Lidocaine-Associated CNS Toxicity at Therapeutic Dosage: A Case Report and Literature Review.

Lidocaine is a commonly used anesthetic. High doses or intravenous administration of lidocaine, as well as other local anesthetics, may result in systemic effects involving the cardiovascular and neurologic systems. Typically, effects are dependent on the serum concentrations of the offending agent. This is a case where a patient presented with symptoms of systemic lidocaine toxicity despite therapeutic dosage and an undetectable serum lidocaine concentration. A 47-year-old Caucasian male received a lumbar medial branch injection of lidocaine and presented with symptoms of perioral numbness, seizure-like activity, and confusion. The patient had a workup, including a CT head without acute findings and an undetectable serum lidocaine level. Due to symptoms consistent with systemic local anesthetic toxicity, intravenous lipid emulsion (ILE) was administered with resolution and without recurrence of symptoms. There should be a low threshold of suspicion for local anesthetic systemic toxicity when patients have neurologic or cardiovascular symptoms following exposure. Toxicity may be present despite therapeutic dosages and low serum concentrations. ILE may be beneficial and should be considered.

Neurodegenerative Diseases: Unraveling the Heterogeneity of Astrocytes.

The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality of the central nervous system (CNS). Astrocytes are vital in orchestrating neuronal development by releasing synaptogenic molecules and eliminating excessive synapses. They also modulate neuronal excitability and contribute to CNS homeostasis, promoting neuronal survival by clearance of neurotransmitters, transporting metabolites, and secreting trophic factors. Astrocytes are highly heterogeneous and respond to CNS injuries and diseases through a process known as reactive astrogliosis, which can contribute to both inflammation and its resolution. Recent evidence has revealed remarkable alterations in astrocyte transcriptomes in response to several diseases, identifying at least two distinct phenotypes called A1 or neurotoxic and A2 or neuroprotective astrocytes. However, due to the vast heterogeneity of these cells, it is limited to classify them into only two phenotypes. This review explores the various physiological and pathophysiological roles, potential markers, and pathways that might be activated in different astrocytic phenotypes. Furthermore, we discuss the astrocyte heterogeneity in the main neurodegenerative diseases and identify potential therapeutic strategies. Understanding the underlying mechanisms in the differentiation and imbalance of the astrocytic population will allow the identification of specific biomarkers and timely therapeutic approaches in various neurodegenerative diseases.

Neurotoxicity of tetrabromobisphenol-A-bis(2,3-dibromopropyl ether) through the GABAergic and serotonergic neurotransmission in Caenorhabditis elegans.

Tetrabromobisphenol-A-bis(2,3-dibromopropyl ether) (TBBPA-BDBPE), a novel additive brominated flame retardant, is being developed for use in polyolefin and copolymers. Despite its emerging application, the neurotoxicity and mechanisms of action of TBBPA-BDBPE remain unexplored. Caenorhabditis elegans was utilized as the model organism to study the neurotoxic effects of TBBPA-BDBPE across environmental concentrations ranging from 0 to 100 µg/L. This investigation focused on various toxicological endpoints such as locomotive behavior, neuronal injury, neurotransmitter transmission, and the regulation of nervous system-related gene expression. Acute exposure to TBBPA-BDBPE at concentrations of 10-100 µg/L significantly impaired nematode movement, indicating potential neurotoxicity. In transgenic nematodes, this exposure also caused damage to γ-aminobutyric acid (GABAergic) and serotonergic neurons, along with notable changes in the levels of GABAergic and serotonergic neurotransmitters. Further molecular studies indicated alterations in neurotransmission-related genes (cat-4, mod-1, unc-25, and unc-47). Molecular docking analysis confirmed the binding affinity of TBBPA-BDBPE to key neurotransmission proteins-CAT-4, MOD-1, UNC-25, and UNC-47. These findings demonstrate that TBBPA-BDBPE exerts neurotoxic effects by impacting GABAergic and serotonergic neurotransmission in nematodes. This study provides new insights into the potential environmental risks of TBBPA-BDBPE.

Responses of zebra and quagga mussels to copper and tribytiltin exposure: Bioconcentration, metabolic and cardiac biomarkers.

One of the top ecological priorities is to find sensitive indicators for pollution monitoring. This study focuses on the bioconcentration and responses (condition index, survival, oxygen consumption, heart rates, and oxidative stress and neurotoxic effect biomarkers) of mussels from the Volga River basin, Dreissena polymorpha and Dreissena bugensis, to long-term exposure to toxic chemicals such as tributyltin (TBT, 25 and 100 ng/L) and copper (Cu, 100 and 1000 µg/L). We found that TBT was present in the tissues of zebra and quagga mussels in comparable amounts, whereas the bioconcentration factor of Cu varied depending on its concentration in water. Differences in responses between the two species were revealed. When exposed to high Cu concentrations or a Cu-TBT mixture, quagga mussels had a lower survival rate and a longer heart rate recovery time than zebra mussels. TBT treatment caused neurotoxicity (decreased acetylcholinesterase activity) and oxidative stress (increased levels of thiobarbituric acid reactive substances) in both species. TBT and Cu levels in mussel tissues correlated positively with the condition index, but correlated with the level of acetylcholinesterase in the mussel gills. The principal component analysis revealed three main components: the first consists of linear combinations of 14 variables reflecting TBT water pollution, TBT and Cu levels in mussel tissues, and biochemical indicators; the second includes Cu water concentration, cardiac tolerance, and mussel size; and the third combines weight, metabolic rate, and heart rates. Quagga mussels are less tolerable to contaminants than zebra mussels, so they may be used as a sensitive indicator.

Impact of food additives on neurodevelopmental processes in zebrafish (Danio rerio): Exploring circadian clock genes and dopamine system.

Assessing the impact of food additives on neurodevelopmental processes extends beyond traditional acute toxicity evaluations to address subtler, long-term effects. This study investigates the impact of common food additives (tartrazine, sunset yellow, sodium benzoate, and aspartame) on neurodevelopment in zebrafish embryos, observed from 18 hours postfertilization (hpf) to 91 days postfertilization (dpf). Results show reduced 96 hpf locomotor activity after aspartame exposure, with elevated additives correlating with decreased heart rates and induced neurodegenerative phenotypes, including bent tails and abnormal pigmentation. Although locomotor activity decreases at 7 days postexposure, a gradual recovery is observed. Transcriptome analysis indicates alterations in clock genes (Cry2 and Per2) and dopamine-related genes (NURR1 and tyrosine hydroxylase) in zebrafish larvae. Dietary additive exposure during embryonic development impacts clock genes, influencing dopamine activity and resulting in neurobehavioral changes. This study underscores potential risks associated with dietary additive exposure during critical developmental stages, warranting reconsideration of consumption guidelines, especially for expectant mothers. Observed neurodevelopmental toxicity, even below recommended levels, emphasizes the importance of safeguarding neurodevelopmental health in early life. Our findings contribute to understanding the neurotoxic effects of dietary additives, emphasizing the necessity of protecting neurodevelopment during vulnerable periods. This study is the first to demonstrate a direct correlation between food additives and the dysregulation of key circadian rhythm and dopaminergic genes in zebrafish, providing new insights into the neurodevelopmental impacts of dietary additives. These findings pave the way for further research into the molecular mechanisms and potential implications for human health.

Neurobehavioral toxicity induced by combined exposure of micro/nanoplastics and triphenyltin in marine medaka (Oryzias melastigma).

Microplastics/nanoplastics (MNPs) inevitably coexist with other pollutants in the natural environment, making it crucial to study the interactions between MNPs and other pollutants as well as their combined toxic effects. In this study, we investigated neurotoxicity in marine medaka (Oryzias melastigma) exposed to polystyrene micro/nanoplastics (PS-MNPs), triphenyltin (TPT), and PS-MNPs + TPT from physiological, behavioral, biochemical, and genetic perspectives. The results showed that marine medaka exposed to 200 ng/L TPT or 200 µg/L PS-NPs alone exhibited some degree of neurodevelopmental deficit, albeit with no significant behavioral abnormalities observed. However, in the PS-MP single exposure group, the average acceleration of short-term behavioral indices was significantly increased by 78.81%, indicating a highly stress-responsive locomotor pattern exhibited by marine medaka. After exposure to PS-MNPs + TPT, the swimming ability of marine medaka significantly decreased. In addition, PS-MNPs + TPT exposure disrupted normal neural excitability as well as activated detoxification processes in marine medaka larvae. Notably, changes in neural-related genes suggested that combined exposure to PS-MNPs and TPT significantly increased the neurotoxic effects observed with exposure to PS-MNPs or TPT alone. Furthermore, compared to the PS-MPs + TPT group, PS-NPs + TPT significantly inhibited swimming behavior and thus exacerbated the neurotoxicity. Interestingly, the neurotoxicity of PS-MPs was more pronounced than that of PS-NPs in the exposure group alone. However, the addition of TPT significantly enhanced the neurotoxicity of PS-NPs compared to PS-MPs + TPT. Overall, the study underscores the combined neurotoxic effects of MNPs and TPT, providing in-depth insights into the ecotoxicological implications of MNPs coexisting with pollutants and furnishing comprehensive data.

Bilateral Optic Neuropathy Associated with Acute Inhaled Marijuana Use: Case Report and Review of the Literature.

Marijuana is the most commonly used federally illegal drug in the United States. Acute marijuana use is associated with several cardiovascular and neuropsychological adverse effects. Ocular complications of marijuana abuse are very rare. Herein, we present the first report of bilateral optic neuropathy following smoking marijuana. A 28-year-old man presented to the emergency room with sudden onset of bilateral blurring of the inferior visual field 8 h after smoking marijuana. His best-corrected visual acuity was 20/30 in the right eye and 20/20 in the left eye. Fundus examination revealed blurring of the optic disc margins in both eyes and a splinter haemorrhage in the right eye. Bilateral inferior visual field defects were detected with greater severity on the right side. Optical coherence tomography confirmed the diagnosis of bilateral optic neuropathy. A urine drug screen test was positive for tetrahydrocannabinol, which is the primary active ingredient in cannabinoids. The rest of the neurological examination and imaging were normal. The patient was treated with intravenous corticosteroids and an anti-platelet drug. His vision recovered to 20/20 in both eyes, with complete resolution of the field defect over a follow-up of 6 months. Optic neuropathy following marijuana abuse is unusual. The results of our report emphasise the need for awareness of marijuana-associated optic neuropathy as part of ocular adverse effects of marijuana intoxication.

The changing of α5-GABAA receptors expression and distribution participate in sevoflurane-induced learning and memory impairment in young mice.

BACKGROUND: Sevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5-GABAAR. METHODS: Using MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%-3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL-6 24 h post-anesthesia. Western blot and RT-PCR were performed to measure the levels of α5-GABAAR, Radixin, P-ERM, P-Radixin, Gephyrin, IL-6, and ROCK. The spatial distribution and expression of α5-GABAAR on neuronal somata were analyzed using histological and three-dimensional imaging techniques. RESULTS: MWM test indicated that partial long-term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL-6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5-GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5-GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5-GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra-synaptic space, the expression level of α5-GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel. CONCLUSION: Dysregulated α5-GABAAR expression and distribution contributes to sevoflurane-induced partial long-term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies.

A pilot study of the contribution of energy-dense Caribbean diets to acrylamide exposure with associated health risks for a population of university students in Trinidad and Tobago.

Previous studies on university students have indicated a significant decline in the consumption of fruits and vegetables complemented by an increase in energy-dense foods. The food toxicant, acrylamide, typically occurs in carbohydrate-rich, energy-dense foods that have been heated. Hence, this work presents an estimated dietary acrylamide exposure for university students in Trinidad and Tobago. A 2-day dietary recall method was used to obtain the food consumption information from 683 university students of differing sociodemographic backgrounds. The acrylamide exposure was estimated using a deterministic approach. The median acrylamide intake was estimated to be 1.39 µg/kg bw/day. The estimated mean acrylamide dietary intakes for the female and male population were 1.40 and 1.37 µg/kg bw/day, respectively. Coffee was determined to be the major dietary contributor to acrylamide exposure. However, bread was the food item that was most frequently consumed among the students. Using multiple linear regression, a possible correlation was detected between the acrylamide exposure and these variables: dietary habits (mostly eat out; p < 0.05), and Indian ethnicity (p < 0.10). Using the margin of exposure approach, dietary acrylamide exposure was found to be a health concern with regards to neurotoxicity and carcinogenicity. An evaluation of the procedures and results from this pilot study was carried out for the potential of conducting a full-scale research project.

An exploratory study on the ability of manganese to supplement rotenone neurotoxicity in rats.

Parkinson's disease (PD) is a complex disorder, primarily of idiopathic origin, with environmental stressors like rotenone and manganese linked to its development. This study explores their potential interaction and resulting neurotoxicity, aiming to understand how environmental factors contribute to PD. In an eight-day experiment, male Wistar rats weighing 280-300 g were subjected to rotenone, manganese, or a combination of both. Various parameters were assessed, including body weight, behavior, serum markers, tissue damage, protein levels (tyrosine hydroxylase, Dopamine- and cAMP-regulated neuronal phosphoprotein -DARPP-32-, and α-synuclein), and mitochondrial function. Manganese heightened rotenone's impact on reducing food intake without causing kidney or liver dysfunction. However, the combined exposure intensified neurotoxicity, which was evident in augmented broken nuclei and decreased tyrosine hydroxylase and DARPP-32 levels in the striatum. While overall mitochondrial function was preserved, co-administration reduced complex IV activity in the midbrain and liver. In conclusion, our findings revealed a parallel toxic effect induced by rotenone and manganese. Notably, while these substances do not target the same dopaminergic regions, a notable escalation in toxicity is evident in the striatum, the brain region where their toxic effects converge. This study highlights the need for further exploration regarding the interaction of environmental factors and their possible impact on the etiology of PD.

Hesperidin neuroprotective effects against carbon monoxide-induced toxicity in male rats.

Carbon monoxide (CO) is produced via incomplete combustion of fossil fuels and it may cause long-term neurological sequel upon exposure. Hesperidin (HES), a flavanone glycoside found in citrus plants, exerts diverse beneficial health effects. The present study mechanistically examined the neuroprotective effects of HES in CO-poisoned rats. Thirty male Wistar rats (five groups of six animals) were exposed to 3000 ppm CO for 1 h. Immediately after the exposure and on the next 4 consecutive days (totally five doses), rats intraperitoneally received either normal saline (the control group) or different doses of HES (25, 50, and 100 mg/kg). A sham group that was not exposed to CO was also considered. After evaluation of spatial learning and memory using a Morris water maze (MWM), animals were sacrificed and oxidative stress status in blood samples, and Akt, Bax, Bcl2, and brain-derived neurotrophic factor (BDNF) expression in brain samples were assessed. Western blot analysis indicated increased Akt but decreased Bax/Bcl2 levels in the HES 100 mg/kg, and induced BDNF levels in all HES-treated groups. MWM results showed that HES significantly decreased memory loss. The current findings indicate that HES could alleviate neurological impairments induced by CO in rats.

Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell acute lymphoblastic leukemia.

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3-4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy.

Enriched Environment Inhibits Neurotoxic Reactive Astrocytes via JAK2-STAT3 to Promote Glutamatergic Synaptogenesis and Cognitive Improvement in Chronic Cerebral Hypoperfusion Rats.

Chronic cerebral hypoperfusion (CCH) is a primary contributor to cognitive decline in the elderly. Enriched environment (EE) is proved to improve cognitive function. However, mechanisms involved remain unclear. The purpose of the study was exploring the mechanisms of EE in alleviating cognitive deficit in rats with CCH. To create a rat model of CCH, 2-vessel occlusion (2-VO) surgery was performed. All rats lived in standard or enriched environments for 4 weeks. Cognitive function was assessed using the novel object recognition test and Morris water maze test. The protein levels of glutamatergic synapses, neurotoxic reactive astrocytes, reactive microglia, and JAK2-STAT3 signaling pathway were measured using Western blot. The mRNA levels of synaptic regulatory factors, C1q, TNF-α, and IL-1α were identified using quantitative PCR. Immunofluorescence was used to detect glutamatergic synapses, neurotoxic reactive astrocytes, and reactive microglia, as well as the expression of p-STAT3 in astrocytes in the hippocampus. The results demonstrated that the EE mitigated cognitive impairment in rats with CCH and enhanced glutamatergic synaptogenesis. EE also inhibited the activation of neurotoxic reactive astrocytes. Moreover, EE downregulated microglial activation, levels of C1q, TNF-α and IL-1α and phosphorylation of JAK2 and STAT3. Our results suggest that inhibition of neurotoxic reactive astrocytes may be one of the mechanisms by which EE promotes glutamatergic synaptogenesis and improves cognitive function in rats with CCH. The downregulation of reactive microglia and JAK2-STAT3 signaling pathway may be involved in this process.

Snake Bite-Induced Leukoencephalopathy: A Rare Case.

Across the globe, snake envenomation causes significant morbidity and mortality. Although many clinical presentations and complications are observed in different types of snake bites, the incidence of leukoencephalopathy is rare. Although most cases of leukoencephalopathy are seen in viper bites, they are rarely seen in neurotoxic snake bites. In this report, we present a unique case of snake bite-induced leukoencephalopathy following a neurotoxic snake bite. The case highlights the importance of considering this rare complication in cases of snake bites presenting with neurological symptoms, particularly in those affecting higher mental functions.

Neurotoxic effects of low dose ranges of environmental metal mixture in a rat model: The benchmark approach.

Metals exert detrimental effects on various systems within the body, including the nervous system. Nevertheless, the dose-response relationship concerning the administration of low doses of metal mixtures remains inadequately explored. The assessment of neurotoxic effects of lead, cadmium, mercury, and arsenic mixture (MIX) administered at low dose ranges, was conducted using an in vivo approach. A subacute study was conducted on a rat model consisting of a control and five treatment groups subjected to oral exposure with gradually increasing doses (from MIX 1 to MIX 5). The results indicated that behavioural patterns in an already developed nervous system displayed a reduced susceptibility to the metal mixture exposure with tendency of higher doses to alter short term memory. However, the vulnerability of the mature brain to even minimal amounts of the investigated metal mixture was evident, particularly in the context of oxidative stress. Moreover, the study highlights superoxide dismutase's sensitivity as an early-stage neurotoxicity marker, as indicated by dose-dependent induction of oxidative stress in the brain revealed through Benchmark analysis. The narrowest Benchmark Dose Interval (BMDI) for superoxide dismutase (SOD) activity (1e-06 - 3.18e-05 mg As/kg b.w./day) indicates that arsenic may dictate the alterations in SOD activity when co-exposed with the other examined metals. The predicted Benchmark doses for oxidative stress parameters were very low, supporting "no-threshold" concept. Histopathological alterations were most severe in the groups treated with higher doses of metal mixture. Similarly, the brain acetylcholinesterase (AChE) activity demonstrated a dose-dependent decrease significant in higher doses, while BMDI suggested Cd as the main contributor in the examined metal mixture. These findings imply varying susceptibility of neurotoxic endpoints to different doses of environmentally relevant metal mixtures, advocating for risk assessment and regulatory measures to address metal pollution and enhance remediation strategies.

Neuroinflammation and acquired traumatic CNS injury: a mini review.

Acquired traumatic central nervous system (CNS) injuries, including traumatic brain injury (TBI) and spinal cord injury (SCI), are devastating conditions with limited treatment options. Neuroinflammation plays a pivotal role in secondary damage, making it a prime target for therapeutic intervention. Emerging therapeutic strategies are designed to modulate the inflammatory response, ultimately promoting neuroprotection and neuroregeneration. The use of anti-inflammatory agents has yielded limited support in improving outcomes in patients, creating a critical need to re-envision novel approaches to both quell deleterious inflammatory processes and upend the progressive cycle of neurotoxic inflammation. This demands a comprehensive exploration of individual, age, and sex differences, including the use of advanced imaging techniques, multi-omic profiling, and the expansion of translational studies from rodents to humans. Moreover, a holistic approach that combines pharmacological intervention with multidisciplinary neurorehabilitation is crucial and must include both acute and long-term care for the physical, cognitive, and emotional aspects of recovery. Ongoing research into neuroinflammatory biomarkers could revolutionize our ability to predict, diagnose, and monitor the inflammatory response in real time, allowing for timely adjustments in treatment regimens and facilitating a more precise evaluation of therapeutic efficacy. The management of neuroinflammation in acquired traumatic CNS injuries necessitates a paradigm shift in our approach that includes combining multiple therapeutic modalities and fostering a more comprehensive understanding of the intricate neuroinflammatory processes at play.

Exploring the neurotoxicity of chiral dinotefuran towards nicotinic acetylcholine receptors: Enantioselective insights into species selectivity.

Dinotefuran is a chiral neonicotinoid that is widely distributed in environmental matrices, but its health risks to different organisms are poorly understood. This study investigated the neurotoxic responses of honeybee/cotton aphid nicotinic acetylcholine receptors (nAChRs) to chiral dinotefuran at the enantiomeric scale and demonstrated the microscopic mechanism of species selectivity in nAChR-mediated enantioselective neurotoxicity. The findings indicated that (S)-dinotefuran had a higher affinity for honeybee nAChR than (R)-dinotefuran whereas both enantiomers exhibited similar bioactivity toward cotton aphid nAChR. The results of dynamic neurotoxic processes indicated the association of conformational changes induced by chiral dinotefuran with its macroscopic neurotoxicity, and (R)-dinotefuran, which exhibit low toxicity to honeybee, was found to induce significant conformational changes in the enantioselective neurotoxic reaction, as supported by the average root-mean-square fluctuation (0.35 nm). Energy decomposition results indicated that electrostatic contribution (ΔGele) is the critical energy term that leads to substantial enantioselectivity, and both Trp-51 (－2.57 kcal mol-1) and Arg-75 (－4.86 kcal mol-1), which form a hydrogen-bond network, are crucial residues in mediating the species selectivity for enantioselective neurotoxic responses. Clearly, this study provides experimental evidence for a comprehensive assessment of the health hazards of chiral dinotefuran.

TDCPP and TiO2 NPs aggregates synergistically induce SH-SY5Y cell neurotoxicity by excessive mitochondrial fission and mitophagy inhibition.

Tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a halogen-containing phosphorus flame retardant, is widely used and has been shown to possess health risks to humans. The sustained release of artificial nanomaterials into the environment increases the toxicological risks of their coexisting pollutants. Nanomaterials may seriously change the environmental behavior and fate of pollutants. In this study, we investigated this combined toxicity and the potential mechanisms of toxicity of TDCPP and titanium dioxide nanoparticles (TiO2 NPs) aggregates on human neuroblastoma SH-SY5Y cells. TDCPP and TiO2 NPs aggregates were exposed in various concentration combinations, revealing that TDCPP (25 µg/mL) reduced cell viability, while synergistic exposure to TiO2 NPs aggregates exacerbated cytotoxicity. This combined exposure also disrupted mitochondrial function, leading to dysregulation in the expression of mitochondrial fission proteins (DRP1 and FIS1) and fusion proteins (OPA1 and MFN1). Consequently, excessive mitochondrial fission occurred, facilitating the translocation of cytochrome C from mitochondria to activate apoptotic signaling pathways. Furthermore, exposure of the combination of TDCPP and TiO2 NPs aggregates activated upstream mitochondrial autophagy but disrupted downstream Parkin recruitment to damaged mitochondria, preventing autophagosome-lysosome fusion and thereby disrupting mitochondrial autophagy. Altogether, our findings suggest that TDCPP and TiO2 NPs aggregates may stimulate apoptosis in neuronal SH-SY5Y cells by inducing mitochondrial hyperfission and inhibiting mitochondrial autophagy.

Mutations at Two Key Sites in PP2A Safeguard Caenorhabditis elegans Neurons from Microcystin-LR Toxicity.

Microcystin-LR (MC-LR) is a secondary metabolite produced by cyanobacteria, globally renowned for its potent hepatotoxicity. However, an increasing body of research suggests that it also exhibits pronounced neurotoxicity. PP2A is a fundamental intracellular phosphatase that plays a pivotal role in cell development and survival. Although extensive research has focused on the binding of MC-LR to the C subunit of PP2A, few studies have explored the key amino acid sites that can prevent the binding of MC-LR to PP2A-C. Due to the advantages of Caenorhabditis elegans (C. elegans), such as ease of genetic editing and a short lifespan, we exposed nematodes to MC-LR in a manner that simulated natural exposure conditions based on MC-LR concentrations in natural water bodies (immersion exposure). Our findings demonstrate that MC-LR exerts comprehensive toxicity on nematodes, including reducing lifespan, impairing reproductive capabilities, and diminishing sensory functions. Notably, and for the first time, we observed that MC-LR neurotoxic effects can persist up to the F3 generation, highlighting the significant threat that MC-LR poses to biological populations in natural environments. Furthermore, we identified two amino acid sites (L252 and C278) in PP2A-C through mutations that prevented MC-LR binding without affecting PP2A activity. This discovery was robustly validated through behavioral studies and neuronal calcium imaging using nematodes. In conclusion, we identified two crucial amino acid sites that could prevent MC-LR from binding to PP2A-C, which holds great significance for the future development of MC-LR detoxification drugs.

Prevalence of occupational co-exposure to biomechanical factors and neurotoxic chemicals in French workers.

OBJECTIVES: Little is known about occupational co-exposure. The objective was to assess the prevalence of exposure and co-exposure to biomechanical factors and neurotoxic chemicals in French workers in 2017. METHODS: Data from the French representative survey SUMER 2017 (SUrveillance Médicale des Expositions aux Risques professionnels) were analyzed. A total of 25 118 workers were included. Exposure to 4 biomechanical factors (manual handling of loads, forceful joint exertion, repetitive movements, and hand-arm transmitted vibrations) and 18 neurotoxic chemicals (n-hexane, perchloroethylene, trichloroethylene, etc.) were assessed using a questionnaire during face-to-face interviews with occupational physicians. RESULTS: Among men, 22.9% were exposed to at least one biomechanical factor and 10.2% were exposed to at least one neurotoxic chemical, mainly single exposures. Among women, 10.8% were exposed to at least one biomechanical factor and 3.1% were exposed to at least one neurotoxic chemical, also mainly single exposures. Occupational co-exposure to biomechanical factors and neurotoxic chemicals was observed among 4.8% of men and 0.7% of women. Workers under 30 yr old, blue-collar workers and those working in small companies were more co-exposed than other workers. In men, the prevalence of co-exposure was higher in the construction sector compared to other economic activities. DISCUSSION: This study stresses the importance of considering multiple occupational exposures while the current prevention measures are designed to focus on preventing occupational factors individually.