Platinum accumulation in oxaliplatin-induced peripheral neuropathy.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high-affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research.

The neurological toxicity of heavy metals: A fish perspective.

The causes of neurodegenerative diseases are complex with likely contributions from genetic susceptibility and environmental exposures over an organism's lifetime. In this review, we examine the role that aquatic models, especially zebrafish, have played in the elucidation of mechanisms of heavy metal toxicity and nervous system function over the last decade. Focus is applied to cadmium, lead, and mercury as significant contributors to central nervous system morbidity, and the application of numerous transgenic zebrafish expressing fluorescent reporters in specific neuronal populations or brain regions enabling high-resolution neurodevelopmental and neurotoxicology research.

Metals and Paraoxonases.

The paraoxonases (PONs) are a three-gene family which includes PON1, PON2, and PON3. PON1 and PON3 are synthesized primarily in the liver and a portion is secreted in the plasma, where they are associated with high-density lipoproteins (HDLs), while PON2 is an intracellular enzyme, expressed in most tissues and organs, including the brain. PON1 received its name from its ability to hydrolyze paraoxon, the active metabolite of the organophosphorus (OP) insecticide parathion, and also more efficiently hydrolyzes the active metabolites of several other OPs. PON2 and PON3 do not have OP-esterase activity, but all PONs are lactonases and are capable of hydrolyzing a variety of lactones, including certain drugs, endogenous compounds, and quorum-sensing signals of pathogenic bacteria. In addition, all PONs exert potent antioxidant effects. PONs play important roles in cardiovascular diseases and other oxidative stress-related diseases, modulate susceptibility to infection, and may provide neuroprotection (PON2). Hence, significant attention has been devoted to their modulation by a variety of dietary, pharmacological, lifestyle, or environmental factors. A number of metals have been shown in in vitro, animal, and human studies to mostly negatively modulate expression of PONs, particularly PON1, the most studied in this regard. In addition, different levels of expression of PONs may affect susceptibility to toxicity and neurotoxicity of metals due to their aforementioned antioxidant properties.

Occupational Metal Exposure and Parkinsonism.

Parkinsonism is comprised of a host of neurological disorders with an underlying clinical feature of movement disorder, which includes many shared features of bradykinesia, tremor, and rigidity. These clinical outcomes occur subsequent to pathological deficits focused on degeneration or dysfunction of the nigrostriatal dopamine system and accompanying pathological inclusions of alpha-synuclein and tau. The heterogeneity of parkinsonism is equally matched with the complex etiology of this syndrome. While a small percentage can be attributed to genetic alterations, the majority arise from an environmental exposure, generally composed of pesticides, industrial compounds, as well as metals. Of these, metals have received significant attention given their propensity to accumulate in the basal ganglia and participate in neurotoxic cascades, through the generation of reactive oxygen species as well as their pathogenic interaction with intracellular targets in the dopamine neuron. The association between metals and parkinsonism is of critical concern to subsets of the population that are occupationally exposed to metals, both through current practices, such as mining, and emerging settings, like E-waste and the manufacture of metal nanoparticles. This review will explore our current understanding of the molecular and pathological targets that mediate metal neurotoxicity and lead to parkinsonism and will highlight areas of critical research interests that need to be addressed.

Neurotoxicity of Metal Mixtures.

Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull's, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels. The Substance Priority List of Agency for Toxic Substances and Disease Registry (ATSDR) ranked substances based on a combination of their frequency, toxicity, and potential for human exposure. In this list, As, Pb, Hg, and Cd occupy the first, second, third, and seventh positions, respectively (ATSDR, Priority list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 2016). Besides existing individually, these metals are also (or mainly) found as mixtures in various parts of the ecosystem (Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L, Chemosphere 132:79-86, 2015). Interactions among components of a mixture may change toxicokinetics and toxicodynamics (Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Stürzenbaum SR, Sci Total Environ 408:3725-3734, 2010) and may result in greater (synergistic) toxicity (Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ, Environ Int 37:663-670, 2011). This is particularly worrisome when the components of the mixture individually attack the same organs. On the other hand, metals such as manganese [Mn], iron [Fe], copper [Cu], and zinc [Zn] are essential metals, and their presence in the body below or above homeostatic levels can also lead to disease states (Annangi B, Bonassi S, Marcos R, Hernández A, Mutat Res 770(Pt A):140-161, 2016). Pb, As, Cd, and Hg can induce Fe, Cu, and Zn dyshomeostasis, potentially triggering neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, changes in heme synthesis have been associated with neurodegeneration, supported by evidence that a decline in heme levels might explain the age-associated loss of Fe homeostasis (Atamna H, Killile DK, Killile NB, Ames BN, Proc Natl Acad Sci U S A 99(23):14807-14812, 2002).The sources, disposition, transport to the brain, mechanisms of toxicity, and effects in the central nervous system (CNS) and in the hematopoietic system of each one of these metals will be described. More detailed information on Pb, Mn, Al, Hg, Cu, and Zn is available in other chapters. A major focus of the chapter will be on Pb toxicity and its interaction with other metals.

Neurotoxicity of Vanadium.

Vanadium (V) is a transition metal that presents in multiple oxidation states and numerous inorganic compounds and is also an ultra-trace element considered to be essential for most living organisms. Despite being one of the lightest metals, V offers high structural strength and good corrosion resistance and thus has been widely adopted for high-strength steel manufacturing. High doses of V exposure are toxic, and inhalation exposure to V adversely affects the respiratory system. The neurotoxicological properties of V are just beginning to be identified. Recent studies by our group and others demonstrate the neurotoxic potential of this metal in the nigrostriatal system and other parts of the central nervous system (CNS). The neurotoxic effects of V have been mainly attributed to its ability to induce the generation of reactive oxygen species (ROS). It is noteworthy that the neurotoxicity induced by occupational V exposure commonly occurs with co-exposure to other metals, especially manganese (Mn). This review focuses on the chemistry, pharmacology, toxicology, and neurotoxicity of V.

Neurotoxicity of Zinc.

Zinc-induced neurotoxicity has been shown to play a role in neuronal damage and death associated with traumatic brain injury, stroke, seizures, and neurodegenerative diseases. During normal firing of "zinc-ergic" neurons, vesicular free zinc is released into the synaptic cleft where it modulates a number of postsynaptic neuronal receptors. However, excess zinc, released after injury or disease, leads to excitotoxic neuronal death. The mechanisms of zinc-mediated neurotoxicity appear to include not only neuronal signaling but also regulation of mitochondrial function and energy production, as well as other mechanisms such as aggregation of amyloid beta peptides in Alzheimer's disease. However, recent data have raised questions about some of our long-standing assumptions about the mechanisms of zinc in neurotoxicity. Thus, this review explores the most recent published findings and highlights the current mechanistic controversies.

Neurotoxicity of Copper.

Copper is an essential trace metal that is required for several important biological processes, however, an excess of copper can be toxic to cells. Therefore, systemic and cellular copper homeostasis is tightly regulated, but dysregulation of copper homeostasis may occur in disease states, resulting either in copper deficiency or copper overload and toxicity. This chapter will give an overview on the biological roles of copper and of the mechanisms involved in copper uptake, storage, and distribution. In addition, we will describe potential mechanisms of the cellular toxicity of copper and copper oxide nanoparticles. Finally, we will summarize the current knowledge on the connection of copper toxicity with neurodegenerative diseases.

Thallium Toxicity: General Issues, Neurological Symptoms, and Neurotoxic Mechanisms.

Thallium (Tl+) is a ubiquitous natural trace metal considered as the most toxic among heavy metals. The ionic ratio of Tl+ is similar to that of potassium (K+), therefore accounting for the replacement of the latter during enzymatic reactions. The principal organelle damaged after Tl+ exposure is mitochondria. Studies on the mechanisms of Tl+ include intrinsic pathways altered and changes in antiapoptotic and proapoptotic proteins, cytochrome c, and caspases. Oxidative damage pathways increase after Tl+ exposure to produce reactive oxygen species (ROS), changes in physical properties of the cell membrane caused by lipid peroxidation, and concomitant activation of antioxidant mechanisms. These processes are likely to account for the neurotoxic effects of the metal. In humans, Tl+ is absorbed through the skin and mucous membranes and then is widely distributed throughout the body to be accumulated in bones, renal medulla, liver, and the Central Nervous System. Given the growing relevance of Tl+ intoxication, in recent years there is a notorious increase in the number of reports attending Tl+ pollution in different countries. In this sense, the neurological symptoms produced by Tl+ and its neurotoxic effects are gaining attention as they represent a serious health problem all over the world. Through this review, we present an update to general information about Tl+ toxicity, making emphasis on some recent data about Tl+ neurotoxicity, as a field requiring attention at the clinical and preclinical levels.

Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain.

Human exposure to toxic heavy metals is a global challenge. Concurrent exposure of heavy metals, such as lead (Pb), cadmium (Cd), arsenic (As) and methylmercury (MeHg) are particularly important due to their long lasting effects on the brain. The exact toxicological mechanisms invoked by exposure to mixtures of the metals Pb, Cd, As and MeHg are still unclear, however they share many common pathways for causing cognitive dysfunction. The combination of metals may produce additive/synergetic effects due to their common binding affinity with NMDA receptor (Pb, As, MeHg), Na+ - K+ ATP-ase pump (Cd, MeHg), biological Ca+2 (Pb, Cd, MeHg), Glu neurotransmitter (Pb, MeHg), which can lead to imbalance between the pro-oxidant elements (ROS) and the antioxidants (reducing elements). In this process, ROS dominates the antioxidants factors such as GPx, GS, GSH, MT-III, Catalase, SOD, BDNF, and CERB, and finally leads to cognitive dysfunction. The present review illustrates an account of the current knowledge about the individual metal induced cognitive dysfunction mechanisms and analyse common Mode of Actions (MOAs) of quaternary metal mixture (Pb, Cd, As, MeHg). This review aims to help advancement in mixture toxicology and development of next generation predictive model (such as PBPK/PD) combining both kinetic and dynamic interactions of metals.

Low concentrations of copper in drinking water increase AP-1 binding in the brain.

Copper (Cu) in trace amounts is essential for biological organisms. However, dysregulation of the redox-active metal has been implicated in different neurological disorders such as Wilson's, Menkes', Alzheimer's, and Parkinson's diseases. Since many households use Cu tubing in the plumbing system, and corrosion causes the metal to leach into the drinking water, there may be adverse effects on the central nervous system connected with low-level chronic exposure. The present study demonstrates that treatment with a biologically relevant concentration of Cu for 3 months significantly increases activation of the redox-modulated transcription factor AP-1 in mouse brains. This was independent of an upstream kinase indicated in AP-1 activation. Another redox-active transcription factor, NF-κB, was not significantly modified by the Cu exposure. These results indicate that the effect of Cu on AP-1 is unique and may involve direct modulation of DNA binding.

MiRNA-210 modulates a nickel-induced cellular energy metabolism shift by repressing the iron-sulfur cluster assembly proteins ISCU1/2 in Neuro-2a cells.

The cellular energy metabolism shift, characterized by the inhibition of oxidative phosphorylation (OXPHOS) and enhancement of glycolysis, is involved in nickel-induced neurotoxicity. MicroRNA-210 (miR-210) is regulated by hypoxia-inducible transcription factor-1α (HIF-1α) under hypoxic conditions and controls mitochondrial energy metabolism by repressing the iron-sulfur cluster assembly protein (ISCU1/2). ISCU1/2 facilitates the assembly of iron-sulfur clusters (ISCs), the prosthetic groups that are critical for mitochondrial oxidation-reduction reactions. This study aimed to investigate whether miR-210 modulates alterations in energy metabolism after nickel exposure through suppressing ISCU1/2 and inactivating ISCs-containing metabolic enzymes. We determined that NiCl2 exposure leads to a significant accumulation of HIF-1α, rather than HIF-1ß, in Neuro-2a cells. The miR-210 overexpression and ISCU1/2 downregulation was observed in a dose- and time-dependent manner. The gain-of-function and loss-of-dysfunction assays revealed that miR-210 mediated the ISCU1/2 suppression, energy metabolism alterations, and ISC-containing metabolic enzyme inactivation after nickel exposure. In addition, the impact of miR-210 on ISC-containing metabolic enzymes was independent from cellular iron regulation. Overall, these data suggest that repression of miR-210 on ISCU1/2 may contribute to HIF-1α-triggered alterations in energy metabolism after nickel exposure. A better understanding of how nickel impacts cellular energy metabolism may facilitate the elucidation of the mechanisms by which nickel affects the human health.

High doses of cobalt induce optic and auditory neuropathy.

The adverse biological effects of continuous exposure to cobalt and chromium have been well defined. In the past, this toxicity was largely an industrial issue concerning workers exposed in occupational setting. Nevertheless, recent reports have described a specific toxicity mediated by the high levels of cobalt and chromium released by metallic prostheses, particularly in patients who had received hip implants. Clinical symptoms, including blindness, deafness and peripheral neuropathy, suggest a specific neurotropism. However, little is known about the neuropathological basis of this process, and experimental evidence is still lacking. We have investigated this issue in an experimental setting using New Zealand White rabbits treated with repeated intravenous injections of cobalt and chromium, alone or in combination. No evident clinical or pathological alterations were associated after chromium administration alone, despite its high levels in blood and tissue while cobalt-chromium and cobalt-treated rabbits showed clinical signs indicative of auditory and optic system toxicity. On histopathological examination, the animals showed severe retinal and cochlear ganglion cell depletion along with optic nerve damage and loss of sensory cochlear hair cells. Interestingly, the severity of the alterations was related to dosages and time of exposure. These data confirmed our previous observation of severe auditory and optic nerve toxicity in patients exposed to an abnormal release of cobalt and chromium from damaged hip prostheses. Moreover, we have identified the major element mediating neurotoxicity to be cobalt, although the molecular mechanisms mediating this toxicity still have to be defined.

α-Synuclein overexpression enhances manganese-induced neurotoxicity through the NF-κB-mediated pathway.

Exposure to manganese (Mn) occurs in both civilian and military operations. Mn exposure results in a movement disorder termed manganism, which resembles Parkinson's disease (PD). However, the pathogenic mechanisms underlying this disorder are not fully understood. α-Synuclein, a presynaptic protein is implicated in some neurodegenerative disorders, including PD and Mn-induced apoptosis, and its overexpression contributes to the loss of dopaminergic neurons. Although the role of α-synuclein in this process is widely documented, its exact function is not clear. The objective of this study was to evaluate the mechanism(s) of dopaminergic degeneration associated with α-synuclein expression in response to Mn exposure and to assess the role of nuclear factor-κB (NF-κB) activation as an intermediary of Mn-induced neurotoxicity. Rat mesencephalic cells (MES 23.5) overexpressing human α-synuclein show enhanced susceptibility to Mn exposure as evidenced by increased apoptosis and NF-κB nuclear translocation. Pretreatment with antioxidants and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 significantly diminished NF-κB activation, supporting a role for oxidative stress and p38 MAPK in Mn-induced NF-κB activation. In addition, increased nitric oxide generation was evident during NF-κB activation, which was blocked by NF-κB (SN50) and MAPK inhibitors. Mn-induced cell death was attenuated by SN-50 and specific nitric oxide synthase (NOS) inhibitor (1400W); corroborating NOS activation is mediated through NF-κB in the mechanism of cell death. These data indicate that the transcription factor NF-κB, p38 MAPK, and apoptotic signaling cascades are activated by Mn in human α-synuclein-overexpressing cells. Thus, α-synuclein may facilitate Mn-induced neurotoxicity, and along with NF-κB, it may play a role in dopaminergic cell death.

Manganese exposure alters the expression of N-methyl-D-aspartate receptor subunit mRNAs and proteins in rat striatum.

Manganese is one of the ubiquitous environmental pollutants that can induce an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. The present study has been carried out to investigate the effect of Mn on the expression of N-methyl-d-aspartate receptor (NR) subunit mRNAs and proteins in rat striatum when rats were in manganism. The rats were divided randomly into four groups of six males and six females each: control group (group 1) and 8, 40, and 200 micromol/kg Mn-treated groups (groups 2-4). The control group rats were subcutaneously (s.c.) injected with normal saline. Manganese-treated rats were s.c. injected with respectively 8, 40, and 200 micromol/kg of MnCl(2) . 6H(2)O in normal saline. The administration of MnCl(2) . 6H(2)O for 4 weeks significantly increased Mn concentration in the striatum. With the increase in administered MnCl(2) dosage, Glu concentration and cell apoptosis rate increased significantly. The relative intensity of NR2A mRNA decreased significantly in 8 micromol/kg Mn-treated rats. However, relative intensities of NR1 and NR2B mRNAs decreased significantly in 40 micromol/kg Mn-treated rats. Similarly, the relative intensity of NR2A protein showed a significant decrease in 40 micromol/kg Mn-treated rats whereas those of NR1 and NR2B decreased significantly in 200 micromol/kg Mn-treated rats. Therefore, the expression of NR2A mRNA and protein were much more sensitive to Mn than that of NR1 and NR2B. In conclusion, the results suggested that Mn induced nerve cell damage by increasing extracellular Glu level and altered expression of NR subunit mRNAs and proteins in rat striatum.

Adverse effects of metal exposure on chemotaxis towards water-soluble attractants regulated mainly by ASE sensory neuron in nematode Caenorhabditis elegans.

Chemotaxis to water-soluble attractants is mainly controlled by ASE sensory neuron whose specification is regulated by che-1 in Caenorhabditis elegans. Our data suggested that exposure to high concentrations of metals, such as Pb, Cu, Ag, and Cr, would result in severe defects of chemotaxis to water-soluble attractants of NaCl, cAMP, and biotin. Moreover, the morphology of ASE neuron structures as observed by relative fluorescent intensities and relative size of fluorescent puncta of cell bodies, relative lengths of sensory endings in ASE neurons, and the expression patterns of che-1 were obviously altered in metal exposed animals when they meanwhile exhibited obvious chemotaxis defects to water-soluble attractants. In addition, the dendrite morphology could be noticeably changed in animals exposed to 150 micromol/L of Pb, Cu, and Ag. Furthermore, we observed significant decreases of chemotaxis to water-soluble attractants in Pb exposed che-1 mutant at concentrations more than 2.5 micromol/L, and in Cu, Ag, and Cr exposed che-1 mutant at concentrations more than 50 micromol/L. Therefore, impairment of the ASE neuron structures and functions may largely contribute to the appearance of chemotaxis defects to water-soluble attractants in metal exposed nematodes.

Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders.

Once considered little more than the glue that holds neurons in place, astrocytes are now becoming appreciated for the key roles they play in central nervous system functions. They supply neurons and oligodendrocytes with substrates for energy metabolism, control extracellular water and electrolyte homeostasis, regulate neurotransmitter release, modulate immune responses, produce trophic factors, and control synapse formation. Astrocytes express receptors for many neurotransmitters, peptides, hormones and cytokines, and show excitability based on intracellular Ca2+ variations. Evidence is mounting that alterations in astrocyte functionality play a crucial role in the pathogenesis of disorders with diverse properties, including migraine, epilepsy, leukodystrophies, inflammatory demyelinating diseases, infections, brain edema and metabolic disorders, metal intoxications, neurodegenerative disorders, and schizophrenia. Targeting astrocyte dysfunction may lead to new therapeutic strategies for these disorders.

Mycorrhizoremediation--an enhanced form of phytoremediation.

Study of plant roots and the diversity of soil micro biota, such as bacteria, fungi and microfauna associated with them, is important for understanding the ecological complexities between diverse plants, microbes, soil and climates and their role in phytoremediation of contaminated soils. The arbuscular mycorrhizal fungi (AMF) are universal and ubiquitous rhizosphere microflora forming symbiosis with plant roots and acting as biofertilizers, bioprotactants, and biodegraders. In addition to AMF, soils also contain various antagonistic and beneficial bacteria such as root pathogens, plant growth promoting rhizobacteria including free-living and symbiotic N-fixers, and mycorrhiza helping bacteria. Their potential role in phytoremediation of heavy metal (HM) contaminated soils and water is becoming evident although there is need to completely understand the ecological complexities of the plant-microbe-soil interactions and their better exploitation as consortia in remediation strategies employed for contaminated soils. These multitrophic root microbial associations deserve multi-disciplinary investigations using molecular, biochemical, and physiological techniques. Ecosystem restoration of heavy metal contaminated soils practices need to incorporate microbial biotechnology research and development. This review highlights the ecological complexity and diversity of plant-microbe-soil combinations, particularly AM and provides an overview on the recent developments in this area. It also discusses the role AMF play in phytorestoration of HM contaminated soils, i.e. mycorrhizoremediation.

Ependymal epithelium disruption after vanadium pentoxide inhalation. A mice experimental model.

The blood-brain barrier (BBB) protects the CNS against chemical insults. Regulation of blood-brain tissue exchange is accomplished by ependymal cells, which possess intercellular tight junctions. Loss of BBB function is an etiologic component of many neurological disorders. Vanadium (V) is a metalloid widely distributed in the environment and exerts potent toxic effects on a wide variety of biological systems. The current study examines the effects of Vanadium pentoxide (V2O5) inhalation in mice ependymal epithelium, through the analysis of the brain metal concentrations and the morphological modifications in the ependymal cells identified by scanning and transmission electron microscopy after 8 weeks of inhalation, in order to obtain a possible explanation about the mechanisms that V uses to enter and alter the CNS. Our results showed that V2O5 concentrations increase from the first week of study, stabilizing its values during the rest of the experiment. The morphological effects included cilia loss, cell sloughing and ependymal cell layer detachment. This damage can allow toxicants to modify the permeability of the epithelium and promote access of inflammatory mediators to the underlying neuronal tissue causing injury and neuronal death. Thus, understanding the mechanisms of BBB disruption would allow planning strategies to protect the brain from toxicants such as metals, which have increased in the atmosphere during the last decades and constitute an important health problem.