Search Results (124)

Microplastics (MPs) and antibiotics have emerged as contaminants of global concern, posing potential threats to ecosystem security and organismal health. To investigate the individual and combined toxicity of microplastics (PS-MPs) and sulfamethoxazole (SMX), we conducted a 120 h acute exposure experiment using embryo–larval zebrafish as a toxicological model. Our findings demonstrate that both PS-MPs and SMX can induce neurodevelopmental toxicity in embryo–larval zebrafish during embryonic development. Notably, PS-MPs and SMX exerted a significant synergistic effect. PS-MPs 1 µm in diameter were restricted to the chorion surface of pre-hatching zebrafish, whereas post-hatching, PS-MPs accumulated mainly in the gut and gills, with accumulation levels increasing progressively with exposure duration. Individual exposure to PS-MPs or SMX reduced spontaneous locomotion, decreased heart rate, and shortened body length in embryo–larval zebrafish. In addition to exacerbating these effects, coexposure further increased the incidence of malformations such as pericardial effusion and spinal curvature. PS-MPs and SMX significantly decreased the levels of dopamine (DA), serotonin (5-HT), and γ-aminobutyric acid (GABA) in zebrafish while also suppressing acetylcholinesterase (AChE) activity and increasing acetylcholine (ACh) levels. Moreover, upon coexposure at high concentrations, PS-MPs and SMX acted synergistically to reduce the levels of DA and GABA. The downregulation of key neurodevelopmental genes (elavl3, gap43, and syn2a) and related neurotransmitter pathway genes indicates that PS-MPs and SMX impaired structural development and functional regulation of the nervous system. An integrated biomarker response (IBR) index confirmed that PS-MPs and SMX significantly enhanced developmental neurotoxicity during early neurodevelopment in embryo–larval zebrafish through synergistic effects. Our study provides critical toxicological evidence for the scientific assessment of the ecological risks posed by microplastic–antibiotic cocontamination. Full article

Early exposure to toxic metals is a growing concern due to its potential neurodevelopmental effects in children. This study investigates whether exposure to multiple metals during pregnancy influences early developmental outcomes in children aged 12–18 months living in a metropolitan setting. We conducted a prospective cohort study in Rio de Janeiro that included 393 children from PIPA project. Umbilical cord blood samples obtained at birth were processed using ICP-MS (Inductively Coupled Plasma Mass Spectrometry) to quantify metals (arsenic, lead and mercury). The children’s neurodevelopment was assessed with the Denver-II tool. We applied logistic regression analyses to explore the relationship between metal concentrations and developmental outcomes, controlling for possible confounding variables. Higher prenatal arsenic levels were linked to poorer gross motor performance, both in continuous models (OR = 1.65; 95% CI: 1.09–2.51) and in subjects with concentrations above the 95th percentile (OR = 8.84; 95% CI: 2.40–32.61), this was consistent across multi-metal models. A negative relationship between Pb concentrations and gross motor delays was observed, with an estimated Odds Ratio of 0.49 (95% CI: 0.24–0.98). Hg exposure demonstrated no association with neurodevelopment in any model. However, the lack of postnatal arsenic exposure data limits the distinction between prenatal and early childhood effects. These findings underscore the need for the continued monitoring and investigation of combined metal exposures during pregnancy. Future studies integrating prenatal and postnatal exposure assessments are warranted. Full article

Polystyrene nanoplastics (PS-NPs) can cross the placenta and blood–brain barrier to accumulate in the fetal brain following inhalation or ingestion, raising concerns about PS-NPs-induced developmental neurotoxicity (DNT). However, current evidence regarding the mechanisms underlying PS-NPs-elicited DNT remains critically scarce. Given the inherent limitations of two-dimensional cell culture techniques, we employed a whole-brain organoid (WBO) model, which more faithfully recapitulates the dynamic changes and substantial alterations during the early development of the human nervous system, to investigate the PS-NPs-induced DNT. Developing WBOs were exposed to 50-nm PS-NPs at concentrations of 50 and 100 μg/mL. Additionally, we established an early developmental exposure model in neonatal rat for robust validation. The results revealed aberrant formation of the tissue architecture of neural epithelial buds in PS-NPs-exposed WBOs, accompanied by significant inflammatory responses and oxidative stress. Marked DNA damage and substantial activation of the TLR9/MyD88 pathway were observed in WBOs and in the cerebral cortex of neonatal rat, leading to significant upregulation of the excitotoxicity marker c-Fos and the excitatory synaptic marker NMDAR. In vitro assays revealed that melatonin treatment could efficiently counteract PS-NPs-mediated neuronal impairment, with both the reduced cell viability and excessive DNA damage induced by PS-NPs being restored to levels close to those of the control group. In conclusion, by establishing WBOs and early developmental exposure models in neonatal rat, we found that PS-NPs can induce DNA double-strand breaks, and activation of the TLR9 pathway mediates PS-NPs-induced excitotoxicity. Full article

Michler’s Ketone (MK) is widely utilized as an additive in pigments, dyes, and other colorants, and has become a non-negligible environmental presence. Currently, environmental monitoring data and toxicity data for MK are extremely limited, and its specific mechanisms of neurotoxicity remain poorly characterized. A zebrafish model was employed to systematically delineate the neurotoxic mechanisms of MK through the integration of network toxicology predictions, transcriptomic profiling, and RT-qPCR validation. The results demonstrated that MK exposure was found to induce oxidative stress in zebrafish larvae, which subsequently disrupted the calcium signaling pathway and triggered apoptosis, ultimately leading to neurodevelopmental and locomotor behavioral impairments. This study provides a fundamental basis for elucidating MK’s developmental neurotoxicity mechanisms, while also holding significant value for its ecological risk assessment. Full article

White-matter development during fetal life represents one of the most vulnerable processes to environmental disruption, as it relies on the precisely timed proliferation, migration, and differentiation of oligodendrocyte lineage cells. Among environmental threats, exposure to toxic compounds contained in tobacco smoke and vaping aerosols represents a major yet preventable risk during pregnancy. Despite growing awareness, tobacco smoking remains widespread, and a substantial proportion of the population—including pregnant women—continues to perceive electronic nicotine delivery systems (ENDS) as less harmful, a misconception that contributes to persistent prenatal exposure. These products expose the fetus to numerous substances that readily cross the placenta and reach the developing brain, including compounds with endocrine-disrupting activity, where they interfere with white-matter development. Epidemiological and neuroimaging studies consistently reveal microstructural alterations in white matter that correlate with long-term cognitive and behavioral impairments in offspring exposed in utero. These alterations may arise from both nicotine-specific pathways and the actions of other toxicants in cigarette smoke and ENDS aerosols that cross the placenta and disrupt white-matter emergence and maturation. Preclinical research provides mechanistic insight: nicotine acts directly on nicotinic acetylcholine receptors (nAChRs) in oligodendrocyte precursor cells, disrupting calcium signaling and differentiation, while additional constituents of smoke and vaping aerosols also affect astrocyte and microglial function and disturb the extracellular milieu required for proper myelination. Full article

Lead (Pb) disrupts mitochondrial function, but its impact on the mitochondrial dynamics and biogenesis during early brain development remains insufficiently understood. This study aimed to investigate the effects of pre- and neonatal Pb exposure on the processes involved in mitochondrial network formation in the brains of rat offspring, simulating environmental exposure. We quantified mRNA expression (qRT-PCR) and protein levels (ELISA) of key mitochondrial fusion (Mfn1, Mfn2, Opa1), fission (Drp1, Fis1) regulators, as well as biogenesis markers (PGC-1α, TFAM, NRF1) in the hippocampus, forebrain cortex, and cerebellum of rats exposed to Pb. Mitochondrial ultrastructure was evaluated using transmission electron microscopy (TEM), and the expression of mitochondrial electron transport chain (ETC) genes was analysed (qRT-PCR). Furthermore, to examine the involvement of the cGAS–STING pathway in Pb-induced neuroinflammation, we measured the expression of ISGs (qRT-PCR), TBK1 phosphorylation (Western blot), and 2′,3′-cGAMP synthesis (ELISA). Our results showed that Pb exposure markedly reduced PGC-1α and region-specific NRF1 levels, broadly supressed fusion proteins (Mfn1, Mfn2, Opa1), increased Fis1, and depleted Drp1. ETC gene expression (mtNd1, mtCyb and mtCo1) were upregulated in a brain-structure-dependent manner. These molecular changes were accompanied by pronounced mitochondrial morphological abnormalities. Despite upregulation of Mx1, Ifi44, and Sting1, along with synthesis of 2′3′-cGAMP, TBK1 activation was not detected. All these findings demonstrate that early-life Pb exposure, even low-dose, disrupts mitochondrial biogenesis and the fusion–fission machinery, thus impairs brain energy homeostasis, and implicates mitochondria as central mediators of Pb-induced neuroinflammation and neurodevelopmental toxicity. Full article

Fetal exposure to toxic metals is a major public health concern, yet the contribution of intrauterine blood transfusion (IUBT) to this exposure remains unclear. This prospective cohort study assessed mercury, cadmium, lead, and arsenic levels in maternal blood, cord blood, and residual IUBT red blood cell (RBC) units from 90 pregnant women enrolled at King Faisal Specialist Hospital & Research Centre. Metals were detected in nearly all maternal and cord blood samples and in every transfusion bag, with several measurements exceeding established benchmark values. Higher maternal mercury and combined mercury–arsenic levels were suggestively associated with small reductions in personal–social scores (approximately −3% to −5%). Elevated cord mercury, arsenic, and combined mercury–arsenic–cadmium levels were associated with modest decreases in problem-solving performance. Increased mercury and mercury–arsenic concentrations in transfused RBCs were linked to lower gross motor scores. Overall, these patterns indicate a potential contribution of IUBT-related metals to fetal exposure, although effect sizes were small. These preliminary findings highlight the importance of monitoring metal content in transfusion materials and reinforce the need for larger studies to clarify their clinical relevance. Full article

Total ammonia nitrogen (TAN) is a common and potent neurotoxic pollutant in aquatic environments. Due to their strong adsorption capacity, titanium dioxide nanoparticles (n-TiO₂), a widely used engineered material, can induce combined toxicity with multiple pollutants. However, the combined neurotoxicity of n-TiO₂ and TAN and its underlying mechanisms remain unclear. In this study, zebrafish embryos were exposed to TAN (0, 0.1, 1, 10 mg/L) and n-TiO₂ (100 µg/L) individually or in combination for 120 h. The results indicated that co-exposure to n-TiO₂ and TAN significantly increased the bioaccumulation of TAN in zebrafish embryos compared to TAN alone. Consequently, this led to exacerbated neurotoxicity, manifested as developmental impairments and abnormal motor behavior. Mechanistic investigations revealed that the co-exposure aggravated developmental neurotoxicity by triggering neuronal apoptosis and oxidative stress, disrupting the cholinergic and dopaminergic systems, and impairing neural and retinal development. Transcriptomic analysis further indicated that the co-exposure predominantly perturbed neurodevelopment, oxidative stress, and apoptosis. In conclusion, this study confirms that n-TiO₂ significantly amplifies TAN-induced neurodevelopmental toxicity by promoting its bioaccumulation and synergistically disrupting multiple neurophysiological processes. These findings provide crucial scientific evidence for assessing the combined ecological risks of nanomaterials and conventional pollutants. Full article

Plastic production and subsequent environmental contamination have increased substantially in recent decades, resulting in pervasive human exposure to microplastics (MPs), nanoplastics (NPs), and plastic-associated additives such as bisphenols and phthalates. These substances are known to induce toxic effects via multiple biological mechanisms, including oxidative stress, inflammation, apoptosis, immune system disruption, and genotoxicity. While exceptions exist, current research generally indicates that these exposures may adversely affect fertility. Notably, children constitute the most vulnerable demographic due to behavioral tendencies, higher intake-to-body-weight ratios, underdeveloped detoxification systems, and critical developmental periods of susceptibility. Evidence demonstrates that exposure commences in utero, with MPs, NPs, and additives identified in placental tissue, amniotic fluid, cord blood, and meconium—factors associated with impaired fetal growth and reduced gestational duration. After birth, additional exposure occurs through diet, inhalation, household dust, feeding equipment, toys, and consumer products. Experimental and epidemiological studies suggest that plastics may adversely affect multiple physiological systems. Reported outcomes include altered pubertal development, reduced fertility, neurodevelopmental abnormalities, respiratory diseases such as asthma, and increased risks of metabolic disorders, including obesity and insulin resistance. However, substantial knowledge gaps remain: the relative toxicity of different polymers and additives, dose–response relationships, critical exposure periods, and long-term consequences are not yet fully defined. Given growing concern and mounting evidence of harm, precautionary measures are warranted. Reducing nonessential plastic use, strengthening regulatory actions, improving product labeling, and promoting public awareness are urgent priorities, particularly in vulnerable and resource-limited communities. Further mechanistic studies and longitudinal human research are essential to clarify health risks, guide safer material substitutions, and inform evidence-based policies aimed at protecting children from avoidable plastic-related toxicity. Full article

Guanidinoacetate Methyl Transferase (GAMT) deficiency is a rare disease characterized by neurodevelopmental derangements, epilepsy, and movement disorders. The condition arises from the combined effect of postnatal brain creatine (Cr) depletion and guanidinoacetate (GAA) toxicity. Consequently, current treatment relies on Cr supplementation and metabolic management to reduce GAA accumulation by limiting its synthesis through ornithine supplementation and precursor reduction. Although effective in preventing the severe GAMT phenotype, the therapy is limited in normalizing these metabolites’ concentrations. Recently, interest has been growing in approaches aimed at restoring the mutant enzyme as the primary step toward a cure. Some of these approaches have been investigated at the preclinical level and are here summarized. Interestingly, a mouse model that replicates most of the patients’ features is now available in various labs, and the strong commitment of the Association for Creatine Deficiency has fostered the coordination and support of many of these models’ initiatives. This review introduces readers to the complexity of this ultrarare condition, describes current therapeutic approaches, provides information about the most accurate methods for an early diagnosis, and outlines the main features of the available animal models. Finally, some current preclinical investigations are described, along with some preliminary expectations of emerging data. Full article

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin–proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal development and wellbeing. Herein, the involvement of the UPS/autophagy system in the regulation of intracellular signaling pathways related to toxic protein accumulation was investigated in cellular/mice AS models, silenced for UB3A (UB3A⁻). The main findings are as follows: (i) autophagy was upregulated in UBE3A⁻ cells with respect to control cells; (ii) a dysregulation of the AKT/mTOR pathway, linked to autophagy/synaptic development, was evidenced in cellular/animal models of AS with respect to controls; (iii) the ubiquitin ligase MDM2 was downregulated, and the tumor suppressor p53, normally inhibited by MDM2, enhanced its expression and transcriptional activity in UB3A⁻ cells with respect to controls. Finally, UB3A⁻ cells presented a significant alteration in the levels of β-amyloids with respect to control cells, and a reduction of α-synuclein levels, typical of neurodevelopmental disorder. Nevertheless, UB3A⁻ cells do not show evident morphological abnormalities. Overall, these data suggest that AS models presented an altered signaling pathway related to autophagy/UPS systems, potentially leading to the accumulation of toxic proteins affecting synaptic development. Full article

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with neurodevelopmental toxicity, yet the effects of exposure during adolescence and adulthood remain underexplored. This scoping review evaluates the neurotoxic outcomes of post-weaning PCB exposure in rodent models. A comprehensive literature search was conducted across PubMed, Embase, and Scopus. Studies were screened according to PRISMA guidelines. Articles were included if they reported neurotoxic or behavioral outcomes in mice or rats exposed to PCBs during post-weaning stages. Thirty-five studies met the inclusion criteria, encompassing a variety of PCB congeners and mixtures administered via oral, inhalation, or intraperitoneal routes. Reported neurotoxic outcomes included histological and morphological brain changes, oxidative stress, disrupted calcium signaling, altered neurotransmitter systems, apoptosis, and gene expression alterations. These outcomes were assessed using diverse methodological approaches, including immunohistochemistry, biochemical assays, and gene expression profiling. Behavioral outcomes affected by PCB exposure included locomotion, anxiety-like behavior, learning and memory, motor coordination, and cognitive flexibility. Effects were often exposure-specific and sex-dependent, with limited female-focused studies and integrative molecular-behavioral assessments. These findings highlight the broad neurotoxic potential of PCBs following adolescent or adult exposure and underscore the need for further mechanistic, sex-specific research to inform health risk assessment and regulatory policy. Full article

Synchronized oscillatory fluctuations in intracellular calcium concentration across extended neuronal networks represent a functional indicator of connectivity and signal coordination. In this study, a model of human immature neurons (differentiated from LUHMES precursors) has been used to establish a robust protocol for generating reproducible intracellular Ca²⁺ oscillations in both two-dimensional monolayers and three-dimensional spheroids. Oscillatory activity was induced by defined ionic conditions in combination with potassium channel blockade. It was characterized by stable frequencies of approximately 0.2 Hz and high synchronization indices across millimeter-scale cultures. These properties were consistently reproduced in independent experiments and across laboratories. Single-cell imaging confirmed that oscillations were coordinated throughout large cell populations. Pharmacological interventions demonstrated that neither excitatory nor inhibitory chemical synaptic transmission influenced oscillatory dynamics. Gap junction blockers completely disrupted synchronization, while leaving individual cell activity unaffected. Functional dye-transfer assays provided additional evidence for electrical coupling. This was further supported by connexin-43 expression profiles and immunostaining. Collectively, these findings indicate that synchronized Ca²⁺ oscillations in LUHMES cultures are mediated by gap junctional communication rather than by conventional synaptic mechanisms. This system offers a practical platform for studying fundamental principles of network coordination and for evaluating pharmacological or toxicological modulators of intercellular coupling. Moreover, it may provide a relevant human-based model to explore aspects of neuronal maturation and to assess compounds with potential neurodevelopmental toxicity. Full article

Background/Objectives: This article aims to investigate the multifaceted effects of alcohol on neurophysiopathological development from gestational stages through adult life and the consequent dynamic-relational challenges in individuals with Fetal Alcohol Spectrum Disorder (FASD). FASD, resulting from prenatal alcohol exposure (PAE), is characterized by a range of neurological, cognitive, behavioral, and sometimes physical impairments. This article explores how alcohol and its toxic metabolites cross the placenta, inducing direct cellular toxicity and epigenetic alterations that disrupt critical neurodevelopmental processes such as neurogenesis and brain circuit formation. Clinically, individuals with FASD exhibit diverse deficits in executive functioning, learning, memory, social skills, and sensory-motor abilities, leading to significant lifelong disabilities. A central focus is the application of the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) criteria to comprehensively frame these disabilities. The ICF’s biopsychosocial model allows for a multidimensional assessment of impairments in body functions and structures, limitations in activities, and restrictions in participation, while also considering the crucial role of environmental factors. Methods: PubMed and Semantic Scholar databases were searched for relevant papers published in English. Results: This article highlights the utility of the ICF in creating individualized functioning profiles to guide interventions and support services, addressing the limitations of traditional assessment methods. Conclusions: While the ICF framework offers a robust approach for understanding and managing FASD, further research is essential to develop and validate FASD-specific ICF-based assessment tools to enhance support and social participation for affected individuals. Full article

Both basic and preclinical research, as well as the development of new therapies, require tools that allow for the selective labelling of specific cell types and the targeted delivery of drugs. The developed tools must then be validated in biological systems. In view of the lack of effective therapies for many neurodevelopmental disorders, including neonatal brain injuries, we decided to use the newly described, innovative SPAchips^® (a4cell, Pozuelo de Alarcón, Spain) tool and test it in labelling neonatal rat neural cells. In our studies, rat primary cultures of neurons and glial cells (astrocytes, oligodendrocytes, and microglia) were incubated with different concentrations of SPAchips^®. At selected time points, uptake of the tested microchips by particular cell types was assessed using lineage-specific antibodies and visualized using a confocal microscope. Additionally, the potential cytotoxicity of added microparticles was verified, as was the possibility of microglia activation. The study indicates that the tested microdevices selectively label neonatal rat microglia and can be a useful tool for visualizing this cell type, as well as a non-toxic tool for developing innovative strategies based on the functionalization of microparticles aimed at modulating neuroinflammatory processes. Full article