Mechanism and impact of heavy metal-aluminum (Al) toxicity on male reproduction: Therapeutic approaches with some phytochemicals.

Heavy metals are ubiquitous environmental toxicants that have been known to have a serious effect on human and animal health. Aluminum (Al) is a widely distributed metal in nature. Al exposure has a detrimental impact on human fertility. This review focused on Al-induced male reproductive toxicity and the potential therapeutic approaches with some phytochemicals. Data from the literature showed that Al exposure is accompanied by a drastic decline in blood levels of FSH, LH, and testosterone, reduced sperm count, and affected sperm quality. Al exposure at high levels can cause oxidative stress by increasing ROS and RNS production, mediated mainly by downregulating Nrf2 signaling. Moreover, several investigations demonstrated that Al exposure evoked inflammation, evidenced by increased TNF-α and IL-6 levels. Additionally, substantial evidence concluded the key role of apoptosis in Al-induced testicular toxicity mediated by upregulating caspase-3 and downregulating Bcl2 protein. The damaging effects of Al on mitochondrial bioenergetics are thought to be due to the excessive generation of free radicals. This review helps to clarify the main mechanism involved in Al-associated testicular intoxication and the treatment strategy to attenuate the notable harmful effects on the male reproductive system. It will encourage clinical efforts to target the pathway involved in Al-associated testicular intoxication.

Gene expression and oxidative stress markers profile associated with toxic metals in patients with renal cell carcinoma.

BACKGROUND: Toxic metals are associated with cancer progression. Studies have reported the relation between some toxic metals and renal cell carcinoma (RCC). METHODS AND RESULTS: Blood levels of Cd and Pb were determined in 94 RCC patients (RCC group) and 91 matched controls as well as blood level of malondialdehyde (MDA) and catalase (CAT) activity as markers of oxidative stress and antioxidant, respectively. Gene expression of MAP kinase pathway (P38 and JNK), hypoxia-inducible factor 1-alpha (HIF1α), vascular endothelial growth factor (VEGF), cytochrome C oxidase subunit 6 (COX6), metallothionein (MT2A), and heat shock protein (HSP90AA1) were evaluated in the obtained tissue specimens. Blood Cd and Pb levels were significantly higher in RCC group comparing to control group with preferential significant increase of Cd in chromophobe RCC (chRCC) sub-type. MDA level was significantly higher and CAT activity was lower in the RCC compared to controls. The difference was evident only in chRCC. The expressions of genes were significantly increased in the cancer tissues than in non-cancerous tissues in RCC sub-types and there was a significant correlation between Cd levels and expression of genes VEGF, MT2A, P38 and JNK in chRCC group. Immunohistochemical staining of clear cell RCC tissues shows a marked expression of VEGF and HIF-1α.While COX6 staining show marked expression in chRCC. CONCLUSIONS: There is a positive correlation between Cd toxicity and the development of RCC, especially chRCC sub-type. Cd is strongly incriminated in the pathogenesis of chRCC through the effort on some genes and oxidative stress markers.

Synthetic Amphoteric Cryogels as an Antidote against Acute Heavy Metal Poisoning.

The effectiveness of an amphoteric cryogel (AAC) as an oral sorbent (enerosorbent) for the treatment of acute poisoning of small animals (rats) with heavy metals (HMs) was studied in in vivo experiments. The morphological structure of the cryogel was examined using scanning electron microscopy/energy-dispersive X-ray analysis and confocal microscopy. The use of the cryogel in the treatment of rats administered an LD50 dose of Cd(NO3)2, CsNO3, Sr(NO3)2, or HgCl2 in aqueous solution showed their high survival rate compared to the control group, which did not receive such treatment. The histological and chemical analysis of internal tissues and the biochemical analysis of the blood of the experimental animals showed the effectiveness of the cryogel in protecting the animals against the damaging effect of HMs on the organism comparable with unithiol, a chelating agent based on 2,3-dimercapto-1-propane sulfonic acid sodium salt (DMPS) approved for the treatment of acute poisoning with some heavy metals.

Iron-responsive-like elements and neurodegenerative ferroptosis.

A set of common-acting iron-responsive 5'untranslated region (5'UTR) motifs can fold into RNA stem loops that appear significant to the biology of cognitive declines of Parkinson's disease dementia (PDD), Lewy body dementia (LDD), and Alzheimer's disease (AD). Neurodegenerative diseases exhibit perturbations of iron homeostasis in defined brain subregions over characteristic time intervals of progression. While misfolding of Aß from the amyloid-precursor-protein (APP), alpha-synuclein, prion protein (PrP) each cause neuropathic protein inclusions in the brain subregions, iron-responsive-like element (IRE-like) RNA stem-loops reside in their transcripts. APP and αsyn have a role in iron transport while gene duplications elevate the expression of their products to cause rare familial cases of AD and PDD. Of note, IRE-like sequences are responsive to excesses of brain iron in a potential feedback loop to accelerate neuronal ferroptosis and cognitive declines as well as amyloidosis. This pathogenic feedback is consistent with the translational control of the iron storage protein ferritin. We discuss how the IRE-like RNA motifs in the 5'UTRs of APP, alpha-synuclein and PrP mRNAs represent uniquely folded drug targets for therapies to prevent perturbed iron homeostasis that accelerates AD, PD, PD dementia (PDD) and Lewy body dementia, thus preventing cognitive deficits. Inhibition of alpha-synuclein translation is an option to block manganese toxicity associated with early childhood cognitive problems and manganism while Pb toxicity is epigenetically associated with attention deficit and later-stage AD. Pathologies of heavy metal toxicity centered on an embargo of iron export may be treated with activators of APP and ferritin and inhibitors of alpha-synuclein translation.

Temperature elevation stage-specifically increases metal toxicity through bioconcentration and impairment of antioxidant defense systems in juvenile and adult marine mysids.

Metals are of serious concern due to their toxicity, persistency, and accumulation potential in aquatic animals. However, limited information is available on the combined effects of metal with temperature elevation, which is one of the future climate changes suggested for the oceans. In this study, the effect of temperature elevation was investigated by analyzing toxicity, bioconcentration, and antioxidant response in juvenile and adult marine mysids upon exposure to 20 °C and 25 °C for 48 h and 96 h. Based on LC50 values, toxicity of metals was highly reliant on temperature, exposure period, and age. Elevation in temperature significantly increased the whole metal toxicity in juveniles. Bioconcentration was elevated by increasing exposure period and metal concentration. Significant elevation of malondialdehyde (MDA) and depletion of glutathione (GSH) was measured in juveniles, while significant elevation of both MDA and GSH was detected in adults. Subsequently, enzymatic activities of antioxidant enzymes in catalase (CAT) and superoxide dismutase (SOD) increased significantly in adults at 48 h and 96 h, whereas most activities were significantly lowered in juveniles at 96 h. These results suggest that the early life stage of marine mysids is more sensitive to the combined effect of metal and temperature than adult stage due to an impairment in the induction of the antioxidant defense system.

Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development.

Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)-short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain-a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs).

The roles of calcium-sensing receptor (CaSR) in heavy metals-induced nephrotoxicity.

The kidney is a vital organ responsible for regulating water, electrolyte and acid-base balance as well as eliminating toxic substances from the blood in the body. Exposure of humans to heavy metals in their natural and occupational environments, foods, water, and drugs has serious implications on the kidney's health. The accumulation of heavy metals in the kidney has been linked to acute or chronic renal injury, kidney stones or even renal cancer, at the expense of expensive treatment options. Therefore, unearthing novel biomarkers and potential therapeutic agents or targets against kidney injury for efficient treatment are imperative. The calcium-sensing receptor (CaSR), a G-protein-coupled receptor (GPCR) is typically expressed in the parathyroid glands and renal tubules. It modulates parathyroid hormone secretion according to the serum calcium (Ca2+) concentration. In the kidney, it modulates electrolyte and water excretion by regulating the function of diverse tubular segments. Notably, CaSR lowers passive and active Ca2+ reabsorption in distal tubules, which facilitates phosphate reabsorption in proximal tubules and stimulates proton and water excretion in collecting ducts. Moreover, at the cellular level, modulation of the CaSR regulates cytosolic Ca2+ levels, reactive oxygen species (ROS) generation and the mitogen-activated protein kinase (MAPK) signaling cascades as well as autophagy and the suppression of apoptosis, an effect predominantly triggered by heavy metals. In this regard, we present a review on the CaSR at the cellular level and its potential as a therapeutic target for the development of new and efficient drugs against heavy metals-induced nephrotoxicity.

The protective effect exerted by dietary borax on toxicity metabolism in rainbow trout (Oncorhynchus mykiss) tissues.

The aim of this study was to evaluate the effectiveness of borax (BX) against heavy metal exposure on the transcriptional and biochemical reaction in vivo and alleviating effect on gill and liver tissues of rainbow trout. Due to this aim, fish were fed with different level of BX and/or copper (Cu) (1.25, 2.5 and 5 mg/kg of BX; 500 and 1000 mg/kg of Cu) for 21·days in pre- and co-treatment options. The transcriptional parameters [(heat-shock protein 70 (hsp70), and cytochromes P450 (cyp1a), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT))], antioxidant enzyme activities (SOD, CAT and GPx), malondialdehyde (MDA), oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG) and caspase-3 levels were investigated in different tissues samples of treated and control fish. Our results revealed that antioxidant enzyme activity was increased and levels of 8-OHdG, Caspase-3 and MDA were decreased in the BX and BX combined groups as compared to the copper combination group and to copper-only application during pre- and co-treatment (p < 0.05). Similarly, hsp70 and cyp1a gene expressions were decreased after treatment with BX. As conclusion, we suggest that borax itself is not an antioxidant it supportes antioxidant defense mechanism of fish disrupted by heavy metals.

Differential protein expression of hippocampal cells associated with heavy metals (Pb, As, and MeHg) neurotoxicity: Deepening into the molecular mechanism of neurodegenerative diseases.

Chronic exposure to heavy metals such as Pb, As, and MeHg can be associated with an increased risk of developing neurodegenerative diseases. Our in vitro bioassays results showed the potency of heavy metals in the order of Pb < As < MeHg on hippocampal cells. The main objective of this study was combining in vitro label free proteomics and systems biology approach for elucidating patterns of biological response, discovering underlying mechanisms of Pb, As, and MeHg toxicity in hippocampal cells. The omics data was refined by using different filters and normalization and multilevel analysis tools were employed to explore the data visualization. The functional and pathway visualization was performed by using Gene ontology and PathVisio tools. Using these all integrated approaches, we identified significant proteins across treatments within the mitochondrial dysfunction, oxidative stress, ubiquitin proteome dysfunction, and mRNA splicing related to neurodegenerative diseases. The systems biology analysis revealed significant alterations in proteins implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). The current proteomics analysis of three metals support the insight into the proteins involved in neurodegeneration and the altered proteins can be useful for metal-specific biomarkers of exposure and its adverse effects. SIGNIFICANCE: The proteomics techniques have been claimed to be more sensitive than the conventional toxicological assays, facilitating the measurement of responses to heavy metals (Pb, As, and MeHg) exposure before obvious harm has occurred demonstrating their predictive value. Also, proteomics allows for the comparison of responses between Pb, As, and MeHg metals, permitting the evaluation of potency differences hippocampal cells of the brain. Hereby, the molecular information provided by pathway and gene functional analysis can be used to develop a more thorough understanding of each metal mechanism at the protein level for different neurological adverse outcomes (e.g. Parkinson's disease, Alzheimer's diseases). Efforts are put into developing proteomics based toxicity testing methods using in vitro models for improving human risk assessment. Some of the key proteins identified can also potentially be used as biomarkers in epidemiologic studies. These heavy metal response patterns shed new light on the mechanisms of mRNA splicing, ubiquitin pathway role in neurodegeneration, and can be useful for the development of molecular biomarkers of heavy metals exposure.

Chronic Kidney Disease and Exposure to Nephrotoxic Metals.

Chronic kidney disease (CKD) is a common progressive disease that is typically characterized by the permanent loss of functional nephrons. As injured nephrons become sclerotic and die, the remaining healthy nephrons undergo numerous structural, molecular, and functional changes in an attempt to compensate for the loss of diseased nephrons. These compensatory changes enable the kidney to maintain fluid and solute homeostasis until approximately 75% of nephrons are lost. As CKD continues to progress, glomerular filtration rate decreases, and remaining nephrons are unable to effectively eliminate metabolic wastes and environmental toxicants from the body. This inability may enhance mortality and/or morbidity of an individual. Environmental toxicants of particular concern are arsenic, cadmium, lead, and mercury. Since these metals are present throughout the environment and exposure to one or more of these metals is unavoidable, it is important that the way in which these metals are handled by target organs in normal and disease states is understood completely.

Do Dietary Habits Influence Trace Elements Release from Fixed Orthodontic Appliances?

The objective was to investigate the effect of dietary habits on the release of Cr and Ni ions from orthodontic appliances by hair mineral analysis. Patients (N = 47) underwent electronic questionnaire survey to investigate the effect of dietary habits on Cr and Ni levels in hair. The research was carried out on hair sampled at the beginning and in the 4th, 8th, and 12th months of the treatment. The content of Cr and Ni in the collected samples was determined by ICP-OES. The study showed that consumption of acidic dietary products may have the effect on increasing the release of Cr and Ni ions from orthodontic appliances. The release of Cr from orthodontic appliances in patients who consumed fruit juice, coffee, yoghurt, and vinegar was higher. The coefficients enabling comparison of metal ions release pattern at a given sampling points were defined. The comparison of the coefficients yielded the information on the possible magnification of metal ions released as the result of the additional factor consumption of acidic food or drink that intensifies metal ions release. The following magnification pattern was found for chromium: coffee (7.57 times) > yoghurt (2.53) > juice (1.86) > vinegar (1.08), and for nickel: vinegar (2.2) > coffee (1.22) > juice (1.05). Yoghurt did not intensify the release of nickel. Concluding, orthodontic patients should avoid drinking/eating coffee, yoghurt, fruit juices, and vinegar.

Attenuating Effect of Zinc and Vitamin E on the Intestinal Oxidative Stress Induced by Silver Nanoparticles in Broiler Chickens.

Silver nanoparticles (AgNPs) have been increasingly used as antimicrobial and disinfectant. However, intestinal model studies have shown that AgNPs induce oxidative stress. Hence, this study aims to investigate the effects of dietary supplemental zinc (Zn) and vitamin E (VE; α-tocopherol acetate) on attenuating AgNP-induced intestinal oxidative stress in broiler chickens. The chickens were divided into two groups as follows: (1) control group fed with a corn-soybean meal basal diet and (2) nano group, received drinking water containing 1000 mg/kg AgNPs. All the nano-exposed birds were divided into six dietary treatment groups, namely, the basal diets supplemented with (1) 60 mg/kg Zn as ZnSO4, (2) 120 mg/kg Zn, (3) 100 mg/kg VE, (4) 200 mg/kg VE, (5) 60 mg/kg Zn and 100 mg/kg VE, and (6) 120 mg/kg Zn and 200 mg/kg VE. Results showed that the AgNPs significantly reduced the body weights of the broilers after 42 days of oral administration of AgNPs (P < 0.05), and this effect was not alleviated by any of the dietary treatments. The activity of superoxide dismutase (CuZn-SOD) increased in all the AgNP-treated birds (P < 0.05); however, CuZn-SOD did not increase in birds fed with basal diet supplemented with 200 mg/kg VE. In this treatment, the VE exerted an antioxidant effect to prevent the activation of the CuZn-SOD enzyme. Furthermore, supplementing Zn increased the activities of catalase and glutathione peroxidase in the jejunal mucosa (P < 0.05), which were accompanied with increased malondialdehyde levels (P < 0.05) in the broilers. AgNP exposure resulted in a significant messenger RNA (mRNA) upregulation of toll-like receptor 4 (TLR4) and TLR2-1 in the jejunal mucosa (P < 0.05). However, supplemental ZnVE did not reduce TLRs' mRNA expression, except for the diminished TLR2-1 mRNA levels in birds fed with basal diet supplemented with 120 mg/kg Zn and 200 mg/kg VE. We concluded that although dietary Zn and VE supplementation did not attenuate growth depression effect of AgNP, it however attenuates intestinal oxidative stress in AgNP-treated broiler chickens.

Zinc-Excess Intake Causes the Deterioration of Renal Function Accompanied by an Elevation in Systemic Blood Pressure Primarily Through Superoxide Radical-Induced Oxidative Stress.

Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn-excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, Nω-nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO-) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO- Indeed, the activity of the endogenous OO- scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8-Hydroxy-2'-deoxyguanosine formation caused by OO- generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO^.