The effect of manganese exposure in Atp13a2-deficient mice.

Loss of function mutations in the P-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein.

Trimethyltin-induced cochlear degeneration in rat.

Trimethyltin (TMT) is an occupational and environmental health hazard behaving as a potent neurotoxin known to affect the central nervous system as well as the peripheral auditory system. However, the mechanisms underlying TMT-induced ototoxicity are poorly understood. To elucidate the effects of TMT on the cochlea, a single injection of 4 or 8 mg/kg TMT was administered intraperitoneally to adult rats.

Carbaryl-induced ototoxicity in rat postnatal cochlear organotypic cultures.

Carbaryl, a widely used carbamate-based insecticide, is a potent anticholinesterase known to induce delayed neurotoxicity following chronic exposure. However, its potential toxic effects on the cochlea, the sensory organ for hearing that contains cholinergic efferent neurons and acetylcholine receptors on the hair cells (HC) and spiral ganglion neurons has heretofore not been evaluated. To assess ototoxic potential of carbaryl, cochlear organotypic cultures from postnatal day 3 rats were treated with doses of carbaryl ranging from 50 to 500 μM for 48 h up to 96 h.

Effect of manganese and manganese plus noise on auditory function and cochlear structures.

The degenerative actions of Mn caused by persistent exposure to high atmospheric levels not only provokes irreversible damage to the CNS with symptoms comparable to that of Parkinson's disease but also may have deleterious consequences to other organs including the auditory system. The putative deleterious consequences of prolonged Mn overexposure on hearing, however, is confounded by the fact that chronically-exposed individuals often work in high noise environments where noise by itself is known to cause hearing loss. Thus, the question as to whether Mn alone is actually ototoxic and whether exposure to Mn when combined with noise increases the risk of hearing loss and cochlear pathology has never been examined.

Ototoxicity of Divalent Metals.

Excess exposure to both essential and non-essential heavy metals can lead to a variety of adverse clinical conditions which selectively affect a variety of organs and cells in the body. The diverse, but highly specific nature of the symptoms produced by each metal indicates that they can interact with a restricted population of cellular targets ultimately resulting in unique clinical manifestations. The symptoms, which can be reversible or irreversible, often present with different patterns and outcomes depending on the net accumulated dose of any given metal.

Quantitative PCR analysis and protein distribution of drug transporter genes in the rat cochlea.

Membrane transporters can be major determinants in the targeting and effectiveness of pharmaceutical agents. A large number of biologically important membrane transporters have been identified and localized to a variety of tissues, organs and cell types. However, little is known about the expression of key membrane transporters in the inner ear, a promising site for targeted therapeutics, as well as a region vulnerable to adverse drug reactions and environmental factors.

Effect of manganese treatment on the accumulation on biologically relevant metals in rat cochlea and brain by inductively coupled plasma mass spectrometry.

Manganese (Mn), iron (Fe), zinc (Zn), and copper (Cu) are essential transitions metals that are required in trace amounts, however chronic exposure to high concentrations can cause severe and irreversible neurotoxicity. Since prolonged exposure to Mn leads to manganism, a disorder exhibiting a diverse array of neurological impairments progressing to a debilitating and irreversible extrapyramidal condition symptomatically similar to Parkinson's disease, we measured the concentration of Mn as well as Fe, Zn and Cu in three region of the brain (globus pallidus, striatum and inferior colliculus) and three regions in the cochlea (stria vascularis, basilar membrane and modiolus) under normal conditions or after 30 or 60 days of oral administration of Mn (10 mg/ml ad libitum). Under normal conditions, Mn, Zn and Fe were typically higher in the cochlea than in the three brain regions whereas Cu was equal to or lower.

Cobalt-Induced Ototoxicity in Rat Postnatal Cochlear Organotypic Cultures.

Cobalt (Co) is a required divalent metal used in the production of metal alloys, batteries, and pigments and is a component of vitamin B12. Excessive uptake of Co is neurotoxic causing temporary or permanent hearing loss; however, its ototoxic effects on the sensory hair cells, neurons, and support cells in the cochlea are poorly understood. Accordingly, we treated postnatal day 3 rat cochlear organotypic cultures with various doses and durations of CoCl2 and quantified the damage to the hair cells, peripheral auditory nerve fibers, and spiral ganglion neurons (SGN).

Neurotoxicity of trimethyltin in rat cochlear organotypic cultures.

Trimethyltin (TMT), which has a variety of applications in industry and agricultural, is a neurotoxin that is known to affect the auditory system as well as central nervous system of humans and experimental animals. However, the mechanisms underlying TMT-induced auditory dysfunction are poorly understood. To gain insights into the neurotoxic effect of TMT on the peripheral auditory system, we treated cochlear organotypic cultures with concentrations of TMT ranging from 5 to 100 μM for 24 h.

Endogenous concentrations of biologically relevant metals in rat brain and cochlea determined by inductively coupled plasma mass spectrometry.

Manganese (Mn), iron (Fe), copper (Cu), and zinc (Zn) are essential nutrients which aid in the proper functioning of cells, but high concentrations of these metals can be toxic to various organs. Little is known about the endogenous concentrations of these metals in the cochlea, the auditory portion of the inner ear which is extremely small and difficult to access. To fill this gap, a trace quantitative digestion and inductively coupled plasma mass spectrometry method was developed to determine the concentrations of these metals in the stria vascularis, organ of Corti, and spiral ganglion, three critically important parts of the cochlea (≤ 1.

Ototoxicity of paclitaxel in rat cochlear organotypic cultures.

Paclitaxel (taxol) is a widely used antineoplastic drug employed alone or in combination to treat many forms of cancer. Paclitaxel blocks microtubule depolymerization thereby stabilizing microtubules and suppressing cell proliferation and other cellular processes. Previous reports indicate that paclitaxel can cause mild to moderate sensorineural hearing loss and some histopathologic changes in the mouse cochlea; however, damage to the neurons and the underlying cell death mechanisms are poorly understood.

Correlation between the biochemical pathways altered by mutated parkinson-related genes and chronic exposure to manganese.

The studies presented in this review attempt to describe the operative properties of the genes involved in generation of early and late onset of Parkinson's disease or Parkinson-like disorders and how mutation in these genes relate to onset of manganism. These include the genes α-synuclein, parkin, PINK1, DJ-1, ATP13A2, and SLC30A10 which are associated with early-onset of Parkinson's as well as those genes linked with late onset of the disorder which include, LRRK2 and VPS35. Since mutations in these genes and excess Mn potentially disrupt similar cellular processes within the basal ganglia, it is reasonable to hypothesize that the expressed symptoms of Parkinson's disease may overlap with that of manganese (Mn) toxicity.

Cellular localization and developmental changes of Zip8, Zip14 and transferrin receptor 1 in the inner ear of rats.

Prior studies have demonstrated that the inner ear can accumulate a variety of essential and potentially toxic heavy metals including manganese, lead, cobalt and cadmium. Metal accumulation is regulated in part by the functionality and affinity of these metals for the different transport systems responsible for uptake across the blood-cochlea barrier and their subsequent uptake into the different cells within the inner ear. Transport of these metals across cell membranes occurs by many of the same transport systems which include DMT1, Zip8 and Zip14.

Cadmium-induced ototoxicity in rat cochlear organotypic cultures.

Cadmium (Cd), a widely used industrial metal, is extremely nephrotoxic and neurotoxic; however, its effects on the peripheral auditory system are poorly understood. To evaluate the ototoxicity of Cd, we treated cochlear organotypic cultures from postnatal day 3 rats with Cd concentrations from 10 to 500 μM for 24 or 48 h. Afterward, we evaluated the degree of damage to hair cells, auditory nerve fibers, and spiral ganglion neurons.

Cellular localization and developmental changes of the different isoforms of divalent metal transporter 1 (DMT1) in the inner ear of rats.

Divalent metal transporter 1 (DMT1) is generally considered to be the major transmembrane protein responsible for the uptake of a variety of divalent cations. Four isoforms of DMT1 have been identified in mammalian cells encoded by a single gene that differ both in their N- and C-terminal sequences with two mRNA isoforms possessing an iron response element (IRE) motif downstream from the stop codon on the message. Two distinct promoter sites regulate production of the 1A or 1B isoforms (translation starts at exon 2) for both the +IRE or -IRE species of the transporter resulting in the generation of four distinct configurations of this protein.

Nicotinamide adenine dinucleotide prevents neuroaxonal degeneration induced by manganese in cochlear organotypic cultures.

Manganese (Mn) is an essential trace mineral for normal growth and development. Persistent exposures to high atmospheric levels of Mn have deleterious effects on CNS and peripheral nerves including those associated with the auditory system. Nicotinamide adenine dinucleotide (NAD) is a coenzyme which functions in the electron transfer system within the mitochondria.

Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity.

The extra-pyramidal symptoms associated with manganism often overlap with that seen in Parkinsonism suggesting a common link between the two disorders. Since wide deviations are observed in susceptibility and characteristics of the symptoms observed in manganism, these differences may be due to underlying genetic variability. Genes linked to early onset of Parkinsonism which includes ATP13A2 and parkin have already been suggested to promote development of Mn toxicity.

The effect of manganese on dopamine toxicity and dopamine transporter (DAT) in control and DAT transfected HEK cells.

Chronic exposure to Mn results in the development of a neurological disorder known as manganism characterized by neurological deficits resembling that seen in Parkinsonism. Although dopaminergic neurons within the nigrostriatal pathway appear intact, Mn-induced irregularities in DA transmission have been observed including decreased amphetamine-induced DA release and loss of the dopamine transporter (DAT). Results of studies to evaluate the effect of Mn and DA on cell viability in control and DAT-transfected HEK cells reveal that Mn is equally toxic to both cell lines whereas DA was only toxic to cells containing DAT.

Manganese-induced toxicity in normal and human B lymphocyte cell lines containing a homozygous mutation in parkin.

Mutations in the parkin gene are linked to development of juvenile onset of Parkinson's disease and recent studies have reported that parkin can protect against increased oxidative stress and mitochondrial dysfunction caused by a variety of oxidative and toxic insults. Overexpression of parkin has also been reported to selectively protect dopaminergic neurons from Mn toxicity. Accordingly, in this paper we compare the effect that mutations in parkin have on Mn toxicity and associated apoptotic signals in normal and human B lymphocyte cell lines containing a homozygous mutation in the gene.

Effect of glutamate and riluzole on manganese-induced apoptotic cell signaling in neuronally differentiated mouse P19 Cells.

Excess exposure to Mn causes a neurological disorder known as manganism which is similar to dystonic movements associated with Parkinson's disease. Manganism is largely restricted to occupations in which high atmospheric levels are prevalent which include Mn miners, welders and those employed in the ferroalloy processing or related industrial settings. T1 weighted MRI images reveal that Mn is deposited to the greatest extent in the globus pallidus, an area of the brain that is presumed to be responsible for the major CNS associated symptoms.

Isoform specific regulation of divalent metal (ion) transporter (DMT1) by proteasomal degradation.

Divalent metal ion transporter (DMT1) is the major transporter for iron entrance into mammalian cells and iron exit from endosomes during the transferrin cycle. Four major mRNA isoforms correspond to four protein isoforms, differing at 5'/3' and N-/C-termini, respectively. Isoforms are designated 1A versus 1B reflecting where transcription starts or +iron responsive element (+IRE) versus -IRE reflecting the presence/absence of an IRE in the 3' end of the mRNA.

Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1.

Abnormal iron accumulation is linked to a variety of neurological disorders and may contribute to the progressive damage seen in these diseases. The biochemical processes responsible for iron accumulation are not known but are likely to entail alteration in transport into injured brain areas. The major transport protein responsible for uptake of iron is divalent metal transporter 1 (DMT1) and recent studies demonstrate that the 1B species is regulated post-translationally by degradation via the proteasomal pathway.

Are there common biochemical and molecular mechanisms controlling manganism and parkisonism.

Over the past several decades there has been considerable progress in our basic knowledge as to the mechanisms and factors regulating Mn toxicity. The disorder known as manganism is associated with the preferential accumulation of Mn in the globus pallidus of the basal ganglia which is generally considered to be the major and initial site of injury. Because the area of the CNS comprising the basal ganglia is very complex and dependent on the precise function and balance of several neurotransmitters, it is not surprising that symptoms of manganism often overlap with that of Parkinson's disease.

Expression of the 1B isoforms of divalent metal transporter (DMT1) is regulated by interaction of NF-Y with a CCAAT-box element near the transcription start site.

The 1B isoforms of the divalent metal transporter (DMT1) have recently been shown to be regulated transcriptionally via NF-kappaB but whether other regulatory elements are present on this promoter, however, have not been determined. Accordingly, studies were performed to delineate a minimal promoter region responsible for basal expression of these isoforms of DMT1. Promoter analysis has established that the 1B promoter is a TATA-less promoter containing a common CCAAT-box element conserved in mouse, rat, and human.

Comparison of mammalian cell lines expressing distinct isoforms of divalent metal transporter 1 in a tetracycline-regulated fashion.

DMT1 (divalent metal transporter; also known as SLC11A2, DCT1 or Nramp2) is responsible for ferrous iron uptake in the duodenum, iron exit from endosomes during the transferrin cycle and some transferrin-independent iron uptake in many cells. Four protein isoforms differ by starting in exon 1A or 2 and ending with alternative peptides encoded by mRNA that contains or lacks an IRE (iron responsive element; +/-IRE). We have compared 1A/+IRE and 2/-IRE DMT1 during regulated ectopic expression.