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Neurodevelopmental disorders have been increasingly associated with maternal immune activation (MIA) during pregnancy, particularly in response to viral infections. However, the impact of human respiratory syncytial virus (hRSV) infection during gestation on offspring neurodevelopment remains poorly understood. This study aimed to characterize hRSV-induced MIA and evaluate its effects on fetal brain development and offspring behavior using a murine model. Pregnant mice were infected with hRSV at gestational day 14, and tissues were analyzed at day 19. Infection induced pulmonary inflammation, evidenced by increased neutrophil infiltration, and viral replication was detected in maternal lungs and placental tissue, but not in fetal organs. Placental infection was associated with increased decidual immune cells and a shift toward a pro-inflammatory cytokine profile, including elevated IL-6, TNF-α, IFN-γ, and IL-1β, along with decreased IL-10 and IFN-λ. Increased levels of IL-6, TNF-α, and IL-4 were also detected in maternal serum and fetal brains, suggesting vertical transfer of cytokines. Additionally, reduced brain-derived neurotrophic factor levels and altered expression of tight junction-related genes were observed in fetal brains. Behavioral analyses revealed that offspring of infected dams exhibited impaired short-term memory and altered anxiety-like and repetitive behaviors, which persisted or intensified with age. These findings demonstrate that maternal hRSV infection induces MIA, disrupts the fetal neuroimmune environment, and leads to long-term behavioral alterations in offspring, highlighting hRSV as a potential risk factor for neurodevelopmental disorders. Show less

Phthalates are well-known emerging contaminants in the environment and food packaging, posing serious risks to human health as endocrine disruptors with significant neurotoxic potential. Epidemiological and experimental evidence have linked early-life phthalate exposure to neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the precise molecular mechanisms responsible for these associations remain poorly understood. This study aimed to comprehensively investigate the putative toxic targets and molecular pathways underlying phthalate-induced ADHD and ASD through integrated network toxicology and molecular docking approaches. Targets related to phthalates, ADHD, and ASD were extracted from various databases, yielding 21 potential targets associated with ADHD and ASD, which are common to the studied phthalates. Network analysis highlighted BDNF and ESR1 as the top two core targets. Functional enrichment analyses demonstrated that the core targets are involved in multiple pathways. Furthermore, the GEO database was queried to identify differentially expressed genes (DEGs) and gene modules through Weighted Gene Co-expression Network Analysis (WGCNA) using the R package. Moreover, molecular docking demonstrated high binding affinity between phthalates and core targets, with di(2-ethylhexyl) phthalate with BDNF and diisononyl phthalate with ESR1, emphasizing the potential role of phthalate exposure in neurodevelopmental disorders. The stability of these complexes was demonstrated through molecular dynamics simulations, which confirmed their binding interactions remained constant throughout the simulation. Our findings contribute to a deeper understanding of the intricate molecular mechanisms of phthalate-induced neurotoxicity, offering a valuable foundation for the development of future therapeutic strategies to mitigate their adverse effects on neurodevelopment. Show less

Maternal immune activation (MIA) is a key environmental risk factor for neurodevelopmental disorders such as schizophrenia. MicroRNAs are critical regulators of brain development, yet their role in MIA-induced pathology remains unclear. We found that miR-322-5p was significantly upregulated in the prefrontal cortex of MIA-exposed offspring and directly targeted the 3' untranslated region of brain-derived neurotrophic factor (BDNF), inhibiting its expression. This upregulation impaired BDNF/TrkB/AKT signaling and reduced the synaptic protein PSD95, leading to hypoactivity, cognitive deficits, social impairments, and disrupted sensorimotor gating. Inhibition of miR-322-5p or overexpression of BDNF in the prefrontal cortex restored signaling and reversed both behavioral and molecular abnormalities. These results identify miR-322-5p as a key mediator of MIA-induced neuropathology via repression of BDNF signaling and suggest its potential as a therapeutic target in neurodevelopmental disorders. Show less

Human studies have reported inconsistent associations between early-life exposure to per- and polyfluoroalkyl substances (PFAS), particularly during critical windows of brain development, and neurodevelopmental outcomes. To address the lack of clarity regarding how PFAS affect neurodevelopment, this study developed the first unified adverse outcome pathway (AOP) network to explore the mechanisms involved in developmental neurotoxicity (DNT). Of 343 AOPs retrieved from AOP-Wiki, 19 linear AOPs associated with DNT satisfied the inclusion criteria. To pinpoint critical nodes and relationships, the constructed DNT-AOP network was examined using topological metrics. Through a combination of qualitative weight of evidence (WoE) assessment and network topology analysis, two critical paths were identified: one based on thyroid hormone disruption and the other on the intracellular calcium (Ca Show less

Axon growth is an essential cellular process during neural development, and its dysregulation contributes to numerous neurodevelopmental disorders. During axon growth, extracellular signals direct neurons to extend projections that connect with their synaptic targets. Paxillin is a key member of adhesion sites that control motility by linking the intracellular actin cytoskeleton to the extracellular matrix. Paxillin also binds to the cytoskeletal protein, tubulin. However, little is known about the role of adhesion proteins in neurons. Here, we use conditional paxillin knockout mice to investigate how loss of paxillin in pyramidal cortical neurons affects developing neuron morphology. Surprisingly, loss of paxillin in pyramidal cortical neurons caused no change in axon length or soma area between control ( Show less