadmium sulphide nanoparticles) (ranged 5-9 nm) was estimated in rat employing specific parameters. Treatment on each alternate day for 45 days with CdSNPs (10 mg/kg b.w.) yielded significant increase in Cd-MT (cadmium metallothionein), lipid peroxidation and H2O2 generation in the kidney of rat in comparison to bulk cadmium. Concentration of creatinine also increased in urine of CdSNPs treated rats. Histopathological observations revealed extensive damage in proximal tubules. Ultrastructural studies showed mitochondrial, nuclear and ER (endoplasmic reticulum) changes. Finally, renal toxicity of CdSNPs was confirmed by loss of alkaline phosphatase from the brush border of proximal convoluted tubules. These observations conclude that CdSNPs manifest greater toxicity in kidney than cadmium sulphide bulk particles. These effects have been attributed to their specific physicochemical properties, greater potential to generate ROS and induction of oxidative stress and impairment of renal structure and function. Present observations suggest that commercial/industrial use of CdSNPs may pose serious renal health problems in man.

Zinc oxide nanoparticles inhibit dimethylnitrosamine induced liver injury in rat.

Dimethylnitrosamine (DMN) is a potent hepatotoxic, carcinogenic and mutagenic compound. It induces massive liver cell necrosis and death in experimental animals. Several drugs have been tested in the past for their protective behavior against DMN toxicity. However, it is for the first time that therapeutic intervention of ZnONPs (zinc oxide nanoparticles) has been studied against its toxicity. Present results show that a post treatment of ZnONPs (50 mg/kg) to DMN (2 µl/100 g body weight) treated rats reduces lipid peroxidation, oxidative stress and fibrosis in the liver. It diminishes serum ALT (alanine transaminases), AST (aspartate transaminases) and LDH (lactate dehydrogenase) showing improvement in liver function. Reduced values of proinflammatory cytokines viz. TNF-α and IL-12 also support its protective effects. Histopathological observations also indicate improvement in liver cell morphology. It is postulated that ZnONPs offer protection through selective toxicity to proliferating tissue including adenomatous islands formed in the liver. Zinc metallothionein (Zn-MT) induced by ZnONPs may also contribute in the amelioration of DMN induced toxic effects. Diminution of oxidative stress by ZnONPs remains to be the key mechanism involved in its protective effects. However, toxicity of ZnONPs in the liver needs to be monitored simultaneously.

Melatonin improves liver function in benzene-treated rats.

In this study, we investigated the beneficial effects of melatonin against benzene-induced liver function impairments in Wistar rats. After 30 days of treatment, it significantly lowered hepatosomatic indices, bilirubin, and hydroxyproline in male and female benzene-treated rats. Even though it did not influence aspartate aminotransferase, melatonin had beneficial effects on alanine aminotransferase and alkaline phosphatase. Our results suggest that melatonin is an effective modulator of liver function in benzene-treated rats thanks to its antioxidative properties.

Ascorbic acid improves mitochondrial function in liver of arsenic-treated rat.

Arsenic is an ubiquitous and well-documented carcinogenic metalloid. The most common source of arsenic is drinking water. The mechanism of arsenic toxicity in a cell has historically been centered around its inhibitory effects on cellular respiration and mitochondrial injury. Ascorbic acid, a low molecular weight, water-soluble antioxidant, improves the reduced glutathione (GSH) status by recycling oxidized glutathione. Ascorbic acid can improve mitochondrial function by improving the thiol status; thereby preventing reactive oxygen species- mediated damage to liver as well as kidney. Ascorbic acid has been shown to protect membrane and other cellular compartments by regenerating vitamin E. Therefore, ascorbic acid seems to be a suitable protective factor against arsenic toxicity. Present reports describe the effect of ascorbic acid on oxidative phosphorylation, adenosine triphosphatase (ATPase), succinic dehydrogenase, caspase-3 and apoptosis in the liver of rats treated with arsenic trioxide (As(III)). Ultrastructural changes in the mitochondria have also been reported. We show that cotreatments with ascorbic acid and As(III) improve mitochondrial structure and function. We attribute these improvements mainly to antioxidative role of ascorbic acid. Apoptosis was restricted due to caspase-3 inhibition. Ascorbic acid could protect DNA from the attack of reactive oxygen species generated by As(III). Consequently its events led to improved ADP:O ratio, normalized ATPase activity and restored the activity of succinic dehydrogenase. Overall, results support the protective role of ascorbic acid against As( III)-induced liver injury.

Melatonin inhibits benzene-induced lipid peroxidation in rat liver.

We studied the antioxidative role of melatonin against benzene toxicity in rat liver. The inhibition of mitochondrial and microsomal lipid peroxidation differed between 24-hour (single-dose), 15-day, and 30-day treatments. Inhibition of mitochondrial lipid peroxidation was the highest after the single dose of melatonin, whereas highest microsomal inhibition was recorded after 30 days of melatonin treatment. No significant difference was recorded between 15-day and 30-day treatments. Cytochrome P 4502E1 (CYP 4502E1) activity declined after the single-dose and 15-day melatonin treatment in the benzene-treated group, but it rose again, though not significantly after 30 days of treatment. Liver histopathology generally supported these findings. Phenol concentration in the urine samples declined in melatonin and benzene-treated rats. Our results show that melatonin affects CYP 4502E1, which is responsible for benzene metabolism. Inhibition of its metabolism correlated with lower lipid peroxidation. In conclusion, melatonin was found to be protective against lipid peroxidation induced by benzene.

Endocrinal toxicity of industrial solvents--a mini review.

Endocrine system can be affected by various organic compounds. The review describes the effects of major industrial solvents on adrenal, thyroid and parathyroid glands in man and experimental animals. Further, their toxicity in pancreas, pituitary, testis and ovary has also been discussed. An attempt has been made to offer a historical and general information on solvent toxicity in endocrine glands. Possible mechanisms, in brief, have also been discussed. Endocrine toxicity caused by industrial solvents deserves more attention than hitherto paid. An understanding of hormonal disorders caused by industrial solvents will be important from occupational health point of view.

Effect of insulin on arsenic toxicity in diabetic rats­liver function studies.

Arsenic (iAs)-induced diabetic mellitus has been debated by several workers. However, role of insulin in iAs-induced diabetes is yet to be investigated. Present report suggests that iAs promotes insulin secretion in diabetic rats and inhibits hyperglycemia. Whereas, reverse effects were recorded after insulin treatment to diabetic and iAs-treated rats. These conditions affect accumulation of iAs in liver. It decreased in diabetic and iAs-treated rats but increased after insulin treatment. Reciprocal effects were observed on serum transaminases and total bilirubin. Nevertheless, activity of glucose-6-phosphatase in the liver was stimulated by insulin treatment to diabetic and arsenic-fed rats. These results suggest that manifestations of arsenic-induced diabetes mellitus are not modulated or reversed by insulin. Observations on liver function further suggest that iAs is less toxic in diabetic rats. This protective effect has been attributed to noninsulin-dependent carbohydrate regulatory mechanisms. Diabetes certainly alters the pharmacodynamics and pharmacokinetics of iAs in rat.

Metals and apoptosis: recent developments.

Apoptosis, also known as programmed cell death is a highly regulated and crucial process found in all multicellular organisms. It is not only implicated in regulatory mechanisms of cells, but has been attributed to a number of diseases, i.e. inflammation, malignancy, autoimmunity and neurodegeneration. A variety of toxins can induce apoptosis. Carcinogenic transition metals, viz. cadmium, chromium and nickel promote apoptosis along with DNA base modifications, strand breaks and rearrangements. Generation of reactive oxygen species, accumulation of Ca(2+), upregulation of caspase-3, down regulation of bcl-2, and deficiency of p-53 lead to arsenic-induced apoptosis. In the case of cadmium, metallothionein expression determines the choice between apoptosis and necrosis. Reactive oxygen species (ROS) and p53 contribute in apoptosis caused by chromium. Immuno suppressive mechanisms contribute in lead-induced apoptosis whereas in the case of mercury, p38 mediated caspase activation regulate apoptosis. Nickel kills the cells by apoptotic pathways. Copper induces apoptosis by p53 dependent and independent pathways. Beryllium stimulates the formation of ROS that play a role in Be-induced macrophage apoptosis. Selenium induces apoptosis by producing superoxide that activates p53. Thus, disorders of apoptosis may play a critical role in some of the most debilitating metal-induced afflictions including hepatotoxicity, renal toxicity, neurotoxicity, autoimmunity and carcinogenesis. An understanding of metal-induced apoptosis will be helpful in the development of preventive molecular strategies.

Effects of progesterone on benzene toxicity in rats.

Benzene is a frequently used industrial solvent. Its toxic manifestations could be modified by sex hormones, but mechanisms of their action are poorly understood. We have examined the influence of progesterone on lipid peroxidation (malondialdehyde), reduced glutathione (GSH), and cytochrome P450 2E1 (CYP2E1) in the liver and kidneys of female rats. Progesterone applied to benzene-treated rats inhibited the formation of reactive oxygen species (ROS), but in ovariectomised benzene-treated rats it significantly increased GSH in the liver. No improvement in CYP2E1 activity was observed in progesterone treated rats. Our results evidence that progesterone changes benzene toxicity (generation of ROS, oxidative stress). However, the probable antioxidative effect of progesterone needs to be confirmed by further studies.

Effect of n-propylthiouracil or thyroxine on arsenic trioxide toxicity in the liver of rat.

Involvement of thyroid gland in the hepatotoxic manifestations of arsenic trioxide (As(III)) has been studied in rat. The effects of n-propylthiouracil (PTU) (a thyrotoxic compound) and L-thyroxine (a thyroid hormone) have been studied with reference to T(3) and T(4) values in the serum, arsenic concentration in the liver, Ca(2+) accumulation in the liver, aspartate transaminase, alanine transaminase and bilirubin values as the indicators of liver function, histopathological observations and finally the ultrastructural studies. It is concluded that hypothyroid condition protects against As(III) toxicity. Scavenging of reactive oxygen species (ROS) that significantly contribute in As(III) toxicity, by high intracellular concentration of reduced glutathione, as a consequence of PTU treatment is proposed as the plausible protective mechanism.