Neurotoxicity In Humans Research Articles

HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers.

Paraquat is an herbicide whose use is associated with Parkinson's disease (PD), a neurodegenerative disorder marked by neuron loss in the substantia nigra pars compacta (SNc). We recently observed that the murine homolog to the human H63D variant of the homeostatic iron regulator (HFE) may decrease paraquat-associated nigral neurotoxicity in mice. The present study examined the potential influence of H63D on paraquat-associated neurotoxicity in humans. Twenty-eight paraquat-exposed workers were identified from exposure histories and compared with 41 unexposed controls. HFE genotypes, and serum iron and transferrin were measured from blood samples. MRI was used to assess the SNc transverse relaxation rate (R2*), a marker for iron, and diffusion tensor imaging scalars of fractional anisotropy (FA) and mean diffusivity, markers of microstructural integrity. Twenty-seven subjects (9 exposed and 18 controls) were H63D heterozygous. After adjusting for age and use of other PD-associated pesticides and solvents, serum iron and transferrin were higher in exposed H63D carriers than in unexposed carriers and HFE wildtypes. SNc R2* was lower in exposed H63D carriers than in unexposed carriers, whereas SNc FA was lower in exposed HFE wildtypes than in either unexposed HFE wildtypes or exposed H63D carriers. Serum iron and SNc FA measures correlated positively among exposed, but not unexposed, subjects. These data suggest that H63D heterozygosity is associated with lower neurotoxicity presumptively linked to paraquat. Future studies with larger cohorts are warranted to replicate these findings and examine potential underlying mechanisms, especially given the high prevalence of the H63D allele in humans.

Multiple toxicity of propineb in developing zebrafish embryos: Neurotoxicity, vascular toxicity, and notochord defects in normal vertebrate development

A dithiocarbamate (DTC) fungicide, propineb, affects thyroid function and exerts immunotoxicity, cytotoxicity, and neurotoxicity in humans. Long-term exposure to propineb is associated with carcinogenicity, teratogenicity, malfunction of the reproductive system, and abnormalities in vital signs during organ development. However, there is no evidence of acute toxicity attributable to propineb in zebrafish. Therefore, in the present study, we assessed the toxicity of propineb in zebrafish by studying its adverse effects on embryo development, angiogenesis, and notochord development. Embryos with propineb exposure developed morphological and physiological defects and in larvae, apoptosis and notochord defects were induced in the early development stage. Transgenic fli1:eGFP zebrafish exposed to propineb showed abnormal larval development with defects in angiogenesis and deformed vasculature. Propineb induced irreversible damage to the neural development of embryos and neurogenic defects in developing zebrafish in transgenic olig2:dsRED zebrafish. These results show that exposure to propineb triggers abnormalities in different organ systems of zebrafish and suggests the physiological complexity of the response to propineb.

Single Low Dose of Cocaine-Structural Brain Injury Without Metabolic and Behavioral Changes.

Chronic cocaine use has been shown to lead to neurotoxicity in rodents and humans, being associated with high morbidity and mortality rates. However, recreational use, which may lead to addictive behavior, is often neglected. This occurs, in part, due to the belief that exposure to low doses of cocaine comes with no brain damage risk. Cocaine addicts have shown glucose metabolism changes related to dopamine brain activity and reduced volume of striatal gray matter. This work aims to evaluate the morphological brain changes underlying metabolic and locomotor behavioral outcome, in response to a single low dose of cocaine in a pre-clinical study. In this context, a Balb-c mouse model has been chosen, and animals were injected with a single dose of cocaine (0.5 mg/kg). Control animals were injected with saline. A behavioral test, positron emission tomography (PET) imaging, and anatomopathological studies were conducted with this low dose of cocaine, to study functional, metabolic, and morphological brain changes, respectively. Animals exposed to this cocaine dose showed similar open field activity and brain metabolic activity as compared with controls. However, histological analysis showed alterations in the prefrontal cortex and hippocampus of mice exposed to cocaine. For the first time, it has been demonstrated that a single low dose of cocaine, which can cause no locomotor behavioral and brain metabolic changes, can induce structural damage. These brain changes must always be considered regardless of the dosage used. It is essential to alert the population even against the consumption of low doses of cocaine.

Manganese Removal by Biofiltration Using Activated Carbon-barium Alginate-entrapped Cells: Morphology, Durability, Settling Velocity, and Treatment Efficiency

Occurrence of manganese in water supplies causes colored water and pipe rusting in water treatment and distribution systems. Moreover, consumption of manganese-contaminated water may lead to neurotoxicity in humans. Biofilters have the potential to alleviate the manganese issue through bio-oxidation, particle separation, and adsorption processes. Biofiltration performance can be enhanced by augmentation of the manganese-oxidizing bacterium entrapped in polymeric materials. This study aimed to investigate the potential of barium alginate-entrapped cells supplemented with powdered activated carbon (PAC) for manganese removal. Streptomyces violarus strain SBP1, an effective manganese-oxidizing bacterium, was selected. The experiments were divided into 2 parts, including 1) characterization of barium alginate bead and 2) manganese removal testing. Effect of PAC content (1, 5, and 10% w/v) in the entrapment material on bead morphology, bead durability, and settling velocity (relative to a filtration medium) was investigated. Micro-structural observation using a scanning electron microscope showed that the PAC was distributed through intra-porous structure of the beads. The PAC-supplemented barium alginate beads improved durability (up to three-time higher Young’s modulus values). The PAC-supplemented barium alginate beads gave similar settling velocity compared to a filtration medium. The manganese removal efficiencies by the PAC-supplemented beads (no cells) ranged from 48 to 53%. Based on barium alginate bead characterization and manganese removal performance, the bead with 5% PAC content was selected for cell entrapment. The investigation revealed that the entrapped cells achieved faster manganese removal rate than free cell system. The findings from this study indicated high potential of the entrapped cells for use in future biofilter applications.

Ketamine inhibits neuronal differentiation by regulating brain-derived neurotrophic factor (BDNF) signaling

Ketamine is widely used in pediatric anesthesia, perioperative sedation, and analgesia. Knowledge of anesthesia neurotoxicity in humans is currently limited by the difficulty of obtaining neurons and performing developmental toxicity studies in fetal and pediatric populations. However, mouse embryonic stem cells (mESCs) derived from embryos at the preimplantation stage demonstrate an unlimited ability to self-renew and generate different cell types and are a valuable tool for clinical research. Thus, in this study, a model was employed to investigate the mechanism by which ketamine (200 nM) influences the neuronal differentiation of mESCs. Mouse ESCs were treated with an anesthetic dose of ketamine, and neuronal differentiation was significantly inhibited on day 5. Downregulation of brain-derived neurotrophic factor (BDNF) by shRNA was found to have the same inhibitory effect. Furthermore, a rescue experiment indicated that BDNF overexpression markedly restored the neuronal differentiation inhibited by ketamine in the ketamine/BDNF group on day 5. Taken together, these data suggested that ketamine inhibited the neuronal differentiation of mESCs, possibly by interfering with BDNF. The results of the current study may provide novel ideas for preventing ketamine toxicity in the developing fetus.

Environment permissible concentrations of glyphosate in drinking water can influence the fate of neural stem cells from the subventricular zone of the postnatal mouse.

The developing nervous system is highly vulnerable to environmental toxicants especially pesticides. Glyphosate pesticide induces neurotoxicity both in humans and rodents, but so far only when exposed to higher concentrations. A few studies, however, have also reported the risk of general toxicity of glyphosate at concentrations comparable to allowable limits set up by environmental protection authorities. Invitro data regarding glyphosate neurotoxicity at concentrations comparable to maximum permissible concentrations in drinking water is lacking. In the present study, we established an invitro assay based upon neural stem cells (NSCs) from the subventricular zone of the postnatal mouse to decipher the effects of two maximum permissible concentrations of glyphosate in drinking water on the basic neurogenesis processes. Our results demonstrated that maximum permissible concentrations of glyphosate recognized by environmental protection authorities significantly reduced the cell migration and differentiation of NSCs as demonstrated by the downregulation of the expression levels of the neuronal ß-tubulin III and the astrocytic S100B genes. The expression of the cytoprotective gene CYP1A1 was downregulated whilst the expression of oxidative stresses indicator gene SOD1 was upregulated. The concentration comparable to non-toxic human plasma concentration significantly induced cytotoxicity and activated Ca2+ signalling in the differentiated culture. Our findings demonstrated that the permissible concentrations of glyphosate in drinking water recognized by environmental protection authorities are capable of inducing neurotoxicity in the developing nervous system.

Plant Polyphenols: Potential Antidotes for Lead Exposure.

Lead is one of the most common heavy metal elements and has high biological toxicity. Long-term lead exposure will induce the contamination of animal feed, water, and food, which can cause chronic lead poisoning including nephrotoxicity, hepatotoxicity, neurotoxicity, and reproductive toxicity in humans and animals. In the past few decades, lead has caused widespread concern because of its significant threat to health. A large number of in vitro and animal experiments have shown that oxidative stress plays a key role in lead toxicity, and endoplasmic reticulum (ER) stress and the mitochondrial apoptosis pathway can also be induced by lead toxicity. Therefore, plant polyphenols have attracted attention, with their advantages of being natural antioxidants and having low toxicity. Plant polyphenols can resist lead toxicity by chelating lead with their special chemical molecular structure. In addition, scavenging active oxygen and improving the level of antioxidant enzymes, anti-inflammatory, and anti-apoptosis are also the key to relieving lead poisoning by plant polyphenols. Various plant polyphenols have been suggested to be useful in alleviating lead toxicity in animals and humans and are believed to have good application prospects.

Acrylamide inhibits autophagy, induces apoptosis and alters cellular metabolic profiles

Acrylamide (ACR) is generated during thermal processing of carbohydrate-rich foods at high temperature and can directly enter the body through ingestion, inhalation and skin contact. The toxicity of ACR has been widely studied. The main results of these studies show that exposure to ACR can cause neurotoxicity in both animals and humans, and show reproductive toxicity and carcinogenicity in rodent animal models. However, the mechanism of toxicity of ACR has not been studied by metabolomics approaches, and the effect of ACR on autophagy remains unknown. Here, U2OS cell were treated with ACR 6 and 24 h and collected for further study. We have demonstrated that ACR inhibited autophagic flux, and increased ROS content. Accumulation of ROS resulted in increase of apoptosis rates and secretion of inflammatory factors. In addition, significant differences in metabolic profiles were observed between ACR treated and control cells according to multiple analysis models. A total of 73 key differential metabolites were identified. They were involved in multiple metabolic pathways. Among them, exposure to ACR caused glycolysis/gluconeogenesis attenuation by decreasing levels of glycolytic intermediates, reduced the rate of the TCA cycle, while elevating levels of several amino acid metabolites and lipid metabolites. In summary, our study provides useful evidence of cytotoxicity caused by ACR via metabolomics and multiple bioanalytic methods.

TrkC Overexpression Protects Sevoflurane-Induced Neurotoxicity in Human Induced Pluripotent Stem Cell-Derived Neurons

Background: Inhaled anesthetic sevoflurane (SEVO) may induce cortical neurotoxicity and memory dysfunction in both animals and humans. In this study, we investigated the toxic effects of SEVO on human induced pluripotent stem cell (iPS)-derived neurons. Methods: Human iPS-derived neurons were exposed to SEVO in vitro. SEVO-induced toxic effects were examined with the viability, live caspase 3/7, and neurite density assays, respectively. The effects of SEVO on the receptors of the tyrosine kinases TrkA, TrkB, and TrkC were assessed by qRT-PCR. TrkA, TrkB, and TrkC were ectopically overexpressed in human iPS-derived neurons. Their functional effects on SEVO-induced human iPS-derived neuron toxicity were further investigated. Results: SEVO induced dose-dependent cell death, caspase 3/7 elevation, neurite degeneration, and the downregulation of Trk receptors in human iPS-derived neurons. Adenovirus-mediated Trk receptor overexpression selectively upregulated endogenous TrkA, TrkB, or TrkC gene expressions in human iPS-derived neurons. Specifically, TrkC overexpression, but not TrkA or TrkB overexpression was found to overcome the neurotoxic effects of SEVO in human iPS-derived neurons. Conclusions: SEVO may induce neurotoxicity in human iPS-derived neurons, and its neurotoxic damage could be protected by the overexpression of TrkC.

Interaction of organophosphate pesticide chlorpyrifos with alpha-2-macroglobulin: Biophysical and molecular docking approach

ABSTRACT Organophosphate class of pesticides causes neurotoxicity and carcinogenicity in humans. Once inside the human body, these pesticides often interact with plasma proteins, such as alpha-2-macroglobulin (α2M) which is the key anti-proteinase. Our work focuses on the structural and functional alteration of α2M by chlorpyrifos (CPF), a member of organophosphates. We explored the binding interaction between alpha-2-macroglobulin and CPF by using UV absorption and fluorescence spectroscopy (steady state and synchronous), circular dichroism and molecular docking approach. The functional activity of α2M was analyzed by anti-proteinase trypsin inhibitory assay which showed dose-dependent decrease in alpha-2-macroglobulin antiproteolytic potential. UV absorption studies and fluorescence quenching experiments suggested the formation of a complex between α2M and CPF. The CD spectra suggested a reduction in the beta helical (β helix) content of α2M. Analysis of thermodynamic parameters suggested the process is spontaneous and endothermic with the ΔG and ΔH values being −5.501 kJ/mol, 11.49 kJ/mol, respectively. CPF binds with Ile-1390, Pro-1391, Leu-1392, Lys-1393, Val-1396, Lys-1397, Arg-1407, Thr-1408, Glu-1409, Val-1410, Asp-282, Glu-281 of α2M as suggested by molecular docking.

Occurrence of domoic acid and cyclic imines in marine biota from Lebanon-Eastern Mediterranean Sea

Marine biotoxins are naturally existing chemicals produced by toxic algae and can accumulate in marine biota. When consumed with seafood, these phycotoxins can cause human intoxication with symptoms varying from barely-noticed illness to death depending on the type of toxin and its concentration. Recently, the occurrence of marine biotoxins has been given special attention in the Mediterranean as it increased in frequency and severity due to anthropogenic pressures and climate change. Up to our knowledge, no previous study reported the presence of lipophilic toxins (LTs) and cyclic imines (CIs) in marine biota in Lebanon. Hence, this study reports LTs and CIs in marine organisms: one gastropod (Phorcus turbinatus), two bivalves (Spondylus spinosus and Patella rustica complex) and one fish species (Siganus rivulatus), collected from various Lebanese coastal areas. The results show values below the limit of detection (LOD) for okadaic acid, dinophysistoxin-1 and 2, pectenotoxin-1 and 2, yessotoxins, azaspiracids and saxitoxins. The spiny oyster (S. spinosus) showed the highest levels of domoic acid (DA; 3.88 mg kg−1), gymnodimine (GYM-B) and spirolide (SPX) (102.9 and 15.07 μg kg−1, respectively) in congruence with the occurrence of high abundance of Pseudo-nitzchia spp., Gymnodinium spp., and Alexandrium spp. DA levels were below the European Union (EU) regulatory limit, but higher than the Lowest Observed Adverse Effect Level (0.9 μg g−1) for neurotoxicity in humans and lower than the Acute Reference Dose (30 μg kg−1 bw) both set by the European Food Safety Authority (EFSA, 2009). Based on these findings, it is unlikely that a health risk exists due to the exposure to these toxins through seafood consumption in Lebanon. Despite this fact, the chronic toxicity of DA, GYMs and SPXs remains unclear and the effect of the repetitive consumption of contaminated seafood needs to be more investigated.

Manganese-contaminated groundwater treatment by novel bacterial isolates: kinetic study and mechanism analysis using synchrotron-based techniques

The occurrence of manganese in groundwater causes coloured water and pipe rusting in water treatment systems. Consumption of manganese-contaminated water promotes neurotoxicity in humans and animals. Manganese-oxidizing bacteria were isolated from contaminated areas in Thailand for removing manganese from water. The selected bacterium was investigated for its removal kinetics and mechanism using synchrotron-based techniques. Among 21 isolates, Streptomyces violarus strain SBP1 (SBP1) was the best manganese-oxidizing bacterium. At a manganese concentration of 1 mg L−1, SBP1 achieved up to 46% removal. The isolate also successfully removed other metal and metalloid, such as iron (81%) and arsenic (38%). The manganese concentration played a role in manganese removal and bacterial growth. The observed self-substrate inhibition best fit with the Aiba model. Kinetic parameters estimated from the model, including a specific growth rate, half-velocity constant, and inhibitory constant, were 0.095 h−1, 0.453 mg L−1, and 37.975 mg L−1, respectively. The synchrotron-based techniques indicated that SBP1 removed manganese via combination of bio-oxidation (80%) and adsorption (20%). The study is the first report on biological manganese removal mechanism using synchrotron-based techniques. SBP1 effectively removed manganese under board range of manganese concentrations. This result showed the potential use of the isolate for treating manganese-contaminated water.

Maternal-fetal disposition of domoic acid following repeated oral dosing during pregnancy in nonhuman primate

Domoic acid (DA) is a marine algal toxin that causes acute and chronic neurotoxicity in animals and humans. Prenatal exposure to DA has been associated with neuronal damage and cognitive and behavioral deficits in juvenile California sea lions, cynomolgus monkeys and rodents. Yet, the toxicokinetics (TK) of DA during pregnancy and the maternal-fetal disposition of DA have not been fully elucidated. In this study, we investigated the TK before, during, and after pregnancy and the maternal-fetal disposition of DA in 22 cynomolgus monkeys following daily oral doses of 0.075 or 0.15mg/kg/day of DA. The AUC0-τ of DA was not changed while the renal clearance of DA was increased by 30-90% during and after pregnancy when compared to the pre-pregnancy values. DA was detected in the infant plasma and in the amniotic fluid at delivery. The infant plasma concentrations correlated positively with both the maternal plasma and the amniotic fluid concentrations. The paired infant-to-maternal plasma DA concentration ratios ranged from 0.3 to 0.6 and increased as a function of time which suggests placental efflux and longer apparent fetal half-life than the maternal half-life. The paired amniotic fluid-to-infant plasma DA concentration ratios ranged from 4.5 to 7.5 which indicates significant accumulation of DA in the amniotic fluid. A maternal-fetal TK model was developed to explore the processes that give the observed maternal-fetal disposition of DA. The final model suggests that placental transport and recirculation of DA between the fetus and amniotic fluid are major determining factors of the maternal-fetal TK of DA.

Exposure to 1-bromopropane vapors during pregnancy enhances the development of hippocampal neuronal excitability in rat pups during lactation.

ObjectivesAlthough 1‐Bromopropane (1‐BP) exposure has been reported to cause neurotoxicity in adult humans and animals, its effects on the development of the central nervous system remain unclear. Recently, we reported delayed developmental neurotoxicity (DNT) upon 1‐BP exposure in rats. Here we aimed to study the effect of prenatal 1‐BP exposure on the hippocampal excitability in the juvenile offspring.MethodsPregnant Wistar rats were exposed to vaporized 1‐BP for 20 days (6 h/d) with concentrations of 0 (control), 400, or 700 ppm. Hippocampal slices were prepared from male offspring during postnatal days (PNDs) 13, 14, and 15. Field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded simultaneously from the CA1 region.ResultsIn the exposed groups, the stimulation/response relationships of fEPSP slope and PS amplitude were enhanced more than in the control group at PND 14. Analysis of fEPSP‐spike coupling demonstrated increased values of Top and Eslope50 in the exposed groups. Real‐time PCR analysis showed a significant increase in the mRNA levels of the adult type Nav1.1 Na+ channel subunit and the GluR1 glutamate receptor subunit in the hippocampus of the 700 ppm group at PND 14.ConclusionsOur results provide evidence that prenatal exposure to 1‐BP accelerates developmental enhancement of hippocampal excitability in the pups before eye‐opening. The current study suggests that our evaluation method of DNT is applicable to the industrial chemical 1‐BP.

High-content imaging of 3D-cultured neural stem cells on a 384-pillar plate for the assessment of cytotoxicity

The assessment of neurotoxicity has been performed traditionally with animals. However, in vivo studies are highly expensive and time-consuming, and often do not correlate to human outcomes. Thus, there is a need for cost-effective, high-throughput, highly predictive alternative in vitro test methods based on early markers of mechanisms of toxicity. High-content imaging (HCI) assays performed on three-dimensionally (3D) cultured cells could provide better understanding of the mechanism of toxicity needed to predict neurotoxicity in humans. However, current 3D cell culture systems lack the throughput required for screening neurotoxicity against a large number of chemicals. Therefore, we have developed miniature 3D neural stem cell (NSC) culture on a unique 384-pillar plate, which is complementary to conventional 384-well plates. Mitochondrial membrane impairment, intracellular glutathione level, cell membrane integrity, DNA damage, and apoptosis have been tested against 3D-cultured ReNcell VM on the 384-pillar plate with four model compounds rotenone, 4-aminopyridine, digoxin, and topotecan. The HCI assays performed in 3D-cultured ReNcell VM on the 384-pillar plates were highly robust and reproducible as indicated by the average Z′ factor of 0.6 and CV values around 12%. From concentration-response curves and IC50 values, mitochondrial membrane impairment appears to be the early stage marker of cell death by the compounds.

Neuroprotective mechanisms of selenium against arsenic-induced behavioral impairments in rats

Environmental pollution due to arsenic is associated with several adverse health effects including neurotoxicity in animals and humans. Selenium is a nutritionally essential trace metalloid well documented to elicit compelling pharmacological activities in vitro and in vivo. Report on the influence of selenium on arsenic-mediated behavioral derangement is lacking in literature. Hence, to fill this knowledge gap, rats were either exposed to arsenic per se in drinking water at 60 μg AsO2Na/L or co-administered with inorganic selenium at 0.25 mg/kg or organic selenium diphenyl diselenide (DPDS) at 2.5 mg/kg body weight for 45 successive days. Neurobehavioural data from rats in a new environment using video-tracking software evinced that inorganic and organic forms of selenium significantly (p < 0.05) abrogated arsenic-induced motor and locomotor insufficiencies such as increased negative geotaxis and fecal pellets numbers as well as the diminution in grip strength, body rotation, maximum speed, absolute turn angle and total distance travelled. The augmentation in the behavioral activities in rats co-administered with arsenic and both forms of selenium was substantiated using track and occupancy plots analyses. Selenium mitigated arsenic-induced decreases in glutathione level and acetylcholinesterase activity as well as the increase in oxidative stress and reactive oxygen and nitrogen species. Moreover, selenium diminished inflammatory parameters (myeloperoxidase activity, nitric oxide, tumour necrosis factor alpha and interleukin-1 beta levels), caspase-3 activity and ameliorated histological lesions in the cerebellum, cerebrum and liver of the rats. Collectively, selenium abated arsenic-induced behavioral derangements via anti-inflammation, antioxidant and anti-apoptotic mechanisms in rats.

Differential effects of fluoxetine and venlafaxine in the neural embryonic stem cell test (ESTn) revealed by a cell lineage map

There is a need for in vitro tests for the evaluation of chemicals and pharmaceuticals that may cause developmental neurotoxicity (DNT) in humans. The neural embryonic stem cell test (ESTn) is such an in vitro test that mimics early neural differentiation. The aim of this study was to define the biological domain of ESTn based on the expression of selective markers for certain cell types, and to investigate the effects of two antidepressants, fluoxetine (FLX) and venlafaxine (VNX), on neural differentiation. A cell lineage map was made to track neural differentiation and the effects of FLX and VNX in ESTn. Whole transcriptome analysis revealed differentiation from an embryonic stem cell population to a mixed culture of neural progenitors, neurons and neural crest cells 7 days into differentiation. Maturing neurons, astrocytes and oligodendrocytes were present after 13 days. Exposure to FLX or VNX led to different expression patterns between compounds at both time points. On day 7, both compounds upregulated most of the stem cell- and immature neuron markers, but had distinct effects on neural subtype markers. FLX downregulated glycinergic markers and upregulated cholinergic markers, while VNX had the opposite effect. On day 13, FLX and VNX affected their specific therapeutic targets, represented by mainly serotonergic markers by FLX- and dopaminergic and noradrenergic markers in VNX-exposed cultures, as well as oligodendrocyte and glycinergic neuron markers. This proof of concept study shows the added value of assessing DNT in ESTn through a cell lineage map and gives mechanistic insight in the potential neurodevelopmental effects of FLX and VNX. More compounds should be tested to further evaluate the use of the cell lineage map.

Perfluorooctane Sulfonate (PFOS) Produces Dopaminergic Neuropathology in Caenorhabditis elegans.

Perfluorooctane sulfonate (PFOS) has been widely utilized in numerous industries. Due to long environmental and biological half-lives, PFOS is a major public health concern. Although the literature suggests that PFOS may induce neurotoxicity, neurotoxic mechanisms, and neuropathology are poorly understood. Thus, the primary goal of this study was to determine if PFOS is selectively neurotoxic and potentially relevant to specific neurological diseases. Nematodes (Caenorhabditis elegans) were exposed to PFOS or related per- and polyfluoroalkyl substances (PFAS) for 72 h and tested for evidence of neuropathology through examination of cholinergic, dopaminergic, gamma-amino butyric acid (GABA)ergic, and serotoninergic neuronal morphologies. Dopaminergic and cholinergic functional analyses were assessed through 1-nonanol and Aldicarb assay. Mechanistic studies assessed total reactive oxygen species, superoxide ions, and mitochondrial content. Finally, therapeutic approaches were utilized to further examine pathogenic mechanisms. Dopaminergic neuropathology occurred at lower exposure levels (25 ppm, approximately 50 µM) than required to produce neuropathology in GABAergic, serotonergic, and cholinergic neurons (100 ppm, approximately 200 µM). Further, PFOS exposure led to dopamine-dependent functional deficits, without altering acetylcholine-dependent paralysis. Mitochondrial content was affected by PFOS at far lower exposure level than required to induce pathology (≥1 ppm, approximately 2 µM). Perfluorooctane sulfonate exposure also enhanced oxidative stress. Further, mutation in mitochondrial superoxide dismutase rendered animals more vulnerable. Neuroprotective approaches such as antioxidants, PFAS-protein dissociation, and targeted (mitochondrial) radical and electron scavenging were neuroprotective, suggesting specific mechanisms of action. In general, other tested PFAS were less neurotoxic. The primary impact is to prompt research into potential adverse outcomes related to PFAS-induced dopaminergic neurotoxicity in humans.

Evaluation of the susceptibility of neurons and neural stem/progenitor cells derived from human induced pluripotent stem cells to anticancer drugs

Various chemicals, including pharmaceuticals, can induce acute or delayed neurotoxicity in humans. Because isolation of human primary neurons is extremely difficult, toxicity tests for these agents have been performed using in vivo or in vitro models. Human induced pluripotent stem cells (hiPSCs) can be used to establish hiPSC-derived neural stem/progenitor cells (hiPSC-NSPCs), which can then be used to obtain hiPSC-neurons. In this study, we differentiated hiPSC-NSPCs into neurons and evaluated the susceptibility of hiPSC-neurons and parental hiPSC-NSPCs to anticancer drugs in vitro by ATP assay and immunocytostaining. The hiPSC-neurons were more resistant to anticancer drugs than the parental hiPSC-NSPCs. In the toxicity tests, high-dose cisplatin reduced the levels of ELAVL3/4, a neuronal marker, in the hiPSC-neurons. These results suggest that our methodology is potentially applicable for efficient determination of the toxicity of any drug to hiPSC-neurons.

Arsenic Neurotoxicity in Humans.

Arsenic (As) contamination affects hundreds of millions of people globally. Although the number of patients with chronic As exposure is large, the symptoms and long-term clinical courses of the patients remain unclear. In addition to reviewing the literature on As contamination and toxicity, we provide useful clinical information on medical care for As-exposed patients. Further, As metabolite pathways, toxicity, speculated toxicity mechanisms, and clinical neurological symptoms are documented. Several mechanisms that seem to play key roles in As-induced neurotoxicity, including oxidative stress, apoptosis, thiamine deficiency, and decreased acetyl cholinesterase activity, are described. The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser effect on motor fibers. A sural nerve biopsy showed the axonal degeneration of peripheral nerves mainly in small myelinated and unmyelinated fibers. Exposure to high concentrations of As causes severe central nervous system impairment in infants, but no or minimal impairment in adults. The exposure dose–response relationship was observed in various organs including neurological systems. The symptoms caused by heavy metal pollution (including As) are often nonspecific. Therefore, in order to recognize patients experiencing health problems caused by As, a multifaceted approach is needed, including not only clinicians, but also specialists from multiple fields.