Neurotoxic Outcomes Research Articles

Combined Restraint Stress and Metal Exposure Paradigms in Rats: Unravelling Behavioural and Neurochemical Perturbations.

Accumulation of heavy metals (Mn and Ni) and prolonged exposure to stress are associated with adverse health outcomes. Various studies have shown the impacts of stress and metal exposures on brain function. However, no study has examined the effects of co-exposure to stress, Mn, and Ni on the brain. This study addresses this gap by evaluating oxidative and glial responses, apoptotic activity, as well as cognitive processes in a rat model. Adult Wistar rats were exposed to vehicle (control), restraint stress, 25mg/kg of manganese (Mn) or nickel (Ni), or combined restraint stress plus Mn or Ni. Following treatment, rats were subjected to several behavioural paradigms to assess cognitive function. Enzyme activity, as well as ATPase levels, were evaluated. Thereafter, an immunohistochemical procedure was utilised to evaluate neurochemical markers of glial function, myelination, oxidative stress, and apoptosis in the hippocampus, prefrontal cortex (PFC), and striatum. Results showed that stress and metal exposure increased oxidative stress markers and reduced antioxidant levels. Further, combined stress and metal exposure reduced various forms of learning and memory ability in rats. In addition, there were alterations in Iba1 activity and Nrf2 levels, reduced Olig2 and myelin basic protein (MBP) levels, and increased caspase-3 expression. These neurotoxic outcomes were mostly exacerbated by co-exposure to stress and metals. Overall, our findings establish that stress and metal exposures impaired cognitive performance, induced oxidative stress and apoptosis, and led to demyelination effects which were worsened by combined stress and metal exposure.

Vanillic acid ameliorates diethyl phthalate and bisphenol S-induced oxidative stress and neuroinflammation in the hippocampus of experimental rats.

Long-term adverse effects on human health are caused by exogenous compounds that alter the functions of biological systems, especially neuroendocrine disruptors like diethyl phthalate (DEP) and bisphenol S (BPS). Although vanillic acid (VA) has pertinent neuropharmacological characteristics, its effect against DEP + BPS-induced neurotoxicity has not been explored. This study proposed that VA may offer protection against the neurotoxicity caused by DEP + BPS. Thirty male Wistar rats were randomly distributed across five groups: a control group receiving DMSO, a group exposed to a mixture of BPS and DEP, two BPS + DEP-exposed groups treated with VA at doses of 25 mg/kg or 50 mg/kg, and a nonexposed group treated with 50 mg VA/kg. After 21 days, the hippocampal tissues were processed for biochemical analyses. Our results indicate that exposure to DEP + BPS upregulated neurosignaling mediators (NTPDase, ADA, MAO-A, and Ca2+), inhibited others (AChE and Ca2+/Mg2+-ATPase), decreased hippocampus antioxidants (GSH, GPx, CAT, and SOD), and elevated markers of oxidative stress/damage (NO, H2O2, MDA, and AOPP). AR, BAX, TNF-α, BAK1, and IL-1β expressions were upregulated, while IL-10 and BDNF expressions were downregulated. NF-κB and caspase-3/9 pathways were also upregulated. Co-treatment with vanillic acid remarkably precluded these neurotoxic outcomes by improving neurosignaling, augmenting antioxidant status, abrogating oxidative damage, inflammation (TNF-α, IL-1β), and apoptosis (BAX, BAK1, caspase-3/9). Vanillic acid also restored IL-10 and BDNF levels, thereby exhibiting neuroprotective effects, corroborated by histological examinations. We posit vanillic acid as a safe and effective therapeutic agent against neurotoxicity occasioned by exposure to neuroendocrine disruptors.

Astrocyte Mitochondria Are a Sensitive Target of PCB52 and its Human-Relevant Metabolites.

Polychlorinated biphenyls (PCBs) are industrial chemicals that are ubiquitously found in the environment. Exposure to these compounds has been associated with neurotoxic outcomes; however, the underlying mechanisms for such outcomes remain to be fully understood. Recent studies have shown that astrocytes, the most abundant glial cell type in the brain, are susceptible to PCB exposure as well as exposure to human-relevant metabolites of PCBs. Astrocytes are critical for maintaining healthy brain function due to their unique functional attributes and positioning within the neuronal networks in the brain. In this study, we assessed the toxicity of PCB52, one of the most abundantly found PCB congeners in outdoor and indoor air, and two of its human-relevant metabolites, on astrocyte mitochondria. We exposed C6 cells, an astrocyte cell line, to PCB52 or its human-relevant metabolites and found that all the compounds showed increased toxicity in galactose-containing media compared to that in the glucose-containing media, indicating the involvement of mitochondria in observed toxicity. Additionally, we also found increased oxidative stress upon exposure to PCB52 metabolites. All three compounds caused a loss of mitochondrial membrane potential, distinct changes in the mitochondrial structure, and impaired mitochondrial function. The hydroxylated metabolite 4-OH-PCB52 likely functions as an uncoupler of mitochondria. This is the first study to report the adverse effects of exposure to PCB52 and its human-relevant metabolites on the mitochondrial structure and function in astrocytes.

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals.

Identification of key neuronal mechanisms triggered by dimethyl fumarate in SH-SY5Y human neuroblastoma cells through a metabolomic approach

Dimethyl fumarate (DMF) is an old drug used for psoriasis treatment that has recently been repurposed to treat relapse–remitting multiple sclerosis, mostly due to its neuro- and immunomodulatory actions. However, mining of a pharmacovigilance database recently ranked DMF as the second pharmaceutical most associated with cognitive adverse events. To our best knowledge, the signaling mechanisms underlying its therapeutic and neurotoxic outcomes remain mostly undisclosed. This work thus represents the first-hand assessment of DMF-induced metabolic changes in undifferentiated SH-SY5Y human neuroblastoma cells, through an untargeted metabolomic approach using gas chromatography–mass spectrometry (GC–MS). The endometabolome was analyzed following 24 h and 96 h of exposure to two pharmacologically relevant DMF concentrations (0.1 and 10 μM). None of these conditions significantly reduced metabolic activity (MTT reduction assay). Our data showed that 24 h-exposure to DMF at both concentrations tested mainly affected metabolic pathways involved in mitochondrial activity (e.g., citric acid cycle, de novo triacylglycerol biosynthesis), and the synthesis of catecholamines and serotonin by changing the levels of their respective precursors, namely phenylalanine (0.68-fold decrease for 10 μM DMF vs vehicle), and tryptophan (1.36-fold increase for 0.1 μM DMF vs vehicle). Interestingly, taurine, whose levels can be modulated via Nrf2 signaling (DMF’s primary target), emerged as a key mediator of DMF’s neuronal action, displaying a 3.86-fold increase and 0.27-fold decrease for 10 μM DMF at 24 h and 96 h, respectively. A 96 h-exposure to DMF seemed to mainly trigger pathways associated with glucose production (e.g., gluconeogenesis, glucose-alanine cycle, malate-aspartate shuttle), possibly related to the metabolism of DMF into monomethyl fumarate and its further conversion into glucose via activation of the citric acid cycle. Overall, our data contribute to improving the understanding of the events associated with neuronal exposure to DMF.

Use of a polymeric implant system to assess the neurotoxicity of subacute exposure to 2,2′,5,5′-tetrachlorobiphenyl-4-ol, a human metabolite of PCB 52, in male adolescent rats

Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that ubiquitously exist in the environment. PCB exposure has been linked to cancer and multi-system toxicity, including endocrine disruption, immune inhibition, and reproductive and neurotoxicity. 2,2′,5,5′-Tetrachlorobiphenyl (PCB 52) is one of the most frequently detected congeners in the environment and human blood. The hydroxylated metabolites of PCB 52 may also be neurotoxic, especially for children whose brains are still developing. However, it is challenging to discern the contribution of these metabolites to PCB neurotoxicity because the metabolism of PCB is species-dependent. In this study, we evaluated the subacute neurotoxicity of a human-relevant metabolite, 2,2′,5,5′-tetrachlorobiphenyl-4-ol (4−52), on male adolescent Sprague Dawley rats, via a novel polymeric implant drug delivery system grafted subcutaneously, at total loading concentrations ranging from 0%, 1%, 5%, and 10% of the implant (w/w) for 28 days. Y-maze, hole board test, open field test, and elevated plus maze were performed on exposure days 24–28 to assess their locomotor activity, and exploratory and anxiety-like behavior. 4–52 and other possible hydroxylated metabolites in serum and vital tissues were quantified using gas chromatography with tandem mass spectrometry (GC-MS/MS). Our results demonstrate the sustained release of 4–52 from the polymeric implants into the systemic circulation in serum and tissues. Dihydroxylated and dechlorinated metabolites were detected in serum and tissues, depending on the dose and tissue type. No statistically significant changes were observed in the neurobehavioral tasks across all exposure groups. The results demonstrate that subcutaneous polymeric implants provide a straightforward method to expose rats to phenolic PCB metabolites to study neurotoxic outcomes, e.g., in memory, anxiety, and exploratory behaviors.

Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice.

Polychlorinated biphenyls (PCBs) are environmental contaminants that can cause neurotoxicity. PCBs, such as PCB 95 (2,2',3,5',6-pentachlorobiphenyl), can be metabolized by cytochrome P450 enzymes into neurotoxic metabolites. To better understand how the metabolism of PCB 95 affects neurotoxic outcomes, we conducted a study on the disposition of PCB 95 in transgenic mouse models. The mice were given a single oral dose of PCB 95 (1.0 mg/kg) and were euthanized 24 h later for analysis. PCB 95 levels were highest in adipose tissue, followed by the liver, brain, and blood. Adipose tissue levels were significantly higher in wild-type (WT) mice than in Cyp2abfgs-null (KO) or CYP2A6-transgenic (KI) mice. We also observed genotype-dependent differences in the enrichment of aS-PCB 95 in female mice, with a less pronounced enrichment in KO than WT and KI mice. Ten hydroxylated PCB 95 metabolites were detected in blood and tissue across all exposure groups. The metabolite profiles differed across tissues, while sex and genotype-dependent differences were less pronounced. Total OH-PCB levels were highest in the blood, followed by the liver, adipose tissue, and brain. Total OH-PCB blood levels were lower in KO than in WT mice, while the opposite trend was observed in the liver. In male mice, total OH-PCB metabolite levels were significantly lower in KI than in WT mice in blood and the liver, while the opposite trend was observed in female mice. In conclusion, the study highlights the differences in the atropselective disposition of PCB 95 and its metabolites in different types of mice, demonstrating the usefulness of these transgenic mouse models for characterizing the role of PCB metabolism in PCB neurotoxicity.

Results from the IRIS systematic review of methylmercury: Developmental neurotoxicity (DNT) outcomes evaluated in the literature

Results from the IRIS systematic review of methylmercury: Developmental neurotoxicity (DNT) outcomes evaluated in the literature

Evidence on Neurotoxicity after Intrauterine and Childhood Exposure to Organomercurials.

Although the molecular mechanisms underlying methylmercury toxicity are not entirely understood, the observed neurotoxicity in early-life is attributed to the covalent binding of methylmercury to sulfhydryl (thiol) groups of proteins and other molecules being able to affect protein post-translational modifications from numerous molecular pathways, such as glutamate signaling, heat-shock chaperones and the antioxidant glutaredoxin/glutathione system. However, for other organomercurials such as ethylmercury or thimerosal, there is not much information available. Therefore, this review critically discusses current knowledge about organomercurials neurotoxicity-both methylmercury and ethylmercury-following intrauterine and childhood exposure, as well as the prospects and future needs for research in this area. Contrasting with the amount of epidemiological evidence available for methylmercury, there are only a few in vivo studies reporting neurotoxic outcomes and mechanisms of toxicity for ethylmercury or thimerosal. There is also a lack of studies on mechanistic approaches to better investigate the pathways involved in the potential neurotoxicity caused by both organomercurials. More impactful follow-up studies, especially following intrauterine and childhood exposure to ethylmercury, are necessary. Childhood vaccination is critically important for controlling infectious diseases; however, the safety of mercury-containing thimerosal and, notably, its effectiveness as preservative in vaccines are still under debate regarding its potential dose-response effects to the central nervous system.

Neurotoxicity Outcomes Following Whole Brain Radiation Therapy in Patients with Primary CNS Lymphoma

<h3>Purpose/Objective(s)</h3> The role of radiation therapy (RT) in the management of primary CNS lymphoma (PCNSL) remains controversial. RT is associated with high response rates and may contribute to improved overall survival (OS). RT may also provide CNS disease control that facilitates successful salvage with stem cell transplantation in patients with chemotherapy-refractory disease. However, the long-term effects and neurologic sequelae from whole brain radiation therapy (WBRT) in younger patients with PCNSL has not been demonstrated. This retrospective study aimed to examine the long-term neurotoxicity outcomes of patients with PCNSL who received WBRT. Oncologic outcomes were also analyzed. <h3>Materials/Methods</h3> We retrospectively reviewed medical records from patients with PCNSL who underwent WBRT from 2011-2022. Patient and tumor-related variables included demographics, immunosuppression, imaging, and toxicities during and after treatment. Cognitive disturbance was evaluated and graded according to the <i>Common Terminology Criteria for Adverse Events (CTCAE)</i> v 2.0 and 3.0. Statistical analysis was conducted using <i>JMP Pro 15.2</i>. <h3>Results</h3> A total of 98 patients were identified with PCNSL from 2011-2022. We excluded patients with orbital primary, which resulted in a cohort of 61 patients. Eleven patients underwent WBRT; 5 between the age of 18-60 years and 6 greater than 60 years. The average age was 53.3 years [Range: 35-87 years]. Among the 5 patients in the younger patient cohort, 3 had a history of HIV; all were non-reactive at evaluation prior to RT. All 6 patients in the older patient cohort were HIV negative. All patients had undergone WBRT as a salvage or consolidation regimen, with dose regimens varying from 27-45 Gy and dose per fraction varying from 1.8-3 Gy. Two of the 11 patients received a boost. Ten out of the 11 patients underwent RT as a salvage regimen, and 1 patient underwent consolidative WBRT. The median progression-free survival (PFS) and OS among patients who had undergone WBRT was 9.5 months and 8 years, respectively. For all ages, cognitive disturbance was grade 0, 1, 2, and 3 in 18.2%, 45.5%, 18.2%, and 9.1%, respectively, at 6 months. At 24 months, cognitive disturbance was detected as grade 0 in 27.3% patients and grade 1 in 27.3%. Among the younger cohort, at 6 months, cognitive disturbance grade 0, 1, 2, and 3 was noted in 0%, 60%, 20%, and 20% respectively. At 24 months, cognitive disturbance was grade 1 in 60%. In the elder cohort, at 6 months, cognitive disturbance was grade 0, 1, and 2 in 33%, 33%, and 17%, respectively. At 24 months, 50% of patients had grade 0 cognitive disturbance. <h3>Conclusion</h3> WBRT demonstrated acceptable levels of cognitive disturbance in patients with PCNSL while maintaining oncologic outcomes. PFS data may be limited by implementation of WBRT, as all patients underwent WBRT as a salvage or consolidative treatment. Even so, WBRT should be considered as an upfront management strategy for younger patients with PCNSL.

Differences in neurotoxic outcomes of organophosphorus pesticides revealed via multi-dimensional screening in adult and regenerating planarians.

Organophosphorus pesticides (OPs) are a chemically diverse class of commonly used insecticides. Epidemiological studies suggest that low dose chronic prenatal and infant exposures can lead to life-long neurological damage and behavioral disorders. While inhibition of acetylcholinesterase (AChE) is the shared mechanism of acute OP neurotoxicity, OP-induced developmental neurotoxicity (DNT) can occur independently and/or in the absence of significant AChE inhibition, implying that OPs affect alternative targets. Moreover, different OPs can cause different adverse outcomes, suggesting that different OPs act through different mechanisms. These findings emphasize the importance of comparative studies of OP toxicity. Freshwater planarians are an invertebrate system that uniquely allows for automated, rapid and inexpensive testing of adult and developing organisms in parallel to differentiate neurotoxicity from DNT. Effects found only in regenerating planarians would be indicative of DNT, whereas shared effects may represent neurotoxicity. We leverage this unique feature of planarians to investigate potential differential effects of OPs on the adult and developing brain by performing a comparative screen to test 7 OPs (acephate, chlorpyrifos, dichlorvos, diazinon, malathion, parathion and profenofos) across 10 concentrations in quarter-log steps. Neurotoxicity was evaluated using a wide range of quantitative morphological and behavioral readouts. AChE activity was measured using an Ellman assay. The toxicological profiles of the 7 OPs differed across the OPs and between adult and regenerating planarians. Toxicological profiles were not correlated with levels of AChE inhibition. Twenty-two “mechanistic control compounds” known to target pathways suggested in the literature to be affected by OPs (cholinergic neurotransmission, serotonin neurotransmission, endocannabinoid system, cytoskeleton, adenyl cyclase and oxidative stress) and 2 negative controls were also screened. When compared with the mechanistic control compounds, the phenotypic profiles of the different OPs separated into distinct clusters. The phenotypic profiles of adult vs. regenerating planarians exposed to the OPs clustered differently, suggesting some developmental-specific mechanisms. These results further support findings in other systems that OPs cause different adverse outcomes in the (developing) brain and build the foundation for future comparative studies focused on delineating the mechanisms of OP neurotoxicity in planarians.

Morin attenuates neurobehavioural deficits, hippocampal oxidative stress, inflammation, and apoptosis in rats co-exposed to bisphenol S and diethyl phthalate

Endocrine-disrupting pollutants (EDPs) remain pervasive in the environment. Bisphenol S (BPS) and diethyl phthalates (DEP) are commonly used to replace the more toxic EDPs. However, it is unclear if they induce neurotoxicity, like their predecessors. Morin possesses relevant neuro-pharmacological activities. Hence, we sought to evaluate the protective effects of morin against the neurotoxic effects previously reported for EDPs. Male Wistar rats were exposed to a mixture of BPS and DEP (MBD) and treated with morin for 21 days. Behavioural assessments were conducted, and the hippocampal tissues were processed for analysis. Rats exposed to MBD presented anxiety-like behaviours, impaired cognitive and motor functions compared to the control group. MBD exposure induced hyperactivity of neurosignalling enzymes (AChE, ADA, MAO-A) and depleted hippocampal antioxidants (SOD, CAT, GPx, and GSH). MBD exposure increased calcium levels and inhibited total Ca2+-ATPase activity. Levels of reactive species (NO and H2O2) and oxidative damage markers (MDA and AOPP) were significantly (P < 0.05) elevated compared to control. The hippocampal expressions of IL-1β, TNFα, BAX, and APAF-1 in the MBD-exposed rats were significantly higher compared to control. Correspondingly, NF-κB and caspase-3 pathways were activated in the hippocampus of MBD-exposed rats, while the expressions of IL-10 and BDNF were repressed. However, co-treatment with morin improved the neurobehavioral outcomes, alleviated the hyperactivity of neurosignalling enzymes, while suppressing hippocampal oxidative stress, inflammation, and apoptosis. Histological and stereological evaluations supported these findings. In conclusion, co-exposure to BPS and DEP elicit similar neurotoxic outcomes as their predecessors, while morin confers marked protection against these outcomes.

Ag2Se quantum dots damage the nervous system of nematode Caenorhabditis elegans.

Silver selenide quantum dots (Ag2Se QDs), as a novel type of QDs, are valuable in the biomedical application due to their low-toxic and excellent optical property in near infrared region, but the biosafety assessment of Ag2Se QDs is rare. In this study, the findings suggested that the accumulation of Ag2Se QDs in the body of nematodes decreased the lifespan and damaged normal neurobehaviors of Caenorhabditis elegan (C. elegans). Furthermore, Ag2Se QDs caused excessive reactive oxygen species (ROS) productions and altered expressions of several genes associated with redox equilibrium, which might contribute to neurotoxic outcomes in nematode C. elegans. According to this study, it is necessary and important for researchers to pay attention to the biosafety assessment of presumed low-toxic nanomaterials, like Ag2Se QDs, especially on sensitively toxic targets, i.e. the nervous system.

Gelatin-derived carbon quantum dots mitigate herbicide-induced neurotoxic effects in vitro and in vivo.

The herbicide and viologen, N, N'-dimethyl-4,4'-bipyridinium dichloride (Paraquat) is known to be toxic to neuronal cells by a multifactorial process involving an elevation in the levels of reactive oxygen species (ROS), the triggering of amyloid-protein aggregation and their accumulation, collectively leading to neuronal dyshomeostasis. We demonstrate that green-chemistry-synthesized sustainable gelatin-derived carbon quantum dots (CQDs) mitigate paraquat-induced neurotoxic outcomes and resultant compromise in organismal mortality. Gelatin-derived CQDs were found to possess antioxidant properties and ameliorated ROS elevation in paraquat-insulted neuroblastoma-derived SHSY-5Y cells, protecting them from herbicide-induced cell death. These CQDs also increased lifespan in paraquat-compromised Caenorhabditis elegans and herbicide-mediated dopamine neuron ablation. Collectively, the data underscore the ability of this sustainably synthesized, environmentally friendly biocompatible nanomaterial to protect cell lines and organisms against neurotoxic outcomes. The study findings strategically position this relatively novel nanoscopic carbon quantum framework for further testing in vertebrate trials of neurotoxic insult.

Adolescence as a sensitive period for neurotoxicity: Lifespan developmental effects of methylmercury

Neurotoxicity resulting from the environmental contaminant, methylmercury (MeHg), is a source of concern for many human populations that rely heavily on the consumption of fish and rice as stable ingredients in the diet. The developmental period of exposure is important both to the qualitative effects of MeHg and to the dose required to produce those effects. MeHg exposure during the sensitive prenatal period causes deleterious and long-lasting changes in neurodevelopment at particularly low doses. The effects include a wide host of cognitive and behavioral outcomes expressed in adulthood and sometimes not until aging. However, neurotoxic outcomes of MeHg when exposure occurs during adolescence are only recently revealing impacts on human populations and animal models. This review examines the current body of work and showcases the sensitivity of adolescence, a period that straddles early development and adulthood, to MeHg neurotoxicity and the implications such toxicity has in our understanding of MeHg's effects in human populations and animal models.

Dose makes poison: Insights into the neurotoxicity of perinatal and juvenile exposure to environmental doses of 16 priority-controlled PAHs

Whether chronic exposure to environmental doses of polycyclic aromatic hydrocarbons (PAHs) can lead to neurotoxic effects is still unclear. Hence, the neurotoxic effects of perinatal and juvenile exposure to 16 priority-controlled PAHs were investigated. The mice were treated with 0, 0.5, 18.75, 50, 1875 μg/kg/day of PAHs corresponding to various population exposure concentrations from gestation to postnatal day 60. Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and hippocampal and cortical neurotransmitter levels were determined using liquid chromatography-tandem mass spectrometry. Typical indicators or outcome of neurotoxicity, including, spatial learning and memory ability, hippocampal long-term potentiation (LTP) and dendritic spine density were evaluated via Morris water maze tests, electrophysiological experiments and Golgi-Cox assays, respectively. The results showed that exposure to different levels of PAH could not increase oxidative DNA damage level. Mice exposed to 0.5, 50 and 1875 μg/kg/day PAHs had significantly longer escape latency than the control group only on the 1st day (p < 0.05). The number of platform crossings and the time spent in target quadrant were similar between the control and the PAHs-exposed mice. Compared with the control mice, only those exposed to 50 μg/kg/day PAHs had significantly lower LTP in hippocampal CA1 region and dendritic spine density in hippocampal DG region (p < 0.05). Except for serotonin, no significant difference in hippocampal and cortical neurotransmitter concentrations was observed between the control and PAHs-exposed groups. Taken together, perinatal and juvenile exposure to environmental doses of PAHs had no profound effect on spatial learning and memory abilities, hippocampal LTP, dendritic spines density, and neurotransmitter levels. These unexpected findings were quite different from previous in vivo studies which commonly used 2–3 orders of magnitude higher PAHs doses to treat animals. Thus, the environmental dose is a crucial reference for future toxicological research to reveal the actual toxic mechanisms and human health effects of PAHs exposure.

Quercetin Mitigates Methamphetamine-Induced Anxiety-Like Behavior Through Ameliorating Mitochondrial Dysfunction and Neuroinflammation.

Methamphetamine (MA) abuse results in neurotoxic outcomes, including increased anxiety and depression. Studies have reported an association between MA exposure and anxiety, nonetheless, the underlying mechanism remains elusive. In the present study, we developed a mouse model of anxiety-like behavior induced by MA administration. RNA-seq was then performed to profile the gene expression patterns of hippocampus (HIPP), and the differentially expressed genes (DEGs) were significantly enriched in signaling pathways related to psychiatric disorders and mitochondrial function. Based on these, mitochondria was hypothesized to be involved in MA-induced anxiety. Quercetin, as a mitochondrial protector, was used to investigate whether to be a potential treatment for MA-induced anxiety; accordingly, it alleviated anxiety-like behavior and improved mitochondrial impairment in vivo. Further experiments in vitro suggested that quercetin alleviated the dysfunction and morphological abnormalities of mitochondria induced by MA, via decreasing the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and increasing the oxygen consumption rate (OCR) and ATP production. Moreover, the study examined the effect of quercetin on astrocytes activation and neuroinflammation, and the results indicated that it significantly attenuated the activation of astrocytes and reduced the levels of IL-1β, TNFα but not IL-6. In light of these findings, quantitative evidence is presented in the study supporting the view that MA can evoke anxiety-like behavior via the induction of mitochondrial dysfunction. Quercetin exerted antipsychotic activity through modulation of mitochondrial function and neuroinflammation, suggesting its potential for further therapeutic development in MA-induced anxiety.

In vivo neurophysiological assessment of in silico predictions of neurotoxicity: Citronellal, 3,4-dichloro-1-butene, and benzyl bromoacetate

Neurotoxicants may be widespread in the environment and can produce serious health impacts in the human population. Screening programs that use in vitro methods have generated data for thousands of chemicals. However, these methods often do not evaluate repeated or prolonged exposures, which are required for many neurotoxic outcomes. Additionally, the data produced by such screening methods may not include mechanisms which play critical biological roles necessary for in vivo neurotoxicity. The Hard and Soft Acids and Bases (HSAB) in silico model focuses on chemical structure and electrophilic properties which are important to the formation of protein adducts. A group of structurally diverse chemicals have been evaluated with an in silico screening approach incorporating HSAB parameters. However, the predictions from the expanded chemical space have not been evaluated using in vivo methods. Three chemicals predicted to be cumulative toxicants were selected for in vivo neurotoxicological testing. Adult male Long-Evans rats were treated orally with citronellal (CIT), 3,4-dichloro-1-butene (DCB), or benzyl bromoacetate (BBA) for 8 weeks. Behavioral observations were recorded weekly to assess motor function. Peripheral neurophysiological measurements were derived from nerve excitability (NE) tests which involved compound muscle action potentials (CMAPs) in the tail and foot, and mixed nerve action potentials (MNAPs) in the tail. Compound nerve action potentials (CNAPs) and nerve conduction velocity (NCV) in the tail were also quantified. Peripheral inputs into the central nervous system were examined using somatosensory evoked potentials recorded from the cortex (SEPCTX) and cerebellum (SEPCEREB). CIT or BBA did not result in significant alterations to peripheral nerve or somatosensory function. DCB reduced grip-strength and altered peripheral nerve function. The MNAPs required less current to reach 50% amplitude and had a lower calculated rheobase, suggesting increased excitability. Increased CNAP amplitudes and greater NCV were also observed. Novel changes were found in the SEPCTX with an abnormal peak forming in the early portion of the waveforms of treated rats, and decreased latencies and increased amplitudes were observed in SEPCEREB recordings. These data contribute to testing an expanded chemical space from an in silico HSAB model for predicting cumulative neurotoxicity and may assist with prioritizing chemicals to protect human health.

Long-Term Outcome After Tacrolimus-Related Neurotoxicity in Pediatric Living Donor Liver Transplantation

Tacrolimus-related neurotoxicity is a serious complication. Posterior reversible encephalopathy syndrome, which is severe neurotoxicity after pediatric living donor liver transplantation (LDLT), is a medication-induced complication related to calcineurin inhibitors. The purpose of this study was to evaluate the long-term outcome of tacrolimus-related neurotoxicity after pediatric LDLT. Pediatric patients who underwent LDLT between 2007 and 2020 at our institution and developed neurologic symptoms with tacrolimus were included in the study. Tacrolimus-related encephalopathy was defined as encephalopathy that resolved after tacrolimus was discontinued. All patients received tacrolimus and a steroid for immunosuppression starting just after LDLT. During the study period, 128 patients underwent LDLT. All patients received tacrolimus and a steroid. Six patients (5%) developed tacrolimus-related encephalopathy. The median age at transplant was 1.6 years. The original diseases were biliary atresia (n=5) and progressive familial intrahepatic cholangiopathy type 2 (n=1). Patients developed encephalopathy at a median of 9 days after LDLT. All patients recovered with conversion to cyclosporine. Posterior reversible encephalopathy syndrome was confirmed by magnetic resonance imaging in 3 patients. The mean tacrolimus level at encephalopathy was 11 ng/dL (range, 5.6-14.6 ng/dL). White blood cell count elevation was observed in all patients. One patient died of pancreatitis. Surviving patients (n=5) were followed for a median of 9 years. All patients resumed tacrolimus a median of 8 months from onset. No neurologic complications were observed after resuming tacrolimus. We observed tacrolimus-induced encephalopathy in 5% of patients after pediatric LDLT. Patients can resume tacrolimus safely without further neurologic symptoms.

Leveraging artificial intelligence to advance the understanding of chemical neurotoxicity

Neurotoxicology is a specialty that aims to understand and explain the impact of chemicals, xenobiotics and physical conditions on nervous system function throughout the life span. Herein, we point to the need for integration of novel translational bioinformatics and chemo-informatics approaches, such as machine learning (ML) and artificial intelligence (AI) to the discipline. Specifically, we advance the notion that AI and ML will be helpful in identifying neurotoxic signatures, provide reliable data in predicting neurotoxicity in the context of genetic variability, and improve the understanding of neurotoxic outcomes associated with exposures to mixtures, to name a few.