搜索结果：Advances in neurotoxicology

During the past century, a vast number of organic chemicals have been manufactured and used in industrial, agricultural, public health, consumer products, and other applications. The widespread use in bulk quantities of halogenated organic chemicals (HOCs; also called Organohalogens), including chlorinated, brominated, and fluorinated compounds, and their persistent nature have resulted in global environmental contamination. Increasing levels of HOCs in environmental media (i.e., air, water, soil, sediment) and in human tissues including adipose tissue, breast milk, and placenta continue to be a cause of ecological and human health concern. Human exposure can occur through multiple pathways including direct skin contact, inhalation, drinking water, and mainly through food consumption. HOCs exposure has been implicated in a myriad of health effects including reproductive, neurological, immunological, endocrine, behavioral, and carcinogenic effects in both wildlife and humans. In addition, recent studies indicate that exposure to HOCs contributes to obesity and type 2 diabetes. Because of these adverse health effects, several regulatory agencies either banned or placed severe restrictions on their production and usage. In turn, many industries withdrew from production and usage of HOCs. This action resulted in decline of older HOCs such as polychlorinated biphenyls (PCBs), but more recent HOCs such as polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl substances (PFAS) show a steady increase/stable with time in the global environment. Based on their use pattern and their persistent chemical properties, human exposure to HOCs will likely continue. Hence, understanding human health effects and taking preventive measures for such exposures are necessary.

The existing data demonstrate that probiotic supplementation affords protective effects against neurotoxicity of exogenous (e.g., metals, ethanol, propionic acid, aflatoxin B1, organic pollutants) and endogenous (e.g., LPS, glucose, Aβ, phospho-tau, α-synuclein) agents. Although the protective mechanisms of probiotic treatments differ between various neurotoxic agents, several key mechanisms at both the intestinal and brain levels seem inherent to all of them. Specifically, probiotic-induced improvement in gut microbiota diversity and taxonomic characteristics results in modulation of gut-derived metabolite production with increased secretion of SFCA. Moreover, modulation of gut microbiota results in inhibition of intestinal absorption of neurotoxic agents and their deposition in brain. Probiotics also maintain gut wall integrity and inhibit intestinal inflammation, thus reducing systemic levels of LPS. Centrally, probiotics ameliorate neurotoxin-induced neuroinflammation by decreasing LPS-induced TLR4/MyD88/NF-κB signaling and prevention of microglia activation. Neuroprotective mechanisms of probiotics also include inhibition of apoptosis and oxidative stress, at least partially by up-regulation of SIRT1 signaling. Moreover, probiotics reduce inhibitory effect of neurotoxic agents on BDNF expression, on neurogenesis, and on synaptic function. They can also reverse altered neurotransmitter metabolism and exert an antiamyloidogenic effect. The latter may be due to up-regulation of ADAM10 activity and down-regulation of presenilin 1 expression. Therefore, in view of the multiple mechanisms invoked for the neuroprotective effect of probiotics, as well as their high tolerance and safety, the use of probiotics should be considered as a therapeutic strategy for ameliorating adverse brain effects of various endogenous and exogenous agents.

Despite currently available drugs for neurological disorders, the incidence of these diseases continues to rise with attendant morbidity, mortality and economic losses. The available treatments oftentimes focus more on either slowing down disease progression or ameliorating symptoms. According to the World Health Organization, some of these disorders, including Parkinson's disease and Alzheimer's diseases are among the leading causes of death globally. Identification of new compounds with neuroprotective properties is a fascinating line of research. Berberine, a plant-derived bioactive compound, of the alkaloid family, has been studied extensively for its neuroprotective properties in a wide range of models of neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, autism spectrum disorders, traumatic brain injuries and amyloid lateral sclerosis. Studies have shown that the neuroprotective property of berberine is linked to its ability to modulate several critical biochemical pathways and to regulate the concentrations and activities of important biomarkers that are both diagnostic and therapeutic targets for neurological disorders. This chapter provides insight into the biosynthesis, pharmacokinetics and neuroprotective mechanisms of berberine. Furthermore, ways to improve the utilization of berberine for its neuroprotective potentials such as combining it with other compounds or nanoparticle delivery are highlighted.

Systemic inhibition of neuropathy target esterase (NTE) with certain organophosphorus (OP) compounds produces OP compound-induced delayed neurotoxicity (OPIDN), a distal degeneration of axons in the central nervous system (CNS) and peripheral nervous system (PNS), thereby providing a powerful model for studying a spectrum of neurodegenerative diseases. Axonopathies are important medical entities in their own right, but in addition, illnesses once considered primary neuronopathies are now thought to begin with axonal degeneration. These disorders include Alzheimer's disease, Parkinson's disease, and motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Moreover, conditional knockout of NTE in the mouse CNS produces vacuolation and other degenerative changes in large neurons in the hippocampus, thalamus, and cerebellum, along with degeneration and swelling of axons in ascending and descending spinal cord tracts. In humans, NTE mutations cause a variety of neurodegenerative conditions resulting in a range of deficits including spastic paraplegia and blindness. Mutations in the Drosophila NTE orthologue SwissCheese (SWS) produce neurodegeneration characterized by vacuolization that can be partially rescued by expression of wild-type human NTE, suggesting a potential therapeutic approach for certain human neurological disorders. This chapter defines NTE and OPIDN, presents an overview of OP compounds, provides a rationale for NTE research, and traces the history of discovery of NTE and its relationship to OPIDN. It then briefly describes subsequent studies of NTE, including practical applications of the assay; aspects of its domain structure, subcellular localization, and tissue expression; abnormalities associated with NTE mutations, knockdown, and conventional or conditional knockout; and hypothetical models to help guide future research on elucidating the role of NTE in OPIDN.

Neurons require protective systems throughout their entire life course to function prop-erly. However, the brain remains highly susceptible to injury with modern environmental dynamics, when threats, produced naturally and synthetically, can bypass the blood-brain barrier (BBB) and cause neurological damage. Among those toxicants, atrazine (ATZ) has been regarded as a neurotoxic environmental pollutant. Both low-dose exposure and variable courses (short- and long-term) carried out in different experimental models demonstrated that ATZ impairs multiple neurochemical pathways. The resultant disruption leads to oxidative stress, mitochondrial dysfunction, and neuroinflammation, culminating in neuronal injury and impaired function. Despite the limited number of existing studies, bioactive compounds such as lycopene, isoflavones, and biflavanone kolaviron have been shown to be promising neuroprotective agents against ATZ neurotoxicity. These compounds, derived from natural bioactive tomato, soybean, walnut, and bitter kola- Garcinia kola, respectively, possess antioxidant and neuroprotective potentials, thus capable of mitigating the toxic actions of ATZ exposure. Overall, in vitro and in vivo studies accentuate that plant-derived bioactive compounds offer therapeutic benefits in mitigating neurotoxicity from ATZ. However, further research is needed to elucidate the detailed mechanisms by which the plants bioactive compounds mitigate ATZ-induced neurotoxicity, including their interactions with the pathways involved in the neurotoxic effects of ATZ.

Increased evidence from epidemiological research and pre-clinical studies have presented a correlation between exogenous neurotoxicants (such as aluminum, arsenic, lead, cadmium, mercury and ethanol) and various neurobiological disorders which contribute to cognitive impairments. The existing data demonstrate that nutraceutical supplementation affords neuroprotective effects against neurotoxicity. Nutraceuticals improved learning and memory impairments, anxiety and depressive-like behavior, locomotor activity and neuropathic pain. The most common molecular and cellular mechanisms in nutraceutical therapy include attenuation of oxidative stress (by suppressing lipid peroxidation and increasing antioxidant enzymes and contents), suppression of apoptosis (by increasing B-cell lymphoma 2 (Bcl2) expression, and reduction in Bcl-2-associated X protein (Bax), caspase-3 and cytochrome c expression), suppression of neuroinflammation (by inhibiting inflammatory cytokines), inhibition of amyloid β (Aβ) plaque and neurofibrillary tangles, and increased synaptic plasticity (by increasing Brain-derived neurotrophic factor (BDNF), and regulating cholinergic and neurotransmitter systems.

Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). Iron (Fe)-dependent programmed cell death known as ferroptosis, plays a crucial role in the etiology and progression of PD. Since SNpc is particularly vulnerable to Fe toxicity, a central role for ferroptosis in the etiology and progression of PD is envisioned. Ferroptosis, characterized by reactive oxygen species (ROS)-dependent accumulation of lipid peroxides, is tightly regulated by a variety of intracellular metabolic processes. Moreover, the recently characterized bi-directional interactions between ferroptosis and the gut microbiota, not only provides another window into the mechanistic underpinnings of PD but could also suggest novel interventions in this devastating disease. Here, following a brief discussion of PD, we focus on how our expanding knowledge of Fe-induced ferroptosis and its interaction with the gut microbiota may contribute to the pathophysiology of PD and how this knowledge may be exploited to provide novel interventions in PD.

Selenoneine, an antioxidant molecule analogous to ergothioneine, is not synthesized by vertebrates but can be acquired through the diet. Both selenoneine and ergothioneine contain redox-active groups: selone (-C=Se) and thioketone (-C = S), respectively. However, the reactivity of the selone group with pro-oxidant intermediates is significantly higher than that of the thioketone group. In the presence of oxygen, selenoneine undergoes oxidation to its diselenide form, which can be regenerated by a molar excess of reduced thiol groups. High levels of selenoneine have been detected in carnivorous fish, aquatic mammals, and populations consuming these species. It has been suggested that both selenoneine and ergothioneine possess health-promoting properties in humans. This chapter explores the potential protective effects of selenoneine against electrophilic mercury forms, such as methylmercury (CH3Hg+) and divalent mercury (Hg2 +).

The gut microbes perform several beneficial functions which impact the periphery and central nervous systems of the host. Gut microbiota dysbiosis is acknowledged as a major contributor to the development of several neuropsychiatric and neurological disorders including bipolar disorder, depression, anxiety, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, and autism spectrum disorder. Thus, elucidation of how the gut microbiota-brain axis plays a role in health and disease conditions is a potential novel approach to prevent and treat brain disorders. The zebrafish (Danio rerio) is an invaluable vertebrate model that possesses conserved brain and intestinal features with those of humans, thus making zebrafish a valued model to investigate the interplay between the gut microbiota and host health. This chapter describes current findings on the utility of zebrafish in understanding molecular mechanisms of neurotoxicity mediated via the gut microbiota-brain axis. Specifically, it highlights the utility of zebrafish as a model organism for understanding how anthropogenic chemicals, pharmaceuticals and bacteria exposure affect animals and human health via the gut-brain axis.

Circadian rhythms describe the behavioral and physiological changes that occur in living organisms in order to attune to a 24 hour cycle of day and night. The most striking aspect of circadian function is the sleep-wake cycle, however many other physiological processes are regulated in 24 hour oscillations, including blood pressure, body temperature, appetite, urine production, and the transcription and translation of thousands of circadian dependent genes. Circadian disruption and sleep disorders are strongly connected to neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and Huntington's disease as well as others. Metal exposures have been implicated in neurodegenerative diseases, in some cases involving metals that are essential micronutrients but are toxic at high levels of exposure (such as manganese, copper, and zinc), and in other cases involving metals that have no biological role but are toxic to living systems (such as lead, mercury, and aluminum). In this review, we examine the evidence for circadian and sleep disorders with exposures to these metals and review the literature for possible mechanisms. We suggest that giving the aging population, the prevalence of environmental exposures to metals, and the increasing prevalence of neurodegenerative disease in the aged, more research into the mechanisms of circadian disruption subsequent to metal exposures is warranted.

Alcohol (ethanol), presumably consumed as wine as far back as 7000 BC, is most likely the first addictive substance known to man. In modern days, its abuse leading to neurotoxicity and a myriad of organ damages, is of considerable social and medical concern. In the United States alone, approximately 180,000 people die yearly because of alcohol-related accidents and diseases. Given its ubiquitous nature, alcohol may interact with many cellular components. In this chapter, we specifically concentrate on its neurotoxic mechanisms involving glial cells and their role in neuroinflammation. Moreover, exploitation of this knowledge for potential novel interventions in alcohol-induced neurotoxicity are touched upon.

Lead (Pb2+) is a non-essential metal with numerous industrial applications that have led to ts ubiquity in the environment. Thus, not only occupational-exposed individuals' health is compromised, but also that of the general population and in particular children. Notably, although the central nervous system is particularly susceptible to Pb2+, other systems are affected as well. The present study focuses on molecular mechanisms that underlie the effects that arise from the presence of Pb2+ in situ in the brain, and the possible toxic effects that follows. As the brain barriers represent the first target of systemic Pb2+, mechanisms of Pb2+ entry into the brain are discussed, followed by a detailed discussion on neurotoxic mechanisms, with special emphasis on theories of ion mimicry, mitochondrial dysfunction, redox imbalance, and neuroinflammation. Most importantly, the confluence and crosstalk between these events is combined into a cogent mechanism of toxicity, by intertwining recent and old evidences from humans, in vitro cell culture and experimental animals. Finally, pharmacological interventions, including chelators, antioxidants substances, anti-inflammatory drugs, or their combination are reviewed as integrated approaches to ameliorate Pb2+ harmful effects in both developing or adult organisms.

Mercury exerts a variety of toxic effects, depending on the specific compound and route of exposure. However, neurotoxicity in virtue of its consequence to health causes the greatest concern for toxicologists. This is particularly true regarding fetal development, where neurotoxic effects are much more severe than in adults, and the toxicity threshold is lower. Here, we review the major concepts regarding the neurotoxicity of mercury compounds (mercury vapor; methylmercury and ethylmercury), from exposure routes to toxicokinetic particularities leading to brain deposition and the development of neurotoxic effects. Albeit research on the neurotoxicity of mercury compounds has significantly advanced from the second half of the twentieth century onwards, several grey areas regarding the mechanism of toxicity still exist. Thus, we emphasize research advances during the last two decades concerning the molecular interactions of mercury which cause neurotoxic effects. Highlights include the disruption of glutamate signaling and excitotoxicity resulting from exposure to mercury and the interaction with redox active residues such as cysteines and selenocysteines which are the premise accounting for the disruption of redox homeostasis caused by mercurials. We also address how immunotoxic effects at the CNS, namely microglia and astrocyte activation modulate developmental neurotoxicity, a major topic in contemporary research.

Environmental exposures and/or alterations in the homeostasis of essential transition metals (ETM), such as Fe, Cu, Zn or Mn, are known to contribute to neurodegenerative diseases (ND), such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Aberrant ETM homeostasis leads to altered distributions, as significant amounts may accumulate in specific brain areas, while causing metal deficiency in others. The disruption of processes reliant on the interplay between these ETM, may lead to loss of metal balance and the ensuing neurotoxicity via shared mechanisms, such as the induction of oxidative stress (OS). Both ETM imbalance and OS may play a role, via complex positive loop processes, in primary neuropathological signatures of AD, such as the accumulation of amyloid plaques and neurofibrillary tangles (NTF), and in PD, α-Syn aggregation and loss of dopamine(DA)rgic neurons. The association between ETM imbalance and ND is rarely approached under the view that metals such as Fe, Cu, Zn and Mn, can act as dangerous endogenous neurotoxic mixtures when their control mechanisms became disrupted. In fact, their presence as mixtures implies intricacies, which should be kept in mind when developing therapies for complex disorders of metal dyshomeostasis, which commonly occur in ND.

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The toxicology of mercury (Hg) is of concern since this metal is ubiquitously distributed in the environment, and living organisms are routinely exposed to Hg at low to high levels. The toxic effects of Hg are well studied and it is known that they may differ depending on the Hg chemical species. In this chapter, we emphasize the neurotoxic effects of Hg during brain development. The immature brain is more susceptible to Hg exposure, since all the Hg chemical forms, not only the organic ones, can harm it. The possible consequences of Hg exposure during the early stages of development, the additive effects with other co-occurring neurotoxicants, and the known mechanisms of action and targets will be addressed in this chapter.

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