Search Results (171)

Cannabis is increasingly utilized for both recreational and medical purposes, and the discovery of the endocannabinoid system (ECS) has renewed interest in its therapeutic potential. Nonetheless, the safety of cannabis and cannabinoid-containing products requires re-evaluation. In this study, zebrafish were employed as a translational in vivo model to comprehensively evaluate the toxicological profiles and the therapeutic potential of phytocannabinoids and synthetic cannabinoids. Current evidence, particularly from studies on key phytocannabinoids such as Δ⁹-THC, CBD, and CBN, along with newly developed synthetic cannabinoids (such as JWH-018), demonstrates a spectrum of embryotoxic outcomes including developmental abnormalities, neurotoxicity, liver damage, reproductive impairments, and disturbances in metabolic regulation, especially during early life stages. By contrast, evidence for therapeutic benefits, such as alleviation of muscle spasms, pain and nausea, as well as neuroprotective and anti-inflammatory effects, is promising but comparatively less abundant and more heterogeneous in study design and outcome measures. Taken together, this imbalance indicates that toxicological risks are supported by more extensive and consistent data, whereas therapeutic efficacy, though encouraging, still requires more rigorous validation. This dual profile underscores the need for a robust, evidence-based framework for cannabinoid development and clinical application. Further investigations are essential to clarify mechanisms of toxicity and therapeutic action, optimize dosing regimens, define safe therapeutic windows, and evaluate long-term health outcomes. Full article

Background/Objectives: Microplastics are ubiquitous pollutants that pose physical toxicity and serve as vectors for antimicrobial agents, altering their bioavailability and toxicity. Unlike previous reviews that focus solely on antibiotics and terrestrial or aquatic ecosystems, this review integrates recent findings on the combined impacts of microplastics and antimicrobials on both aquatic and terrestrial animals, highlighting their biological responses. Methods: Recent experimental studies involving aquatic and terrestrial animals published in peer-reviewed journals were reviewed. These studies employed co-exposure designs using microplastics of different sizes, aging conditions, and surface chemistries in combination with antimicrobial compounds. Results: Microplastics combined with antimicrobials cause species-specific and often synergistic toxicity in aquatic organisms, affecting reproduction, immunity, oxidative stress, gene expression, and microbiota, with co-exposure often amplifying adverse physiological and developmental effects. Similarly, co-exposure to microplastics and antimicrobials in rodents, amphibians, birds, and soil invertebrates frequently leads to synergistic toxicity, oxidative stress, disrupted gut microbiota, and enhanced accumulation and bioavailability of pollutants, promoting inflammation, neurotoxicity, metabolic dysfunction, and increased antibiotic resistance gene propagation. Particle size, aging, and antimicrobial type influence toxicity severity. Certain microplastic-antimicrobial combinations can exhibit antagonistic effects, though less frequently reported. Conclusions: The interactions between microplastics and antimicrobials pose heightened risks to the health of organisms and ecological stability. These findings underscore the need to revise current risk assessment protocols to consider pollutant mixtures and microplastics-mediated transport. Future research should focus on environmentally relevant exposures, mechanistic studies using omics tools, and long-term ecological impacts. Integrated regulatory strategies are essential to address the compounded effects of microplastics and chemical contaminants. Full article

Background: Foods containing nutraceuticals from the mineral element group are being developed to compensate for the problem of deficiency in billions of people around the world. This research focuses on essential elements of patented cereal-based mixtures to complement the deficiencies of these elements and, at the same time, assesses their safety in terms of toxic elements in the human diet. Methods: The mineral and trace element contents in the mixtures were determined using the ICP-MS method with a subsequent evaluation of the contributions of the mixtures to the essential and toxic reference values based on dietary intakes and exposures for adults at 60, 80 and 100 kg of adult body weight and a portion size of 50 g. The potential health risk was evaluated using a metal pollution index. Results: The concentrations of minerals and trace elements in the cereal-based mixtures analyzed were as follows: K (up to 4150 µg/g) ≥ P > Mg > Ca > Na > Fe > Zn > Mn > Cu > Al > Ba (up to 4.40 µg/g) > Sr (up to 480 ng/g) ≥ Ti ≥ Ni > Ce ≥ Co > As ≥ Cs > Ag ≥ Li > Se > Be > Cr > Tl > Pb ≥ Hg > Ho > Cd > Sn (up to 1.12 ng/g). The mixtures contribute significantly to the reference values for Mn, Cu, Zn, Fe, and P for adults. Individual dietary exposure values of toxic elements for adults weighing 60 kg decrease in this order: Al (10.1 µg/kg bw/day) > Ni (362 ng/kg bw/day) > As ≥ Pb > Ag > Hg > Cd > and Sn (0.93 ng/kg bw/day). Conclusions: In terms of Regulation (EU) No 1924/2006 of the European Parliament and of the Council on nutrition and health claims made on foods, the cereal-based mixtures could be labelled “source of” Mn, Cu, Zn, Fe, and P when their contributions to the reference values exceeded 15%; in addition, “low sodium/salt” or “very low sodium/salt” can be applied. The mixtures contribute insignificantly to the toxic reference values of Al, Sn, Hg, Cd, Ni, and Ag, and the exposure values of Pb for developmental neurotoxicity, nephrotoxicity, and cardiovascular effects were considered safe. Regarding the metal pollution index of mixtures, there is no concern for potential health effects. Cereal-based mixtures are suitable for use in the food industry as a potential source of beneficial micronutrients for the human diet, although bioaccessible studies should not be neglected. Full article

Identifying reliable negative control compounds is essential for determining the sensitivity and specificity of screening assays. However, well-characterized negative controls for developmental neurotoxicity behavioral assays in larval zebrafish (Danio rerio) are lacking. This study evaluated nine chemicals with no reported evidence of mammalian developmental neurotoxicity, and a positive control (fluoxetine) for developmental and neurodevelopmental (i.e., behavioral) toxicity in zebrafish. Embryos were exposed to each chemical (≤100 µM) during development, 0–5 days post-fertilization (dpf), then assessed as larvae (6 dpf) using a locomotor behavior light–dark transition test. Behavior was analyzed using two methods: (1) the traditional method, comparing the average total distance moved, and (2) a 13-endpoint approach analyzing 13 aspects of the locomotor profile. Results showed that ibuprofen, omeprazole, and fluoxetine induced developmental toxicity (teratogenesis), with fluoxetine also causing behavioral neurotoxicity. Behavioral effects of developmental exposure to selegiline hydrochloride depended on the analysis method. Exposure to the other six chemicals (D-mannitol, glycerol, L-ascorbic acid, metformin hydrochloride, saccharin, and sodium benzoate), as well as ibuprofen or omeprazole, did not produce behavioral effects using either analysis method. Identifying negative control chemicals is essential for evaluating behavioral alterations precipitated by unknown substances and will assist with screening new chemicals for neurodevelopmental toxicity. Full article

Compounds, which rely on metabolism to exhibit toxicity, pose a challenge for next-generation risk assessment (NGRA). Since many of the currently available non-animal new approach methods (NAMs) lack metabolic activity, their use may lead to an underestimation of the true hazard to humans (false negative predictions). We explored here strategies to deal with metabolite-mediated toxicity in assays for developmental neurotoxicity. First, we present an overview of substances that may serve as potential positive controls for metabolite-related neurotoxicity. Then, we demonstrate, using the MitoMet (UKN4b) assay, which assesses the adverse effects of chemicals on neurites of human neurons, that some metabolites have a higher toxic potency than their parent compound. Next, we designed a strategy to integrate elements of xenobiotic metabolism into assays used for (developmental) neurotoxicity testing. In the first step of this approach, hepatic post-mitochondrial fractions (S9) were used to generate metabolite mixtures (“metabolisation module”). In the second step, these were applied to a NAM (exemplified by the UKN4b assay) to identify metabolite-mediated toxicity. We demonstrate the applicability and transferability of these approaches to other assays, by an exemplary study on the basis of the cMINC (UKN2) assay, another NAM of the developmental neurotoxicity in vitro battery. Based on the experience gained from these experiments, we discuss key issues to be addressed if this approach is to be used more broadly for NAM in the NGRA context. Full article

Microglia and macrophages are critical immune cells within the central nervous system (CNS), with distinct roles in development, homeostasis, and disease. Once viewed as passive bystanders, these cells are now recognized for their dynamic phenotypic plasticity, which enables them to respond to a wide range of physiological and pathological stimuli. During homeostasis, microglia and CNS-resident macrophages actively participate in synaptic pruning, neuronal support, myelin regulation, and immune surveillance, contributing to CNS integrity. However, under pathological conditions, these cells can adopt neurotoxic phenotypes, exacerbating neuroinflammation, oxidative stress, and neuronal damage in diseases such as Alzheimer’s, Parkinson’s, multiple sclerosis, and glioblastoma. This review synthesizes emerging insights into the molecular, epigenetic, and metabolic mechanisms that govern the behavior of microglia and macrophages, highlighting their developmental origins, niche-specific programming, and interactions with other CNS cells. We also explore novel therapeutic strategies aimed at modulating these immune cells to restore CNS homeostasis, including nanotechnology-based approaches for selective targeting, reprogramming, and imaging. Understanding the complex roles of microglia and macrophages in both health and disease is crucial for the development of precise therapies targeting neuroimmune interfaces. Continued advances in single-cell technologies and nanomedicine are paving the way for future therapeutic interventions in neurological disorders. Full article

The tomato leafminer (Tuta absoluta) is a globally invasive pest that causes severe yield losses in tomato crops. Nanotechnology-based strategies offer promising alternatives to conventional insecticides. This study examines the physiological, biochemical, and demographic responses of T. absoluta following exposure to mesoporous silica nanoparticles (MSNs) applied to tomato leaves at concentrations of 0, 3, 30, and 300 mg L⁻¹. Comprehensive assessments were conducted, including digestive and detoxifying enzyme activities in the insect, neurotoxicity indicators, life table parameters, and antioxidant responses in the host plant. At 30 mg L⁻¹, MSNs significantly impaired larval development, fecundity, and survival of T. absoluta without inducing phytotoxicity. Tomato plants treated at this concentration exhibited enhanced antioxidant enzyme activity (SOD, CAT, POD) and a reduced malondialdehyde (MDA) content, indicating an active oxidative defense. These plant responses were significantly correlated with changes in insect fitness traits, suggesting a plant-mediated effect on pest physiology. Digestive enzyme disruption, decreased acetylcholinesterase activity, and extended developmental periods contributed to suppressed population growth, as evidenced by reductions in the intrinsic rate of increase (r), net reproductive rate (R₀), and fecundity. At 300 mg L⁻¹, however, severe phytotoxicity and enzymatic collapse were observed in both plant and insect systems. These findings highlight moderate concentration of MSNs (30 mg L⁻¹) as a promising dose for sustainable and host-safe pest management, offering multi-targeted suppression of T. absoluta through combined plant and insect biochemical pathways. Full article

Currently regulated per- and polyfluoroalkyl substances (PFAS) have been associated with immune, endocrine, and neurotoxicity following gestational exposures. As a result, industries have effectively replaced them with next-generation PFAS, including perfluorohexanoic acid (PFHxA). PFHxA is increasingly found in the serum of pregnant women and in breast milk, and adult human post-mortem studies indicate that PFHxA is found in the brain, with the highest concentrations in the cerebellum and hypothalamus. Despite evidence of gestational, lactational, and nervous system exposure to PFHxA, developmental neurotoxicity (DNT) testing in mammals has not been conducted. For DNT evaluation, we exposed pregnant C57Bl/6J mice daily from gestational day 0 through postnatal day (P) 21 to two PFHxA exposure levels (a lower (0.32 mg/kg of body weight (bw), or higher (50 mg/kg of bw) dose of PFHxA)) or ddH₂O using treat-based administration. Given the high PFHxA levels in the cerebellum in post-mortem studies and the cerebellum’s protracted developmental window, we assessed acute transcriptional dysregulation and cellular morphology in this brain region on the last day of exposure at P21. Using bulk-RNA sequencing, we found that PFHxA exposure had subtle effects on transcripts related to neurons and glia, with females having a greater number of dysregulated transcripts than males. Using immunohistochemistry, we found that Purkinje cell linear frequency was increased in specific lobules in the higher-exposure group and that microglial morphology underwent subtle changes in specific cerebellar layers in the lower-exposure group in both sexes. Together these data suggest that PFHxA exposure may have lobule-specific impacts on the development of both neurons and glia in the cerebellum, highlighting the importance of studying the neurotoxicity of PFHxA in both sexes. Full article

Chlorpyrifos (CPF) is a widely used organophosphate insecticide; however, global concerns exist regarding its potential health risks, particularly developmental neurotoxicity. This study aimed to determine CPF residues in locally sourced tomatoes and cucumbers and assess the potential chronic and acute dietary risks associated with their consumption by the adult population of Armenia. As part of the national residue monitoring program, samples of the two most commonly consumed vegetables (tomato and cucumber) were collected from various regions of Armenia and analyzed using gas chromatography–tandem mass spectrometry (GC-MS/MS). Two databases were used for dietary exposure assessment: one containing CPF residue levels and another containing individual food consumption data from a food frequency questionnaire completed by 1329 Armenian residents. Chronic risk was assessed using the Margin of Exposure (MOE), while acute risk was evaluated using the Hazard Quotient (HQ) and the Hazard Index (HI). CPF residues were detected in 15% of tomato and 28.6% of cucumber samples, with a mean content of 0.003 mg/kg. Deterministic and probabilistic assessments indicated no health concern (i.e., MOE > 300 and >1000, HQ and HI < 1) for the general adult population at current exposure levels. However, higher cumulative risk estimates obtained for high-consumption groups emphasize the significance of these studied vegetables as notable contributors to overall CPF intake. The findings indicate the importance of establishing vegetable-specific maximum residue levels, strengthening monitoring, and considering vulnerable population groups in future research. Broader assessments, including other plant-origin products, are recommended to ensure comprehensive risk assessment and support science-based policy decisions for improved food safety and public health protection in Armenia. Full article

Honeybees (Apis mellifera) are indispensable pollinators vital to global biodiversity, ecosystem stability, and agricultural productivity, and they promote over 35% of food crops and 75% of flowering plants. Yet, they are in unprecedented decline, partly as a result of neonicotinoid pesticide use elsewhere. These effects on honey bee health are synthesized in this paper through molecular, physiological, and behavioral data showing that sublethal effects of neonicotinoids impair honey bee health. As neurotoxic insecticides that target nicotinic acetylcholine receptors (nAChRs), these insecticides interfere with neurotransmission and underlie cognitive impairment, immune suppression, and oxidative stress. Developmental toxicity is manifested in larvae as retarded growth, reduced feeding, and increased death; queen and drone reproduction are impaired, lowering colony viability. As a result, adult bees have shortened lives and erratic foraging, are further disoriented, and experience impaired navigation, communication, and resource collection. Together, these effects cascade to reduced brood care, thermoregulatory failure, and heretofore unrecognized increased susceptibility to pathogens, increasing the probability of colony collapse at the colony level. Contaminants such as pesticides may cause pollinator exposure and, in turn, may cause their population to be undermined if they are not mitigated; therefore, urgent mitigation strategies, including integrated pest management (IPM), regulatory reforms, and adoption of biopesticides, are needed to mitigate pollinator exposure. The focus of this review lies in the ecological necessity of restructuring how agriculture is managed to simultaneously meet food security and the conservation of honeybee health, the linchpin of global ecosystems. Full article

As typical environmental hormones, endocrine-disrupting chemicals (EDCs) have become a global environmental health issue of high concern due to their property of interfering with the endocrine systems of organisms. As a commonly used substitute for bisphenol A (BPA), bisphenol E (BPE) has been frequently detected in environmental matrices such as soil and water in recent years. Existing research has unveiled the developmental and reproductive toxicity of BPE; however, only one in vitro cellular experiment has preliminarily indicated potential neurotoxic risks, with its underlying mechanisms remaining largely unelucidated in the current literature. Potential toxic mechanisms and action targets of BPE were predicted using the zebrafish model via network toxicology and molecular docking, with RT-qPCRs being simultaneously applied to uncover neurotoxic effects and associated mechanisms of BPE. A significant decrease (p < 0.05) in the frequency of embryonic spontaneous movements was observed in zebrafish at exposure concentrations ≥ 0.01 mg/L. At 72 hpf and 144 hpf, the larval body length began to shorten significantly from 0.1 mg/L to 1 mg/L, respectively (p < 0.01), accompanied by a reduced neuronal fluorescence intensity and a shortened neural axon length (p < 0.01). By 144 hpf, the motor behavior in zebrafish larvae was inhibited. Through network toxicology and molecular docking, HSP90AB1 was identified as the core target, with the cGMP/PKG signaling pathway determined to be the primary route through which BPE induces neurotoxicity in zebrafish larvae. BPE induces neuronal apoptosis and disrupts neurodevelopment by inhibiting the cGMP/PKG signaling pathway, ultimately suppressing the larval motor behavior. To further validate the experimental outcomes, we measured the expression levels of genes associated with neurodevelopment (elavl3, mbp, gap43, syn2a), serotonergic synaptic signaling (5-ht1ar, 5-ht2ar), the cGMP/PKG pathway (nos3), and apoptosis (caspase-3, caspase-9). These results offer crucial theoretical underpinnings for evaluating the ecological risks of BPE and developing environmental management plans, as well as crucial evidence for a thorough comprehension of the toxic effects and mechanisms of BPE on neurodevelopment in zebrafish larvae. Full article

Eriobotrya japonica (Thunb.) Lindl. leaves are rich in polyphenolic compounds, yet their toxicological effects in aquatic models remain poorly understood. This study evaluated the impact of a hydroethanolic E. japonica leaf extract on zebrafish embryos through the use of morphological, behavioral, and biochemical parameters. The 96 h LC₅₀ was determined as 189.8 ± 4.5 mg/L, classifying the extract as practically non-toxic, according to OECD guidelines. Thereby, embryos were exposed for 90 h to 75 and 150 mg/L concentrations of the E. japonica leaf extract. While no significant effects were noted at the lowest concentration of 150 mg/L, significant developmental effects were observed, including reduced survival, delayed hatching, underdevelopment of the swim bladder, and retention of the yolk sac. These malformations were accompanied by marked behavioral impairments. Biochemical analysis revealed a concentration-dependent increase in superoxide dismutase (SOD) and catalase (CAT) activity, suggesting the activation of antioxidant defenses, despite no significant change in reactive oxygen species (ROS) levels. This indicates a potential compensatory redox response to a pro-oxidant signal. Additionally, the acetylcholinesterase (AChE) activity was significantly reduced at the highest concentration, which may have contributed to the observed neurobehavioral changes. While AChE inhibition is commonly associated with neurotoxicity, it is also a known therapeutic target in neurodegenerative diseases, suggesting concentration-dependent dual effects. In summary, the E. japonica leaf extract induced concentration-dependent developmental and behavioral effects in zebrafish embryos, while activating antioxidant responses without triggering oxidative damage. These findings highlight the extract’s potential bioactivity and underscore the need for further studies to explore its safety and therapeutic relevance. Full article

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant widely used in consumer products. TBBPA is often detected in soil, water, organisms, and even in human blood and breast milk. Hence, it is accessible to developing fetuses and nursing offspring after maternal exposure. The reported evidence for the endocrine disruption of TBBPA in the brain has raised concerns regarding its effects on neurodevelopmental and behavioral functions. This study investigated the effects of TBBPA exposure on neurodevelopment. A cell-based developmental neurotoxicity assay was performed to determine whether TBBPA is a developmental neurotoxicant. The assay revealed TBBPA to be a developmental neurotoxicant. C57BL/6N maternal mice were administered TBBPA at 0, 0.24, and 2.4 mg/kg during pregnancy and lactation, and their offspring underwent behavioral testing. The behavioral experiments revealed sex-specific effects. In females, only a deterioration of the motor ability was observed. In contrast, deteriorations in motor function, memory, and social interaction were noted in males. Furthermore, we validated changes in the expression of genes associated with behavioral abnormalities, confirming that perinatal exposure to TBBPA, at the administered doses, can affect neurodevelopment and behavior in offspring. These findings highlight the need for more in-depth and multifaceted research on the toxicity of TBBPA. Full article

Developmental exposure to polybrominated diphenyl ethers (PBDEs), which are commonly used as flame retardants, results in irreversible cognitive impairments. Postnatal hippocampal neurogenesis, which occurs in the subgranular zone (SGZ) of the dentate gyrus, is critical for neuronal circuits and plasticity. Wnt7a-Frizzled5 (FZD5) is essential for both neurogenesis and synapse formation; moreover, Wnt signaling participates in PBDE neurotoxicity and also contributes to the neuroprotective effects of melatonin. Therefore, we investigated the impacts of perinatal decabromodiphenyl ether (BDE-209) exposure on hippocampal neurogenesis and synaptogenesis in juvenile rats through BrdU injection and Golgi staining, as well as the alleviation of melatonin pretreatment. Additionally, we identified the structural basis of Wnt7a and two compounds via molecular docking. The hippocampal neural progenitor pool (Sox2+BrdU+ and Sox2+GFAP+cells), immature neurons (DCX+) differentiated from neuroblasts, and the survival of mature neurons (NeuN+) in the dentate gyrus were inhibited. Moreover, in BDE-209-exposed offspring rats, it was observed that dendritic branching and spine density were reduced, alongside the long-lasting suppression of the Wnt7a-FZD5/β-catenin pathway and targeted genes (Prox1, Neurod1, Neurogin2, Dlg4, and Netrin1) expression. Melatonin alleviated BDE-209-disrupted memory, along with hippocampal neurogenesis and dendritogenesis, for which the restoration of Wnt7a-FZD5 signaling may be beneficial. This study suggested that melatonin could represent a potential intervention for the cognitive deficits induced by PBDEs. Full article

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants that continue to raise concern owing to their ability to accumulate in living organisms. In recent years, a growing body of research has shown that PFAS can exert their toxicity through disruption of both DNA integrity and epigenetic regulation. This includes changes in DNA methylation patterns, histone modifications, chromatin remodeling, and interference with DNA repair mechanisms. These molecular-level alterations can impair transcriptional regulation and cellular homeostasis, contributing to genomic instability and long-term biological dysfunction. In neural systems, PFAS exposure appears particularly concerning. It affects key regulators of neurodevelopment, such as BDNF, synaptic plasticity genes, and inflammatory mediators. Importantly, epigenetic dysregulation extends to non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which mediate post-transcriptional silencing and chromatin remodeling. Although direct evidence of transgenerational neurotoxicity is still emerging, animal studies provide compelling hints. Persistent changes in germline epigenetic profiles and transcriptomic alterations suggest that developmental reprogramming might be heritable by future generations. Additionally, PFAS modulate nuclear receptor signaling (e.g., PPARγ), further linking environmental cues to chromatin-level gene regulation. Altogether, these findings underscore a mechanistic framework in which PFAS disrupt neural development and cognitive function via conserved epigenetic and genotoxic mechanisms. Understanding how these upstream alterations affect long-term neurodevelopmental and neurobehavioral outcomes is critical for improving risk assessment and guiding future interventions. This review underscores the need for integrative research on PFAS-induced chromatin disruptions, particularly across developmental stages, and their potential to impact future generations. Full article