Selenium abates manganese-induced striatal and hippocampal toxicity via abrogation of neurobehavioral deficits, biometal accumulation, oxidative stress, inflammation, and caspase-3 activation in rats.

Excessive exposure to manganese (Mn) is associated with neurotoxicity characterized by oxidative stress, inflammation, and apoptosis induction. Selenium (Se) has been shown to possess antioxidant, anti-inflammatory, and anti-apoptotic properties in humans and animals. The present study investigated the neuroprotective mechanism of Se in rats sub-chronically treated with Mn at 30 mg/kg body weight or orally co-treated with Se at 0.2 and 0.4 mg/kg body weight for 35 consecutive days. Locomotive and exploratory profiles were recorded and computed with the aid of ANY-Maze (a video-tracking software) for 5-min trial, in a novel apparatus. The ANY-Maze analysis showed that Se significantly (p < 0.05) abated Mn-induced locomotive impairment evidenced by increased in maximum speed, total time traveled, absolute turn angle, number of line crossing, rotation and forelimb grip and decreased total time immobile, grooming, and negative geotaxis as verified by the enhanced track plot density. Furthermore, the striatum and hippocampus of the rats were excised and the levels of Mn and Se, oxidative stress markers, proinflammatory cytokines including acetylcholinesterase and caspase-3 activities were assayed. The result shows that Se abates Mn-mediated accumulation of Mn. Also, Se ameliorated Mn-induced decrease in antioxidant enzymes as well as glutathione level and increase in acetylcholinesterase activity, lipid peroxidation, proinflammatory cytokines (i.e., interleukin (IL)-6, IL-1ß, tumor necrosis factor alpha), and caspase-3 activation in the striatum and hippocampus of the rats. Collectively, Se abated Mn-induced striatal and hippocampal toxicity via abrogation of neurobehavioral deficits, biometal accumulation, oxidative stress, inflammation, and caspase-3 activation in rats. Se may serve as a neuroprotective agent against Mn-mediated neurotoxicity.

Ethanol exacerbates manganese-induced oxidative/nitrosative stress, pro-inflammatory cytokines, nuclear factor-κB activation, and apoptosis induction in rat cerebellar cortex.

Manganese (Mn) exposure is causing public health concerns as well as heavy alcohol consumption. This study investigates the mechanisms of neurotoxicity associated with Mn and ethanol (EtOH) exposure in the rat cerebellar cortex. Experimental animals received 30 mg/kg of Mn alone, 5 g/kg of EtOH alone, co-exposed with 30 mg/kg of Mn and 1.25 or 5 g/kg EtOH, while control animals received water by oral gavage for 35 days. Subsequently, alterations in the neuronal morphology of the cerebellar cortex, oxidative/nitrosative stress, acetylcholinesterase (AChE) activity, neuro-inflammation and protein expression of p53, BAX, caspase-3, and BCL-2 were investigated. The results indicate that Mn alone and EtOH alone induce neuronal alterations in the cerebellar cortex, decrease glutathione level and antioxidant enzyme activities, along with an increase in AChE activity, lipid peroxidation, and hydrogen peroxide generation. Mn alone and EtOH alone also increased neuro-inflammatory markers, namely nitric oxide, myeloperoxidase activity, interleukin-1ß, tumor necrosis factor-α, and nuclear factor-κB (NF-κB) levels in the cerebellar cortex. Immunohistochemistry analysis further revealed that exposure of Mn alone and EtOH alone increases the protein expression of cyclooxygenase-2, BAX, p53, and caspase-3 and decrease BCL-2 in the rat cerebellar cortex. Furthermore, the results indicated that Mn co-exposure with EtOH at 1.25 and 5 g/kg EtOH significantly (p ≤ .05) increases the toxicity in the cerebellum when compared with the toxicity of Mn or EtOH alone. Taken together, co-exposure of Mn and EtOH exacerbates neuronal alterations, oxidative/nitrosative stress, AChE activity, pro-inflammatory cytokines, NF-κB signal transcription, and apoptosis induction in the rat cerebellar cortex.

Toenail Metal Exposures in Fishermen from Bodo City, Nigeria.

We conducted exposure assessment using toenails from 20 fishermen living in Bodo City, a community of the Niger delta region in Nigeria. This community has been affected by over 4000 oil spills and environmental disasters. Fishing is the primary source of food and income for individuals in this community. Previous research in Bodo City found elevated metal levels in fish. Toenails were used as a biomarker to investigate the feasibility for use in risk assessment studies in developing countries. The toenails collected had significantly higher manganese levels (median 5.8 µg/g) and lead levels (median 0.98 µg/g) than those reported in more developed countries, comparable levels to those from other low-middle incomes countries. These exposure levels are likely a direct result of exposures from the environmental disasters the community has experienced and would be related to increased risks for many diseases previously associated with heavy metal exposures.

Ethanol increases manganese-Induced spatial learning and memory deficits via oxidative/nitrosative stress induced p53 dependent/independent hippocampal apoptosis.

Manganese (Mn) is an essential nutrient element. However, Mn is causing great environmental and occupational exposure health risk concern globally, even high rate of alcohol consumption. There is dearth of scientific information on the interaction of manganese (Mn) and ethanol (EtOH) on hippocampal functions. This study was designed to investigate the effect of EtOH on Mn - induced hippocampal toxicity with special reference to spatial learning and memory and its underlying mechanism in adults male Wistar Rats. Rats were exposed to Mn alone at 30 mg/kg or co-expose with EtOH at 1.25 and 5 g/kg body weight by oral gavage for 35 consecutive days. Morris Water Maze task was used to assessed spatial learning and memory. Subsequently, oxidative/nitrosative stress, neuro-inflammation (myeloperoxidase and cyclooxygenase-2) and protein expression of apoptotic proteins (p53 and Bax), active executioner caspase (caspase-3) and B - cell lymphoma - 2 (Bcl - 2) markers in the hippocampus were investigated. The results indicate that Mn and EtOH exposure induces spatial learning and memory deficits, increase oxidative/nitrosative stress, neuro-inflammation resulting in enhanced hippocampal apoptosis. Moreover, the results indicated that Mn co-exposure with EtOH at 1.25 and 5 g/kg body weight further exacerbates neurotoxicity in rat hippocampus when compared with single dose of Mn and EtOH alone. Collectively, EtOH increases Mn - induced oxidative/nitrosative stress, neuro-inflammation and hippocampal apoptosis via mechanism involving oxidative damages of cellular constituents, neuronal inflammation and subsequent upregulation of Bax and caspase-3 and downregulation of Bcl-2 protein expression via p53 dependent/independent pathways to induced hippocampal apoptosis associated with impaired spatial learning and memory.

Rutin abrogates manganese-Induced striatal and hippocampal toxicity via inhibition of iron depletion, oxidative stress, inflammation and suppressing the NF-κB signaling pathway.

Excess exposure to Manganese (Mn) promotes oxidative stress and neuro-inflammation. Rutin (RUT) has been found to exhibit both anti-oxidative stress and anti-inflammatory properties. This study aimed to investigate the effects of RUT on Mn accumulation, endogenous iron (Fe) depletion, oxidative stress, inflammation and nuclear factor kappa B (NF-κB) signaling pathways in the hippocampus and striatum of Mn - induced rats. Rats were treated with 30 mg/kg Mn body weight alone or orally co-treated by gavage with RUT at 50 and at 100 mg/kg body weight for 35 consecutive days. Thereafter, we investigated Mn and endogenous Fe levels, acetylcholinesterase activity, oxidative stress markers, pro-inflammatory cytokines and nuclear factor kappa B (NF-κB) in the hippocampus and striatum of rats. The results indicate that Mn induced Mn - accumulation, Fe depletion, oxidative stress, inflammation and the activation of acetylcholinesterase activity and NF-κB signaling pathways in the hippocampus and striatum of the rats. However, RUT attenuated Fe depletion, oxidative stress and inflammation and suppressed acetylcholinesterase activity and NF-κB pathway via downstream regulations of tumor necrosis factor alpha, interleukin I beta and interleukin 6. Taken together, our present study demonstrates that RUT abrogates Mn - induced striatal and hippocampal toxicity via inhibition of Fe depletion, oxidative stress, inflammation and suppressing the NF-κB signaling pathways. Our results indicate that RUT may be of use as a neuroprotective agent against Mn - induced neuronal toxicity.

Ethanol via Regulation of NF-κB/p53 Signaling Pathway Increases Manganese-Induced Inflammation and Apoptosis in Hypothalamus of Rats.

The diet is a major route of manganese (Mn) exposure for humans. Interestingly, several epidemiological data demonstrated an increase in the incidence of alcohol consumption globally. Chemical-chemical interaction subsequent to chemical mixtures exposure may result in a synergism or antagonism effects. The present study investigated the influence of co-exposure to ethanol (EtOH) and Mn on inflammation and apoptosis in the hypothalamus of rats. The study consisted of five groups of rats that were exposed to drinking water alone, EtOH alone at 5 g/kg, Mn alone at 30 mg/kg or co-expose with EtOH at 1.25 and 5 g/kg body weight by oral gavage for 35 consecutive days. The results indicated that the significant (p < 0.05) increases in pro-inflammatory cytokines, namely tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß) as well as cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB) activation in the hypothalamus following individual exposure to Mn and EtOH to rats were intensified in the co-exposure group. Moreover, immunohistochemistry analysis showed marked decrease in B cell lymphoma-2 (Bcl-2) protein expression as well as the increases in the apoptotic proteins, namely Bax and caspase-3 along with p53 in the hypothalamus of rats treated with Mn or EtOH alone were intensified in the co-exposure group. Taken together, these findings highlight that EtOH exacerbated the induction of inflammatory and apoptotic biomarkers via regulation of NF-κB/p53 signaling pathways in the hypothalamus of rats. These alterations may have profound disrupting effects on the hypothalamus functions such as impairment of it metabolic and autonomic nervous system functions.

Ethanol Exacerbates Manganese-Induced Neurobehavioral Deficits, Striatal Oxidative Stress, and Apoptosis Via Regulation of p53, Caspase-3, and Bax/Bcl-2 Ratio-Dependent Pathway.

This study investigated the effects of ethanol (EtOH) on manganese (Mn)-induced striatal toxicity in rat by evaluating the neurobehavioral changes, biochemical and molecular events in rats exposed to Mn alone at 30 mg/kg, or their combination with EtOH at 1.25- and 5-g/kg body weight for 35 consecutive days. Locomotive and exploratory profiles were assessed using a video tracking software (ANY-Maze software) during a 5-min trial in a novel environment. Subsequently, acetylcholinesterase (AChE) activity, oxidative stress markers, histological morphology, and expression of apoptotic proteins (p53 and Bax and caspase-3) and anti-apoptotic protein (Bcl-2) were assessed in the striatum. Results showed that Mn, EtOH, and their combination induced locomotor and motor deficits. Track plot analysis indicated that EtOH exacerbated the Mn-induced reduction in exploratory profiles of exposed rats. Similarly, exposure of rats to Mn, EtOH, or combination of Mn and EtOH resulted in decreased activities of anti-oxidant enzymes, diminished level of reduced glutathione, downregulated Bcl-2 expression, increased AChE activity, enhanced hydrogen peroxide and lipid peroxidation levels, and upregulated expressions of p53, Bax, and caspase-3. Moreover, potentiation of Mn-induced striatal toxicity by EtOH co-exposure was dose dependent. Taken together, it seems that EtOH exacerbates Mn-induced neurobehavioral deficits, oxidative stress, and apoptosis induction via the regulation of p53, caspase-3, and Bax/Bcl-2 ratio-dependent pathway in rat striatum.

Validation of x-ray fluorescence measurements of metals in toenail clippings against inductively coupled plasma mass spectrometry in a Nigerian population.

OBJECTIVE: Metal exposures have been linked with many adverse health outcomes affecting nearly every system in the body. Exposure to metals has been tracked primarily using blood. Blood metal concentrations have drawbacks as biomarkers stemming from the metals' short biologic half-lives, shipping and storage requirements, and invasive collection procedures. Toenails, which capture a longer exposure period, can be collected non-invasively and stored at room temperature, and can be more feasible and cost-effective for large-scale population studies. APPROACH: Inductively coupled plasma mass spectrometry (ICP-MS) has been used for analysis of toenail metal concentrations, but x-ray fluorescence (XRF) has many advantages in versatility and cost effectiveness over these analyses. This study compared toenail concentrations of manganese (Mn) and lead (Pb) measured with XRF against ICP-MS, in samples collected from 20 adults in Nigeria. To do this we developed a novel calibration method that corrects XRF measurements for toenail weight and thickness to reduce the variability in XRF measurements of toenail clippings. MAIN RESULTS: We found a high correlation (R = 0.91) between toenail manganese metal measurements made with XRF and ICP-MS and a correlation of (R = 0.32) between toenail lead XRF and ICP-MS with over half of the lead results below the detection limit of the instrumentation. SIGNIFICANCE: XRF can be used effectively to quantify metals at the part per million level or lower depending on the XRF equipment used in the measurements.

Ethanol exacerbates manganese - induced functional alterations along the hypothalamic-pituitary-gonadal axis of male rats.

Manganese (Mn) exposure has been reported to induce reproductive dysfunction in animal and humans. Studies have shown that a large percentage of adolescent and adult populations tend to consume alcohol in a binge pattern. However, there is no information on the influence of alcohol on Mn - induced functional alteration along the hypothalamic - pituitary - gonadal axis. This study aimed to evaluate the influence of ethanol (EtOH) on Mn - induced functional alteration along the hypothalamic - pituitary - gonadal axis. Rats were exposed to Mn alone at 30 mg/kg body weight or co-expose with EtOH at 1.25 and 5 g/kg body weight for 35 consecutive days. Results showed that EtOH exposure significantly (p ≤ 0.05) exacerbated Mn - induced decrease in antioxidant enzymes activities, glutathione level and increased oxidative stress biomarkers in the hypothalamus, testes an epididymis of the exposed rats. Moreover, induction of inflammation was associated with disruption of histo-architecture of the hypothalamus, testes and epididymis of rats treated with Mn alone, EtOH alone or in combination. Furthermore, EtOH significantly exacerbated Mn - induced diminution in reproductive hormones and marker enzymes of testicular functions coupled with decreased sperm quantity and quality. Taken together, EtOH exacerbates Mn - induced functional alteration along the hypothalamic - pituitary - gonadal axis in rats via mechanisms involving induction of oxidative/nitrosative stress, lipid peroxidation and inflammation in rats.

Rutin attenuates neurobehavioral deficits, oxidative stress, neuro-inflammation and apoptosis in fluoride treated rats.

Studies have shown that high exposure to fluoride (NaF) induces neurotoxicity. Rutin (RUT), a citrus flavonoid, has been reported to have antioxidant, anti-inflammatory and anti-apoptotic properties. The aim of this study was to investigate the neuroprotective mechanism(s) of RUT on NaF - induced neurotoxicity. Rats were exposed to NaF alone in drinking water at 15 mg/L alone ad libitum or orally co-treated by gavage with RUT at 50 and 100 mg/kg body weight for 31 consecutive days. A video-tracking software was used to monitor the motor and locomotive behavior during a 5 - min trial time in a novel environment. Thereafter, acetylcholinesterase (AChE) activity, oxidative stress markers, pro-inflammatory cytokines and caspase - 3 activity were determined in the cerebrum and striatum. The result indicates that NaF - induced neurobehavioral deficits. RUT mediated the reversal of the neurobehavioral deficits and enhanced the exploratory profile of NaF - treated rats as supported by the track plot analyses. Moreover, RUT attenuated the NaF - induced inhibition of antioxidant enzymes and AChE activity and inhibits lipid peroxidation, neuro-inflammation and apoptosis in the cerebrum and striatum of the rats. Collectively, the present study demonstrated that RUT attenuates NaF - Induced toxicity in the cerebrum and striatum of rats via mechanisms involving enhancement of AChE activity, antioxidant status with concomitant inhibition of lipid peroxidation, neuro-inflammation and apoptosis in rats. RUT may be used as a neuroprotective agent against NaF - induced neurotoxicity.

Potential Human Health Risk Assessment of Heavy Metals via Consumption of Root Tubers from Ogoniland, Rivers State, Nigeria.

This study was designed to investigate the concentration of heavy metals and their associated human health risk via consumption of root tubers cultivated in three major communities in Ogoniland, Rivers State, Nigeria. The concentration of heavy metals, especially, Cr and Pb in soil, indicates a moderate contamination (˃ 1.00 mg/kg) level. The concentrations of heavy metals in the root tubers Manihot esculenta, Colocasia esculenta, and Dioscorea alata harvested from Choba, Kpean, and Bodo City ranged from 0.20 ± 0.01-0.84 ± 0.04, 0.01 ± 0.001-0.09 ± 0.02, 0.01 ± 0.002-0.63 ± 0.04, 2.11 ± 0.03-11.8 ± 2.12, and 6.30 ± 1.18-118.6 ± 0.19 mg/kg for Cr, Pb, Ni, Mn, and Fe respectively, while Cd had the same value of 0.01 ± 0.001 mg/kg in the three samples across the three sites. The bio-accumulation factor (BAF) for Cd was ˃ 1. The estimated daily intake were below the FAO/WHO permissible limit, while the target hazard quotient (THQ) has a trend of Mn> Fe> Pb> Cd> Ni> Cr, and were ˂ 1 for all the sampling areas. The HI values for M. esculenta for children in Choba, Kpean, and Bodo City were ˃ 1, indicating that children among the local populace were susceptible to heavy metals health risks. The carcinogenic risk (CR) value of Cr indicates that there was appreciable lifetime cancer risk for Cr as the CR value in all the sampling sites were ˃ 10-4. Furthermore, CR values of Ni and Cd were also within the predicted lifetime risks of carcinogens. Heavy metal contamination of root tubers cultivated in Ogoniland may posed a great health risk to local populace especially for children via consumption of root tubers.

Toxicity Effect of Sub-Chronic Oral Administration of Class Bitters® - A Polyherbal Formula on Serum Electrolytes and Hematological Indices in Male Wistar Albino Rats.

The indiscriminate administration of ready-to-use herbal formulations has become a major concern due to their potential health risk. The study investigated the effect of class bitters® (CB) - a polyherbal formula prepared with Mondia whitei, Khaya senegalensis, Capparis erythrocarpus, Thoningia sanguinea and Xylopia aethiopica on serum electrolytes and hematological parameters in male Wistar albino rats. Two doses (500 and 1000 mg kg-1) of the polyherbal drugs were administered orally to male Wistar albino rats for a period of 9 weeks. The results showed that administration of 500 and 1000 mg kg-1 body weight of CB recorded a marked increase in the levels of sodium and chlorum when compared with control. However, there was a marked reduction in the levels of potassium and hydrogen carbonate. The results of the study also showed a significant (P≤0.05) decrease in the level of hematological parameters such as hemoglobin (Hb), packed cell volume (PCV), red blood cells (RBCs) and platelets levels in the male Wistar albino rats, when compared with control. The marked decrease in Hb, PCV, RBCs and platelets concentrations observed in experimental rats in this study suggest that CB may have an adverse effect on erythropoiesis. These observations therefore showed that long-term administration of CB might cause renal disease and anemia.