Manganese exposure leads to depressive-like behavior through disruption of the Gln-Glu-GABA metabolic cycle.

There is a correlation between long-term manganese (Mn) exposure and the Parkinson's-like disease (PD), with depression as an early symptom of PD. However, the direct relationship between Mn exposure and depression, and the mechanisms involved, remain unclear. We found that Mn exposure led to depressive-like behavior and mild cognitive impairment in mice, with Mn primarily accumulating in the cornu ammonis 3 (CA3) area of the hippocampus. Mice displayed a reduction in neuronal dendritic spines and damage to astrocytes specifically in the CA3 area. Spatial metabolomics revealed that Mn downregulated glutamic acid decarboxylase 1 (GAD1) expression in astrocytes, disrupting the Glutamine-Glutamate-γ-aminobutyric acid (GlnGluGABA) metabolic cycle in the hippocampus, leading to neurotoxicity. We established an in vitro astrocyte Gad1 overexpression (OEX) model and found that the cultured medium from Gad1 OEX astrocytes reversed neuronal synaptic damage and the expression of gamma-aminobutyric acid (GABA) related receptors. Using the astrocyte Gad1 OEX mouse model, results showed that OEX of Gad1 ameliorated depressive-like behavior and cognitive dysfunction in mice. These findings provide new insight into the important role of GAD1 mediated GlnGluGABA metabolism disorder in Mn exposure induced depressive-like behavior. This study offers a novel sight to understanding abnormal emotional states following central nervous system damage induced by Mn exposure.

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.

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.

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.

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.

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.

Acute and chronic toxicity in Sprague-Dawley rats of orally-administered total lignans from Arctii Fructus, a potential therapeutic drug for diabetes.

Arctii Fructus is the dried ripe fruit of Arctium lappa L. (family Asteraceae) and is in the Chinese pharmacopoeia. Previous research showed that the total lignans from Arctii Fructus (TLAF) have pharmacological activities related to diabetes. This study evaluated the acute and chronic (26 weeks) toxicities associated with oral daily administration of TLAF in Sprague-Dawley (SD) rats. An acute-toxicity test showed that TLAF caused 10% mortality at 3,000 mg/kg × 2 (6-h interval), with toxic symptoms, such as dyspnea and tonic convulsions, indicating potential neurotoxicity. A chronic-toxicity study showed no mortality after administration. The no observed adverse-effect level was 1,800 mg/kg (approximately 54 times higher than the human clinical dose) for 26 weeks of TLAF oral administration in SD rats, with toxicity signs of excessive oral and nasal secretions and moist circumferential hair that recovered after TLAF discontinuation. In the toxicokinetic study, the two main components of TLAF, arctigenin plasma level was positively correlated with dose and tended to accumulate after multiple doses. At 1,800 mg/kg, arctiin plasma level increased and tended to accumulate after multiple doses. These results indicated that TLFA has relatively low toxicity and the potential for clinical treatment of diabetes.

Neurotoxicity of Titanium Dioxide Nanoparticles: A Comprehensive Review.

The increasing use of titanium dioxide nanoparticles (TiO2 NPs) across various fields has led to a growing concern regarding their environmental contamination and inevitable human exposure. Consequently, significant research efforts have been directed toward understanding the effects of TiO2 NPs on both humans and the environment. Notably, TiO2 NPs exposure has been associated with multiple impairments of the nervous system. This review aims to provide an overview of the documented neurotoxic effects of TiO2 NPs in different species and in vitro models. Following exposure, TiO2 NPs can reach the brain, although the specific mechanism and quantity of particles that cross the blood-brain barrier (BBB) remain unclear. Exposure to TiO2 NPs has been shown to induce oxidative stress, promote neuroinflammation, disrupt brain biochemistry, and ultimately impair neuronal function and structure. Subsequent neuronal damage may contribute to various behavioral disorders and play a significant role in the onset and progression of neurodevelopmental or neurodegenerative diseases. Moreover, the neurotoxic potential of TiO2 NPs can be influenced by various factors, including exposure characteristics and the physicochemical properties of the TiO2 NPs. However, a systematic comparison of the neurotoxic effects of TiO2 NPs with different characteristics under various exposure conditions is still lacking. Additionally, our understanding of the underlying neurotoxic mechanisms exerted by TiO2 NPs remains incomplete and fragmented. Given these knowledge gaps, it is imperative to further investigate the neurotoxic hazards and risks associated with exposure to TiO2 NPs.

Neurotoxicity of melittin: Role of mitochondrial oxidative phosphorylation system in synaptic plasticity dysfunction.

Melittin (Mel), a main active peptide component of bee venom, has been proven to possess strong antitumor activity. Previous studies have shown that Mel caused severe cell membrane lysis and acted on the central nervous system (CNS). Here, this study was designed to investigate the effects of Mel on CNS and explore the potential mechanism. We confirmed the neurotoxic effect of melittin by in vivo and in vitro experiments. After subcutaneous administration of Mel (4 mg/kg, 8 mg/kg) for 14 days, the mice exhibited obvious depression-like behavior in a dose dependent manner. Besides, RNA-sequencing analysis revealed that oxidative phosphorylation (OXPHOS) signaling pathway was mostly enriched in hippocampus. Consistently, we found that Mel distinctly inhibited the activity of OXPHOS complex I and induced oxidative stress injury. Moreover, Mel significantly induced synaptic plasticity dysfunction in hippocampus via BDNF/TrkB/CREB signaling pathway. Taken together, the neurotoxic effect of Mel was involved in impairing OXPHOS system and hippocampal synaptic plasticity. These novel findings provide new insights into fully understanding the health risks of Mel and are conducive to the development of Mel related drugs.

Influence of sucralose, acesulfame-k, and their mixture on brain's fish: A study of behavior, oxidative damage, and acetylcholinesterase activity in Daniorerio.

Sucralose (SUC) and acesulfame-k (ACE-K) are widely used artificial sweeteners worldwide; however, they are frequently detected in aquatic environments due to their low metabolism and inadequate removal during wastewater treatment. The harmful effects of these compounds on hydrobionts have yet to be fully understood, as data on their toxicity is limited and inconclusive. This research aimed to determine the impact of SUC (50, 75, 125 µg/L) and ACE-K (50, 75, 125 µg/L), individually and in combination, on fish's swimming behavior, acetylcholinesterase activity, and oxidative stress response after four months of exposure. Following exposure, adult Danio rerio displayed anxiety-like behavior, as evidenced by increased freezing time and decreased swimming activity. Additionally, analysis of fish brain tissue revealed a disruption of REDOX homeostasis, leading to oxidative stress, which may be responsible for the observed inhibition of AChE activity. The results indicated that ACE-K was more toxic than SUC, and the mixture of both compounds produced a more detrimental effect than when each compound was administered alone. These findings highlight the hazardous impacts of SUC and ACE-K on fish in environmentally relevant concentrations, suggesting that these compounds should be added to the priority pollutant list.

The lysosome-mitochondrion crosstalk engaged in silver nanoparticles-disturbed mitochondrial homeostasis.

Given their increasing industrial and biomedical applications, silver nanoparticles (AgNPs) have become widely present in the environment. However, to date, studies on their potential health risks have been far from sufficient, especially those regarding their neurotoxic effects. This study investigated the neurotoxic effects of AgNPs on neural PC-12 cells in the context of mitochondria, which play an important role in AgNP-induced cellular metabolism disturbance and even cell death. Our results show that the endocytosed AgNPs, and not extracellular Ag+, appear to directly determine cell fate. Importantly, endocytosed AgNPs led to mitochondrial swelling and vacuolation without direct interaction. Although mitophagy, a selective autophagy process, was invoked to rescue damaged mitochondria, it failed to function in mitochondrial degradation and recycling. Discovery of the underlying mechanism showed that the endocytosed AgNPs could directly translocate into lysosomes and then cause lysosome perturbation, which is the main factor leading to mitophagy blockade and the subsequent accumulation of defective mitochondria. After lysosomal reacidification via cyclic adenosine monophosphate (cAMP), AgNP-induced dysfunctional autolysosome formation and disturbed mitochondrial homeostasis were reversed. In summary, this study reveals that lysosome-mitochondrion crosstalk is a main mechanism for AgNP-induced neurotoxic effects, offering an inspiring perspective on the neurotoxic effects of AgNPs.

[Pathomorphological characteristics of sequelae of the black mamba bite]. / Patomorfologicheskaya kharakteristika posledstvii ukusa chernoi mamby.

Pathomorphological changes in internal organs due to the toxic effects of the black mamba venom are nonspecific in nature and presume its neurotoxic and cardiotoxic effects with the development of the DIC syndrome, pulmonary edema, and brain edema in the terminal period. In forensic medicine, the development of specific diagnostic criteria, as well as an algorithm for detecting toxins of the black mamba venom in biological fluids and tissues of internal organs can become a promising topic for scientific research.

Are biopesticides safe for the environment? Effects of pyrethrum extract on the non-target species Daphnia magna.

Biopesticides are natural compounds considered more safe and sustainable for the environment. However, it is also important to evaluate the potential risk in non-target organisms. Pyrethrum extract (PE) is a biopesticide, widely used for agriculture, veterinary, and aquaculture. This work aimed to evaluate acute (0.6 - 40.0 µg/L; 96 h; E(L)C50 toxicity) and sub-chronic (0.7 - 1.1 µg/L; 10 d; life-history parameters) effects of PE on Daphnia magna. Moreover, a biomarkers approach using antioxidant and biotransformation capacity, lipid peroxidation (LPO), neurotoxicity, and energy reserves content were evaluated. Acute effects (mortality, changes in swimming behavior, oxidative stress, lipid peroxidation, neurotoxicity) were recorded with the increase in PE concentration. Sub-chronic assay showed an increase in energy reserves content, antioxidant parameters, and LPO demonstrating that PE unbalances oxidative metabolism. This study can conclude that PE potentiates toxic effects in D. magna and demonstrates the vulnerability of a non-target organism to PE that is considered environmentally safe.

Ecotoxicological evaluation of oxidative stress-mediated neurotoxic effects, genetic toxicity, behavioral disorders, and the corresponding mechanisms induced by fluorene-contaminated soil targeted to earthworm (Eisenia fetida) brain.

Fluorene is a commonly identified PAH pollutant in soil and exhibits various worrisome hazardous effects to soil organisms. Currently, the toxicity profiles of fluorene on earthworm brain are rare, and the mechanisms and their corresponding pathways involved in fluorene-triggered neurotoxicity, genotoxicity, and behavior changes have not been reported hitherto. Herein, earthworm (Eisenia fetida) brain was chosen as targeted receptor to explore the neurotoxic effects, genetic toxicity, behavioral disorders, and related mechanisms caused by fluorene-induced oxidative stress pathways. The results showed excess fluorene initiated the release of excessive quantities of ROS in earthworm brain, which have caused oxidative stress and accompanied by serious oxidative effects, including LPO (lipid peroxidation) and DNA injury. To minimize the damage effects, the antioxidant defense mechanisms (antioxidant enzymes and non-enzymatic antioxidants) were activated, and entailed a decrease of the antioxidant capacity in E. fetida brain, which, in turn, causes further ROS-induced ROS release. Exposure of fluorene induced the abnormal mRNA expression of genes relevant to oxidative stress (e.g., GST, SOD, CAT, GPx, MT, and Hsp70) and neurotoxicity (e.g., H02, C04, D06, and E08) in E. fetida brain. Specifically, fluorene can bind directly to AChE, destroying the conformation of this protein, and even affecting its physiological functions. This occurrence caused the inhibition of AChE activity and excess ACh accumulation at the nicotinic post-synaptic membrane, finally triggering neurotoxicity by activation of pathways related to oxidative stress. Moreover, the avoidance responses and burrowing behavior were obviously disturbed by oxidative stress-induced neurotoxicity after exposure to fluorene. The results form IBR suggested more severe poisoning effects to E. fetida brain initiated by high-dose and long-term exposure of fluorene. Among, oxidative stress injury and genotoxic potential are more sensitive endpoint than others. Collectively, fluorene stress can provoke potential neurotoxicity, genotoxicity, and behavioral disturbances targeted to E. fetida brain through the ROS-mediated pathways involving oxidative stress. These findings are of great significance to estimate the detrimental effects of fluorene and the corresponding mechanisms on soil eco-safety.

Ferroptosis contributes to nickel-induced developmental neurotoxicity in zebrafish.

Nickel (Ni) is a widely utilized heavy metal that can cause environmental pollution and health hazards. Its safety has attracted the attention of both the environmental ecology and public health fields. While the central nervous system (CNS) is one of the main targets of Ni, its neurotoxicity and the underlying mechanisms remain unclear. Here, by taking advantage of the zebrafish model for live imaging, genetic analysis and neurobehavioral studies, we reveal that the neurotoxic effects induced by exposure to environmentally relevant levels of Ni are closely related to ferroptosis, a newly-described form of iron-mediated cell death. In vivo two-photon imaging, neurobehavioral analysis and transcriptome sequencing consistently demonstrate that early neurodevelopment, neuroimmune function and vasculogenesis in zebrafish larvae are significantly affected by environmental Ni exposure. Importantly, exposure to various concentrations of Ni activates the ferroptosis pathway, as demonstrated by physiological/biochemical tests, as well as the expression of ferroptosis markers. Furthermore, pharmacological intervention of ferroptosis via deferoxamine (DFO), a classical iron chelating agent, strongly implicates iron dyshomeostasis and ferroptosis in these Ni-induced neurotoxic effects. Thus, this study elucidates the cellular and molecular mechanisms underlying Ni neurotoxicity, with implications for our understanding of the physiologically damaging effects of other environmental heavy metal pollutants.

Cefepime-induced Neurotoxicity: A Retrospective Cohort Study in a South-Indian Tertiary Healthcare Facility.

BACKGROUND: Cefepime is a fourth-generation cephalosporin with a broad spectrum coverage and anti-pseudomonal activity. The safety profile of cefepime was relatively favourable until neurotoxicity was first reported in 1999. Despite cefepime-induced neurotoxicity (CIN), it continues to be a principal part of parenteral treatment for various infections. OBJECTIVE: The study aimed to determine the incidence and risk factors for CIN compared to other antibiotics. METHODS: A retrospective cohort study was conducted involving 738 patients over eight months in Kasturba Medical College and Hospital, Manipal, India. Patients with cefepime were selected as study cohort (SC; n= 496), and other antibiotics were included in the reference cohort (RC; n=242). RESULTS: The results showed that 53 (10.7%) patients developed neurotoxicity in the SC, whereas 12 (5%) patients in the RC. A significant association was found between neurotoxicity and cefepime use (X2 =6.641; p=0.01). SC has a 2.29 times increased risk of neurotoxicity than RC (OR: 2.29; 95% CI: 1.2-4.38). Risk estimation showed that renal failure patients had a 5.5 times higher risk for CIN than non-renal failure patients (OR: 5.5; 95% CI: 2.98 - 10.17). CIN symptoms were disorientation (38.5%), loss of consciousness (23.1%), drowsiness (18.5%), etc. The calculated number needed to harm (NNH) for cefepime was 17.2. CONCLUSION: The study found a higher incidence of CIN compared to other antibiotics-induced neurotoxicity and a harmful association between cefepime use and CIN development. Besides, renal failure is a risk factor for CIN. Therefore, the study warrants the use of cefepime, where no other alternatives are available.

Toxic Effects of Glyphosate on the Nervous System: A Systematic Review.

Glyphosate, a non-selective systemic biocide with broad-spectrum activity, is the most widely used herbicide in the world. It can persist in the environment for days or months, and its intensive and large-scale use can constitute a major environmental and health problem. In this systematic review, we investigate the current state of our knowledge related to the effects of this pesticide on the nervous system of various animal species and humans. The information provided indicates that exposure to glyphosate or its commercial formulations induces several neurotoxic effects. It has been shown that exposure to this pesticide during the early stages of life can seriously affect normal cell development by deregulating some of the signaling pathways involved in this process, leading to alterations in differentiation, neuronal growth, and myelination. Glyphosate also seems to exert a significant toxic effect on neurotransmission and to induce oxidative stress, neuroinflammation and mitochondrial dysfunction, processes that lead to neuronal death due to autophagy, necrosis, or apoptosis, as well as the appearance of behavioral and motor disorders. The doses of glyphosate that produce these neurotoxic effects vary widely but are lower than the limits set by regulatory agencies. Although there are important discrepancies between the analyzed findings, it is unequivocal that exposure to glyphosate produces important alterations in the structure and function of the nervous system of humans, rodents, fish, and invertebrates.

Concurrent water- and foodborne exposure to microplastics leads to differential microplastic ingestion and neurotoxic effects in zebrafish.

Organisms constantly ingest microplastics directly from the environment or indirectly via trophic transfer due to the pervasiveness of microplastic pollution. However, most previous studies have only focused on waterborne exposure at the individual level, while few studies have investigated the contribution of trophic transfer to the exposure in organisms. We comprehensively evaluated the differences in microplastic ingestion and toxic effects in zebrafish exposed to microplastics via two concurrent routes (waterborne and foodborne). The polyethylene microplastics (40-47 µm, 0.1-10 mg/L) concentration used here was set in a range closed to the environmentally relevant microplastic concentrations, especially considering the extreme high concentration scenarios in wastewater. The concentration of microplastics resulting from foodborne exposure (0.01±0.01 µg/mg; 0.1±0.1 particles/mg) was significantly lower than that through waterborne exposure (0.06±0.02 µg/mg; 0.8±0.3 particles/mg), suggesting the ingestion of microplastics in their tissues occurs mainly through direct environmental uptake rather than food chain transfer (though the initial microplastic concentration was 1000 folds lower). However, more sublethal impacts, including the significant abnormal hyperactive swimming behaviour (107±5% induction; p< 0.05), were observed in the foodborne group than waterborne group. Additionally, ingenuity pathway analysis predicted both exposure routes caused obvious nervous system interference but through opposite modes of action. This was further verified by the alteration of neurotransmitter biomarkers that neurotoxicity mechanisms were completely different for the two exposure routes. The neurotoxic effects of microplastics are non-negligible and can exert together through both water- and foodborne exposure routes, which deserves further attention.

Neurotoxicity induced by combined exposure of microcystin-LR and nitrite in male zebrafish (Danio rerio): Effects of oxidant-antioxidant system and neurotransmitter system.

With the intensification of water eutrophication around the world, cyanobacterial blooms have been becoming a common environmental pollution problem. The levels of microcystin-LR (MC-LR) and nitrite rise sharply during the cyanobacterial bloom period, which may have potential joint toxicity on aquatic organisms. In this study, adult male zebrafish were immersed into different joint solutions of MC-LR (0, 3, 30 µg/L) and nitrite (0, 2, 20 mg/L) for 30 days to explore the neurotoxic effects and underlying mechanisms. The results showed that single factor MC-LR or nitrite caused a concentration-dependent damage in brain ultrastructure and the effects of their joint exposure were much more intense. Downregulated expression of mbp and bdnf associated with myelination of nerve fibers further confirmed that MC-LR and nitrite could damage the structure and function of neuron. The decreases in dopamine content, acetylcholinesterase activity and related gene mRNA levels indicated that MC-LR and nitrite adversely affected the normal function of the dopaminergic and cholinergic systems in zebrafish brain. In addition, the significant increase in malondialdehyde content suggested the occurrence of oxidative stress caused by MC-LR, nitrite and their joint-exposure, which paralleled a significant decrease in antioxidant enzyme­manganese superoxide dismutase activity and its transcription level. In conclusion, MC-LR + Nitrite joint-exposure has synergistic neurotoxic effects on the structure and neurotransmitter systems of fish brain, and antioxidant capacity disruption caused by these two factors might be one of the underlying synergistic mechanisms. Therefore, there is a risk of being induced neurotoxicity in fish during sustained cyanobacterial bloom events.