Advances in neurotoxicology最新文献

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.

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.

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.