Search Results (159)

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

Zebrafish (Danio rerio) combine accessible behavioral phenotypes with conserved neurochemical pathways and molecular features of vertebrate brain function, positioning them as a powerful model for investigating early neurodegenerative processes and screening neuroprotective strategies. In this context, integrated behavioral and proteomic analyses provide valuable insights into the initial pathophysiological events shared by conditions such as Parkinson’s disease and related disorders—including mitochondrial dysfunction, oxidative stress, and synaptic impairment—which emerge before overt neuronal loss and offer a crucial window to understand disease progression and evaluate therapeutic candidates prior to irreversible damage. To investigate this early window of dysfunction, zebrafish larvae were exposed to 500 μM 1-methyl-4-phenylpyridinium (MPP⁺) from 1 to 5 days post-fertilization and evaluated through integrated behavioral and label-free proteomic analyses. MPP⁺-treated larvae exhibited hypokinesia, characterized by significantly reduced total distance traveled, fewer movement bursts, prolonged immobility, and a near-complete absence of light-evoked responses—mirroring features of early Parkinsonian-like motor dysfunction. Label-free proteomic profiling revealed 40 differentially expressed proteins related to mitochondrial metabolism, redox regulation, proteasomal activity, and synaptic organization. Enrichment analysis indicated broad molecular alterations, including pathways such as mitochondrial translation and vesicle-mediated transport. A focused subset of Parkinsonism-related proteins—such as DJ-1 (PARK7), succinate dehydrogenase (SDHA), and multiple 26S proteasome subunits—exhibited coordinated dysregulation, as visualized through protein–protein interaction mapping. The upregulation of proteasome components and antioxidant proteins suggests an early-stage stress response, while the downregulation of mitochondrial enzymes and synaptic regulators reflects canonical PD-related neurodegeneration. Together, these findings provide a comprehensive functional and molecular characterization of MPP⁺-induced neurotoxicity in zebrafish larvae, supporting its use as a relevant in vivo system to investigate early-stage Parkinson’s disease mechanisms and shared neurodegenerative pathways, as well as for screening candidate therapeutics in a developmentally responsive context. Full article

Background: Butylated hydroxyanisole (BHA) has been extensively used in several commercial industries as a preservative. It causes severe cellular and neurological damage affecting the developing fetus and might induce attention deficit hyperactivity disorder (ADHD). Methods: Zebrafish embryos were subjected to five distinct doses of BHA—0.5, 1, 2, 4, and 8 ppb up to 96 h post fertilization (hpf). Hatching rate, heart rate, and body malformations were assessed at 48 hpf, 72 hpf, and 48–96 hpf, respectively. After exposure, apoptotic activity, neurobehavioral evaluation, neurotransmitter assay, and antioxidant activity were assessed at 96 hpf. At 120 hpf, the expression of genes DRD4, COMT, 5-HTR1aa, and BDNF was evaluated by real-time PCR. Results: BHA exposure showed a delay in the hatching rate and a decrease in the heart rate of the embryo when compared with the control. Larvae exhibited developmental deformities such as bent spine, yolk sac, and pericardial edema. A higher density of apoptotic cells was observed in BHA-exposed larvae at 96 hpf. There was a decline in catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and superoxide dismutase (SOD) activity, indicating oxidative stress. There was a significant decrease in Acetylcholinesterase (AChE) activity and serotonin levels with an increase in concentration of BHA, leading to a dose-responsive increase in anxiety and impairment in memory. A significant decrease in gene expression was also observed for DRD4, COMT, 5-HTR1aa, and BDNF. Conclusions: Even at lower concentrations of BHA, zebrafish embryos suffered from developmental toxicity, anxiety, and impaired memory due to a decrease in AChE activity and serotonin levels and altered the expression of the mentioned genes. Full article

Inorganic arsenic [As(III) and As(V)] is a pervasive environmental contaminant in groundwater systems, early-life exposure to which is associated with an impaired cognitive ability and an increased risk of neurobehavioral disorders. Although the effect of As(III) on the neurons is well studied, the involvement of the microglia remains unclear. In this study, the effects of sodium arsenite (NaAsO₂) on microglial activation and the underlying NLRP3 inflammasome mechanism were determined. Pregnant rats were gavaged with NaAsO₂ (0, 1, 4, and 10 mg/kg body weight), which dissociates in aqueous solutions into bioactive arsenite species [As(OH)₃], from gestational day 1 (GD1) to postnatal day 21 (PND21). The results showed that As(III) induces learning and memory impairments and microglial activation in the hippocampus of offspring rats (PND21). Increased expression of NLRP3, the activation of caspase-1, and the production of interleukin-1β were observed in both the hippocampus of As(III)-exposed offspring rats and As(III)-exposed microglial BV2 cells under culture conditions. Interestingly, blocking the NLRP3 inflammasome using MCC950 mitigated its activation. Furthermore, inhibition of NADPH oxidase 2 (NOX2) using apocynin or specific siRNA significantly reduced As(III)-induced microglial NLRP3 inflammasome activation. In addition, inactivation of the microglial NLRP3 inflammasome or NOX2 markedly rescued As(III)-induced neurotoxicity in the hippocampal HT22 cells. Taken together, this study reveals that NOX2/NLRP3-inflammasome-dependent microglial activation promotes As(III)-induced learning and memory impairments in developmental rats. Full article

Heavy metal contamination, particularly lead (Pb) poisoning, is a significant public health issue worldwide. In Bangladesh, Pb contamination of water, soil, air, and food is detected alarmingly. Chronic exposure to Pb leads to severe health complications in the human body, including neurotoxicity, cardiovascular disease, developmental delays, and kidney damage. Research has established that there is “no safe level” of Pb exposure, as even minimal exposure can cause detrimental effects. Although existing physical and chemical methods are widely used, they come with limitations, such as high costs and the generation of toxic byproducts. As a green, sustainable alternative, the potential of probiotics as an effective biosorption agent has been explored to reduce Pb contamination in food, especially meat, while preserving its nutritional and sensory properties. This paper aims to integrate current knowledge from these two fields and highlight their capacity to decontaminate Pb-laden meat, the primary protein source in Bangladesh. The study also investigates optimal biosorption parameters, including temperature, pH, and exposure time, to enhance effectiveness. The proposed application of lactic acid bacteria (LAB) in meat processing and packaging is expected to significantly lower Pb levels in meat, ensuring safer consumption. Full article

Brain endothelial cells (BECs) constitute the core component of the blood–brain barrier (BBB), regulating substance exchange between blood and the brain parenchyma to maintain central nervous system homeostasis. In pathological states, the BBB exhibits the disruption of tight junctions, endothelial cell (EC) damage, and increased permeability, accompanied by neuroinflammation, oxidative stress, and abnormal molecular signaling pathways, leading to neurotoxic effects in the brain parenchyma and exacerbating neurodegeneration and disease progression. This review systematically summarizes the developmental origin, structural characteristics, and pathological mechanisms of BECs in diseases such as Alzheimer’s disease, multiple sclerosis, stroke, and glioblastoma with a particular focus on the regulatory mechanisms of the Wnt/β-catenin and VEGF signaling pathways. By integrating the latest research advances, this review aims to provide a comprehensive perspective for understanding the role of BECs in physiological and pathological states and to provide a theoretical basis for the development of BBB-based therapeutic approaches for neurological diseases. Full article

The brain accounts for about 2% of the body’s weight, but it consumes about 20% of the body’s energy at rest, primarily derived from ATP produced in mitochondria. The brain thus has a high mitochondrial density in its neurons because of its extensive energy demands for maintaining ion gradients, neurotransmission, and synaptic activity. The brain is also extremely susceptible to damage and dysregulation caused by inflammation (neuroinflammation) and oxidative stress. Many systemic challenges to the brain can be mitigated by the phytochemical sulforaphane (SF), which is particularly important in supporting mitochondrial function. SF or its biogenic precursor glucoraphanin, from broccoli seeds or sprouts, can confer neuroprotective and cognitive benefits via diverse physiological and biochemical mechanisms. SF is able to cross the blood–brain barrier as well as to protect it, and it mitigates the consequences of destructive neuroinflammation. It also protects against the neurotoxic effects of environmental pollutants, combats the tissue and cell damage wrought by advanced glycation end products (detoxication), and supports healthy glucose metabolism. These effects are applicable to individuals of all ages, from the developing brains in periconception and infancy, to cognitively, developmentally, and traumatically challenged brains, to those in later life as well as those who are suffering with multiple chronic conditions including Parkinson’s and Alzheimer’s diseases. Full article

Detailed research analysis of the contents of eight toxic trace elements in non-cereal flours was conducted using inductively coupled plasma mass spectrometry, and the release of elements from the flour matrixes after in vitro digestion was investigated. It also examines dietary intake and evaluates the metal pollution index. The highest digestibility value was measured with banana flour (92.6%), while grape seed flour was the least digestible, only 44%. The most abundant element was Al, followed by Ni, which was present (except banana flour) at concentrations of more than twice that found in food generally. The flax and milk thistle seed flours showed two orders of magnitude higher amounts of Cd than those measured in other flours. When consuming a 100 g portion of non-cereal flours, a consumer weighing 60 kg is exposed to the highest dietary exposures to Al and Ni (in the order of µg/kg bw); the exposures for the intake of Cd, Sn, Hg, As, Ag, and Pb are of the order of ng/kg bw. Grape seed flour was assessed as a significant contributor to the provisional tolerable weekly intake (PTWI) value of Al (16%); in addition, significant contributions of banana, pumpkin, grape, and milk thistle flours to the PTWI value of Hg, ranging from 15 to 22%, were determined. Furthermore, the contributions of milk thistle and flax seed flours to the provisional tolerable monthly intake (PTMI) value of Cd were also recognized as significant (specifically, 26 and 49%, respectively). The contributions of milk thistle, flax seed, and pumpkin seed flour to tolerable daily intake for Ni were estimated between 19 and 57%. The margin of exposure values for developmental neurotoxicity, nephrotoxicity, and cardiovascular effects obtained for the intake of Pb were considered safe. During the digestion process, the toxic elements that were the most retained in the matrices of grape and pumpkin seed flour were easily released from the banana flour. The retention factor, which was above 50% for Hg in the grape seed flour, was examined as the highest. All toxic trace elements, which were found to still be part of the undigested portion of the flours, could theoretically pass into the large intestine. In the future, more research is needed to clarify the possible carcinogenesis effect of toxic trace elements in the colon. Full article

Background/Objectives: Anticancer research is a constantly evolving field due to cancer’s complexity and adaptability. This study aims to evaluate the hemolytic behavior and cytotoxic properties of ten 3,3-dichlorolactams against A431 tumor and 3T3 fibroblast cells, with a particular focus on their selective toxicity. Methods: To achieve this, we assessed the hemocompatibility and cytotoxic effects of the lactams, determining their impact on cell viability through MTT and NRU assays. Additionally, AO/EtBr double staining was used to confirm apoptosis as a mechanism of cell death. To complement the in vitro findings, in vivo experiments were conducted using Zebrafish embryos to evaluate acute, developmental, and neurotoxic effects. Results: The results demonstrated that all lactams were hemocompatible, with the cytotoxicity influenced mainly by their structure and the tested concentration. β-Lactam 1 was the most efficient in inducing selective toxicity against A431 cells, showing the lowest IC₅₀ values (71 μg/mL and 210 μg/mL (MTT) and 35 μg/mL and >250 μg/mL (NRU) for A431 and 3T3 cell lines, respectively), with SI values close to 3 and >7. Moreover, cell death induction through apoptosis was confirmed by AO/EtBr double staining. Finally, despite its lower acute toxicity compared to other anticancer agents, the in vivo experiments revealed that 1 induced developmental toxicity and neurotoxic effects in Zebrafish embryos at concentrations lower than those affecting A431 cancer cells. Conclusions: the study highlights the potential of β-lactam derivatives as promising anticancer agents while emphasizing the need for comprehensive safety assessments. Future research should further explore structural modifications to enhance efficacy and specificity while minimizing adverse effects. Full article

Prenatal alcohol exposure (PAE) affects around 40,000 newborns every year and poses a significant health risk. Although much is already known about the neurotoxic mechanisms of PAE, new findings continue to emerge. Studies with mouse models show that PAE leads to overexpression of proinflammatory cytokines and chemokines in the brain, which disrupts important neurodevelopmental processes such as cell migration, survival and proliferation of neurons. The chemokine CXCL16 is overexpressed in the brain following various impairments, including PAE. This study shows that CXCL16 expression varies by developmental stage and sex, consistent with known sexual dimorphism in immune responses. In females, CXCL16 expression may be influenced by estrogen-related mechanisms, possibly related to the alcohol-mediated rebound effect described here. In contrast, the male hippocampus shows greater resilience to PAE-induced CXCL16 changes. Furthermore, the presence of CXCL16 in neuronal nuclei suggests a role in gene regulation, similar to other chemokines such as CCL5 and CXCL4. These findings shed light on the role of chemokines in hippocampal neuroplasticity and may pave the way for better treatment of fetal alcohol spectrum disorder (FASD). Full article

Polybrominated biphenyls (PBBs) are commonly used flame retardants that pose severe risks to humans. However, there is a lack of systematic research on the transformation process and biological toxicities of PBBs in the environment, which is not conducive to the prevention and control of pollution risks of PBBs. Therefore, the transformation pathways (i.e., photodegradation, microbial degradation, combustion oxidation, and in vivo metabolism) of PBBs and previously designed PBB substitutes were deduced first. Then the potential rodent carcinogenicity, rodent toxicity, mutagenicity, developmental toxicity, skin and eye irritation, skin sensitization, and aquatic toxicity of the transformation products were evaluated using the toxicokinetics (TOPKAT) model. Finally, 3D quantitative structure activity relationship (3D-QSAR) models were constructed to assess the human toxicity (i.e., carcinogenicity, developmental toxicity, hepatotoxicity, epigenetic toxicity, neurotoxicity, and immunotoxicity) of PBBs, PBBs substitutes, and their transformation products. Results showed that the transformation products of PBBs and their substitutes exhibit high toxicity risks (i.e., potential carcinogenicity, mutagenicity, and developmental toxicity) to organisms. The D3-A1 molecule had the highest carcinogenic risk probability at 0.826. The dihydroxy metabolite 2,2′-OH-PBB-80 of the PBB-80 molecule presented the highest potential developmental toxicity risk (toxicity probability 0.713). Polybrominated dibenzofuran (PBDF) showed the strongest skin irritation (probability 0.995). The combustion oxidation products of PBBs exhibited higher potential ecological and human health risks than other transformation products. Among potential toxicity risks to humans, the developmental toxicity of the transformation products of PBBs and their substitutes was theoretically significant, with characterization values ranging from 70.53 to 100.87. This is the first study to comprehensively evaluate the ecological and human health risks of PBBs and their transformation products by combining the inference of transformation pathways with the prediction of transformation product toxicities, providing theoretical support for the design of environmentally friendly PBB substitutes in future studies. Full article

Volcanoes, during their explosive and post-explosive phases, as well as through continuous degassing processes, release a range of pollutants hazardous to human health, including toxic gases, fine particulate matter, and heavy metals. These emissions impact over 14% of the global population living in proximity to volcanoes, with effects that can persist for days, decades, or even centuries. Living conditions in these regions often involve chronic exposure to contaminants in the air, water, and soil, significantly increasing the risk of developing neurological disorders. Prolonged exposure to elements such as lead (Pb), mercury (Hg), and cadmium (Cd), among others, results in the accumulation of metals in the brain, which increases oxidative stress and causes neuronal damage and severe neurotoxicity in animals. An examination of metal accumulation in brain cells, particularly astroglia, provides valuable insights into the developmental neurotoxicity of these metals. Moreover, microglia may activate itself to protect from cytotoxicity. In this review, we consider the implications of living near an active volcano for neurotoxicity and the common neurodegenerative diseases. Additionally, we encourage governments to implement public health strategies and mitigation measures to protect vulnerable communities residing near active volcanoes. Full article

Copper (Cu) is a global environmental pollutant that poses a serious threat to humans and ecosystems. Copper induces developmental neurotoxicity, but the underlying molecular mechanisms are unknown. Neurons are nonrenewable, and they are unable to mitigate the excessive accumulation of pathological proteins and organelles in cells, which can be ameliorated by autophagic degradation. In this study, we established an in vitro model of Cu²⁺-exposed (0, 15, 30, 60 and 120 μM) SH-SY5Y cells to explore the role of autophagy in copper-induced developmental neurotoxicity. The results showed that copper resulted in the reduction and shortening of neural synapses in differentiated cultured SH-SY5Y cells, a downregulated Wnt signaling pathway, and nuclear translocation of β-catenin. Exposure to Cu²⁺ increased autophagosome accumulation and autophagic flux blockage in terms of increased sequestosome 1 (p62/SQSTM1) and microtubule-associated protein 1 light chain 3B (LC3B) II/LC3BI expressions and inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway. Furthermore, copper induced apoptosis, characterized by increased expressions of Bcl2 X protein (Bax), caspase 3, and Poly (ADP-ribose) polymerase (PARP) and decreased expression of B-cell lymphoma 2 (Bcl2). Compared with the 120 μM Cu²⁺ exposure group alone, autophagy activator rapamycin pretreatment increased expression of Wnt and β-catenin nuclear translocation, decreased expression of LC3BII/LC3BI and p62, as well as upregulated expression of Bcl2 and downregulated expressions of caspase 3 and PARP. In contrast, after autophagy inhibitor chloroquine pretreatment, expressions of Wnt and β-catenin nuclear translocation were decreased, expression levels of LC3BII/LC3BI and p62 were upregulated, expression of Bcl2 was decreased, while expression levels of caspase 3, Bax, and PARP were increased. In conclusion, the study demonstrated that autophagosome accumulation and autophagic flux blockage were associated with copper-induced developmental neurotoxicity via the Wnt signaling pathway, which might deepen the understanding of the developmental neurotoxicity mechanism of environmental copper exposure. Full article