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Molecular Research in Neurotoxicology 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 23789

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Special Issue Editor

Dr. G. Jean Harry

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Guest Editor

Neurotoxicology Group, NIEHS and National Toxicology Program, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709, USA
Interests: neurotoxicants; aging; development; inflammation; oxidative stress; signal transduction; hormones; neuropathology; pharmaceuticals; alternative models
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Special Issue Information

Dear Colleagues,

Alterations in nervous system functioning as a result of environmental factors, pharmaceuticals, genetic variability, and health status remain an issue of concern for human health. Recent advancements have been made in our understanding of common biological processes related to neurotoxicity associated with disease states and age-related or genetic vulnerabilities. These advances have been possible due to the ability to examine molecular aspects underlying neurodevelopment, neurodegeneration, and associated processes of neurotoxicity. The integration of this molecular data into the field of neurotoxicology, as it applies to the broad spectrum of environmental exposure now offers a mechanistic framework for understanding the dynamics of neurotoxicity. Further work on epigenetic mechanisms associated with nervous system functioning, e.g., learning and memory, provide additional mechanisms by which regulation of the nervous system can be altered by environmental exposure or by which events occurring during early life stages can influence responses later in life. This topical collection will focus on the integration of established biological processes and molecular events as they relate to the regulation of cellular and functional changes within the nervous system and how this may contribute to neurotoxicity. The collection will include aspects of neurological and neurodegenerative disease, neurodevelopmental disorders, and specific neurotoxicity from environmental or pharmaceutical agents. We are seeking novel research and/or review articles highlighting 1) the variety of molecular signals and integrated networks that underlie adverse responses in the nervous system, 2) how these alterations in molecular signaling translate to alterations in the structure or function of the nervous system (biochemical, physiology, behavior), 3) molecular events occurring during early life that can shift susceptibility in the adult, 4) epigenetic regulatory events as they contribute to neurotoxicity and 5) contributions to life stage events influencing human health.

Dr. G. Jean Harry
Guest Editor

Manuscript Submission Information

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Keywords

oxidative stress
organophosphorus pesticides
neuropathy target esterase (nte)
animal models
transcription factor signaling
cell death
receptor mediated events
receptor mediated events
glia
kynurenines
quinolinic acid
inflammation
cytokines
heat shock protein 70
neurobehavior
neuroprotection
seizures
neurotrophic factors
ischemia/hypoxia
microglia
cyanobacteria
heavy metals
pharmacological models
neurodegeneration
ischemia
perinatal brain injury
neurotoxicants
neurodegenerative diseases
zinc

Published Papers (7 papers)

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Research

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15 pages, 3089 KiB

Open AccessArticle

Dietary Exposure to Flame Retardant Tris (2-Butoxyethyl) Phosphate Altered Neurobehavior and Neuroinflammatory Responses in a Mouse Model of Allergic Asthma

by Tin-Tin Win-Shwe, Rie Yanagisawa, Thet-Thet Lwin, Fumitaka Kawakami, Eiko Koike and Hirohisa Takano

Int. J. Mol. Sci. 2022, 23(2), 655; https://doi.org/10.3390/ijms23020655 - 07 Jan 2022

Cited by 6 | Viewed by 2159

Abstract

Tris (2-butoxyethyl) phosphate (TBEP) is an organophosphate flame retardant and used as a plasticizer in various household products such as plastics, floor polish, varnish, textiles, furniture, and electronic equipment. However, little is known about the effects of TBEP on the brain and behavior. We aimed to examine the effects of dietary exposure of TBEP on memory functions, their-related genes, and inflammatory molecular markers in the brain of allergic asthmatic mouse models. C3H/HeJSlc male mice were given diet containing TBEP (0.02 (TBEP-L), 0.2 (TBEP-M), or 2 (TBEP-H) μg/kg/day) and ovalbumin (OVA) intratracheally every other week from 5 to 11 weeks old. A novel object recognition test was conducted in each mouse at 11 weeks old. The hippocampi were collected to detect neurological, glia, and immunological molecular markers using the real-time RT-PCR method and immunohistochemical analyses. Mast cells and microglia were examined by toluidine blue staining and ionized calcium-binding adapter molecule (Iba)-1 immunoreactivity, respectively. Impaired discrimination ability was observed in TBEP-H-exposed mice with or without allergen. The mRNA expression levels of N-methyl-D aspartate receptor subunits Nr1 and Nr2b, inflammatory molecular markers tumor necrosis factor-α oxidative stress marker heme oxygenase 1, microglia marker Iba1, and astrocyte marker glial fibrillary acidic protein were significantly increased in TBEP-H-exposed mice with or without allergen. Microglia and mast cells activation were remarkable in TBEP-H-exposed allergic asthmatic mice. Our results indicate that chronic exposure to TBEP with or without allergen impaired object recognition ability accompanied with alteration of molecular expression of neuronal and glial markers and inflammatory markers in the hippocampus of mice. Neuron-glia-mast cells interaction may play a role in TBEP-induced neurobehavioral toxicity. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology 2.0)

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21 pages, 4700 KiB

Open AccessArticle

Nicotine Neurotoxicity Involves Low Wnt1 Signaling in Spinal Locomotor Networks of the Postnatal Rodent Spinal Cord

by Jaspreet Kaur, Graciela L. Mazzone, Jorge B. Aquino and Andrea Nistri

Int. J. Mol. Sci. 2021, 22(17), 9572; https://doi.org/10.3390/ijms22179572 - 03 Sep 2021

Cited by 6 | Viewed by 3430

Abstract

The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiological changes after injury. While low dose nicotine (1 µM) induces neuroprotection, how higher doses affect spinal networks is unknown. Using spinal preparations of postnatal wild-type Wistar rat and Wnt1Cre2:Rosa26Tom double-transgenic mouse, we studied the effect of nicotine (0.5–10 µM) on locomotor networks in-vitro. Nicotine 10 µM induced motoneuron depolarization, suppressed monosynaptic reflexes, and decreased fictive locomotion in rat spinal cord. Delayed fall in neuronal numbers (including motoneurons) of central and ventral regions emerged without loss of dorsal neurons. Conversely, nicotine (0.5–1 µM) preserved neurons throughout the spinal cord and strongly activated the Wnt1 signaling pathway. High-dose nicotine enhanced expression of S100 and GFAP in astrocytes indicating a stress response. Excitotoxicity induced by kainate was contrasted by nicotine (10 µM) in the dorsal area and persisted in central and ventral regions with no change in basal Wnt signaling. When combining nicotine with kainate, the activation of Wnt1 was reduced compared to kainate/sham. The present results suggest that high dose nicotine was neurotoxic to central and ventral spinal neurons as the neuroprotective role of Wnt signaling became attenuated. This also corroborates the risk of cigarette smoking for the foetus/newborn since tobacco contains nicotine. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology 2.0)

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18 pages, 3141 KiB

Open AccessArticle

Decreased Expression and Uncoupling of Endothelial Nitric Oxide Synthase in the Cerebral Cortex of Rats with Thioacetamide-Induced Acute Liver Failure

by Krzysztof Milewski, Anna Maria Czarnecka, Jan Albrecht and Magdalena Zielińska

Int. J. Mol. Sci. 2021, 22(13), 6662; https://doi.org/10.3390/ijms22136662 - 22 Jun 2021

Cited by 9 | Viewed by 2620

Abstract

Acute liver failure (ALF) is associated with deregulated nitric oxide (NO) signaling in the brain, which is one of the key molecular abnormalities leading to the neuropsychiatric disorder called hepatic encephalopathy (HE). This study focuses on the effect of ALF on the relatively unexplored endothelial NOS isoform (eNOS). The cerebral prefrontal cortices of rats with thioacetamide (TAA)-induced ALF showed decreased eNOS expression, which resulted in an overall reduction of NOS activity. ALF also decreased the content of the NOS cofactor, tetrahydro-L-biopterin (BH4), and evoked eNOS uncoupling (reduction of the eNOS dimer/monomer ratio). The addition of the NO precursor L-arginine in the absence of BH4 potentiated ROS accumulation, whereas nonspecific NOS inhibitor L-NAME or EDTA attenuated ROS increase. The ALF-induced decrease of eNOS content and its uncoupling concurred with, and was likely causally related to, both increased brain content of reactive oxidative species (ROS) and decreased cerebral cortical blood flow (CBF) in the same model. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology 2.0)

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24 pages, 4500 KiB

Open AccessArticle

Nrf2 Activation Attenuates Acrylamide-Induced Neuropathy in Mice

by Chand Basha Davuljigari, Frederick Adams Ekuban, Cai Zong, Alzahraa A. M. Fergany, Kota Morikawa and Gaku Ichihara

Int. J. Mol. Sci. 2021, 22(11), 5995; https://doi.org/10.3390/ijms22115995 - 01 Jun 2021

Cited by 19 | Viewed by 5033

Abstract

Acrylamide is a well characterized neurotoxicant known to cause neuropathy and encephalopathy in humans and experimental animals. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in acrylamide-induced neuropathy, male C57Bl/6JJcl adult mice were exposed to acrylamide at 0, 200 or 300 ppm in drinking water and co-administered with subcutaneous injections of sulforaphane, a known activator of the Nrf2 signaling pathway at 0 or 25 mg/kg body weight daily for 4 weeks. Assessments for neurotoxicity, hepatotoxicity, oxidative stress as well as messenger RNA-expression analysis for Nrf2-antioxidant and pro-inflammatory cytokine genes were conducted. Relative to mice exposed only to acrylamide, co-administration of sulforaphane protected against acrylamide-induced neurotoxic effects such as increase in landing foot spread or decrease in density of noradrenergic axons as well as hepatic necrosis and hemorrhage. Moreover, co-administration of sulforaphane enhanced acrylamide-induced mRNA upregulation of Nrf2 and its downstream antioxidant proteins and suppressed acrylamide-induced mRNA upregulation of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) in the cerebral cortex. The results demonstrate that activation of the Nrf2 signaling pathway by co-treatment of sulforaphane provides protection against acrylamide-induced neurotoxicity through suppression of oxidative stress and inflammation. Nrf2 remains an important target for the strategic prevention of acrylamide-induced neurotoxicity. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology 2.0)

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33 pages, 8400 KiB

Open AccessArticle

A Confocal Microscopic Study of Gene Transfer into the Mesencephalic Tegmentum of Juvenile Chum Salmon, Oncorhynchus keta, Using Mouse Adeno-Associated Viral Vectors

by Evgeniya V. Pushchina, Ilya A. Kapustyanov, Ekaterina V. Shamshurina and Anatoly A. Varaksin

Int. J. Mol. Sci. 2021, 22(11), 5661; https://doi.org/10.3390/ijms22115661 - 26 May 2021

Cited by 2 | Viewed by 2447

Abstract

To date, data on the presence of adenoviral receptors in fish are very limited. In the present work, we used mouse recombinant adeno-associated viral vectors (rAAV) with a calcium indicator of the latest generation GCaMP6m that are usually applied for the dorsal hippocampus of mice but were not previously used for gene delivery into fish brain. The aim of our work was to study the feasibility of transduction of rAAV in the mouse hippocampus into brain cells of juvenile chum salmon and subsequent determination of the phenotype of rAAV-labeled cells by confocal laser scanning microscopy (CLSM). Delivery of the gene in vivo was carried out by intracranial injection of a GCaMP6m-GFP-containing vector directly into the mesencephalic tegmentum region of juvenile (one-year-old) chum salmon, Oncorhynchus keta. AAV incorporation into brain cells of the juvenile chum salmon was assessed at 1 week after a single injection of the vector. AAV expression in various areas of the thalamus, pretectum, posterior-tuberal region, postcommissural region, medial and lateral regions of the tegmentum, and mesencephalic reticular formation of juvenile O. keta was evaluated using CLSM followed by immunohistochemical analysis of the localization of the neuron-specific calcium binding protein HuCD in combination with nuclear staining with DAPI. The results of the analysis showed partial colocalization of cells expressing GCaMP6m-GFP with red fluorescent HuCD protein. Thus, cells of the thalamus, posterior tuberal region, mesencephalic tegmentum, cells of the accessory visual system, mesencephalic reticular formation, hypothalamus, and postcommissural region of the mesencephalon of juvenile chum salmon expressing GCaMP6m-GFP were attributed to the neuron-specific line of chum salmon brain cells, which indicates the ability of hippocampal mammal rAAV to integrate into neurons of the central nervous system of fish with subsequent expression of viral proteins, which obviously indicates the neuronal expression of a mammalian adenoviral receptor homolog by juvenile chum salmon neurons. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology 2.0)

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Review

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22 pages, 2073 KiB

Open AccessReview

Early Development of the GABAergic System and the Associated Risks of Neonatal Anesthesia

by David A. Gascoigne, Natalya A. Serdyukova and Daniil P. Aksenov

Int. J. Mol. Sci. 2021, 22(23), 12951; https://doi.org/10.3390/ijms222312951 - 30 Nov 2021

Cited by 14 | Viewed by 2853

Abstract

Human and animal studies have elucidated the apparent neurodevelopmental effects resulting from neonatal anesthesia. Observations of learning and behavioral deficits in children, who were exposed to anesthesia early in development, have instigated a flurry of studies that have predominantly utilized animal models to further interrogate the mechanisms of neonatal anesthesia-induced neurotoxicity. Specifically, while neonatal anesthesia has demonstrated its propensity to affect multiple cell types in the brain, it has shown to have a particularly detrimental effect on the gamma aminobutyric acid (GABA)ergic system, which contributes to the observed learning and behavioral deficits. The damage to GABAergic neurons, resulting from neonatal anesthesia, seems to involve structure-specific changes in excitatory-inhibitory balance and neurovascular coupling, which manifest following a significant interval after neonatal anesthesia exposure. Thus, to better understand how neonatal anesthesia affects the GABAergic system, we first review the early development of the GABAergic system in various structures that have been the focus of neonatal anesthesia research. This is followed by an explanation that, due to the prolonged developmental curve of the GABAergic system, the entirety of the negative effects of neonatal anesthesia on learning and behavior in children are not immediately evident, but instead take a substantial amount of time (years) to fully develop. In order to address these concerns going forward, we subsequently offer a variety of in vivo methods which can be used to record these delayed effects. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology 2.0)

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22 pages, 1191 KiB

Open AccessReview

Influence of the Aryl Hydrocarbon Receptor Activating Environmental Pollutants on Autism Spectrum Disorder

by Hevna Dhulkifle, Abdelali Agouni, Asad Zeidan, Mohammed Saif Al-Kuwari, Aijaz Parray, Mohamed Tolefat and Hesham M. Korashy

Int. J. Mol. Sci. 2021, 22(17), 9258; https://doi.org/10.3390/ijms22179258 - 26 Aug 2021

Cited by 6 | Viewed by 3766

Abstract

Autism spectrum disorder (ASD) is an umbrella term that includes many different disorders that affect the development, communication, and behavior of an individual. Prevalence of ASD has risen exponentially in the past couple of decades. ASD has a complex etiology and traditionally recognized risk factors only account for a small percentage of incidence of the disorder. Recent studies have examined factors beyond the conventional risk factors (e.g., environmental pollution). There has been an increase in air pollution since the beginning of industrialization. Most environmental pollutants cause toxicities through activation of several cellular receptors, such as the aryl hydrocarbon receptor (AhR)/cytochrome P450 (CYPs) pathway. There is little research on the involvement of AhR in contributing to ASD. Although a few reviews have discussed and addressed the link between increased prevalence of ASD and exposure to environmental pollutants, the mechanism governing this effect, specifically the role of AhR in ASD development and the molecular mechanisms involved, have not been discussed or reviewed before. This article reviews the state of knowledge regarding the impact of the AhR/CYP pathway modulation upon exposure to environmental pollutants on ASD risk, incidence, and development. It also explores the molecular mechanisms involved, such as epigenesis and polymorphism. In addition, the review explores possible new AhR-mediated mechanisms of several drugs used for treatment of ASD, such as sulforaphane, resveratrol, haloperidol, and metformin. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology 2.0)

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