Identifying possible neurodevelopmental effects of per- and polyfluoroalkyl substances (PFAS) through an adverse outcome pathway (AOP) network for human developmental neurotoxicology.

In utero lead exposure and auditory neural myelination in premature infants.

The role of DNA methylation in alcohol-mediated neurodevelopmental toxicity.

Investigating the neurodevelopmental toxicity of graphene oxides using 3D human brain organoids and zebrafish models: emphasis on GABAergic neuron alterations at single-cell resolution.

5-Hydroxymethylfurfural triggers developmental toxicity and neurotoxicity in zebrafish larvae

The nematode perspective: Caenorhabditis elegans as a versatile biosensor for pesticide toxicity and mechanistic studies.

Developmental exposure to benzalkonium chloride induces defects in mechanosensory hair cells and nociceptive responses in zebrafish.

Neurodevelopmental toxicity induced by iron oxide nanoparticles: Insights from chick and zebrafish embryonic models.

This study aimed to evaluate the response mechanisms of zebrafish larvae to Norfloxacin nicotinate (NOR-N) exposure. Embryos were exposed to NOR-N from 4 h post-fertilization (hpf) until 96 hpf. The exposure concentrations included 0.002, 0.2, 1, and 5 mg/L (simulating both normal and exceptionally high environmentally relevant levels of NOR), as well as a high dose of 25 mg/L. Subsequent analyses focused on apoptosis, neurodevelopment, and DNA methylation in the resulting zebrafish larvae. The results showed that high-dose NOR-N (≥5 mg/L) induced obvious apoptotic cell death in zebrafish larvae, accompanied by increased activities of Cas3 and Cas9, up-regulated P53, Bax, Puma, Apaf1, Cas3 and Cas9 genes expression, and reduced Mdm2 levels and Bcl2/Bax ratio. Moreover, exposure to 5 and/or 25 mg/L NOR-N resulted in a significant up-regulation of neurodevelopment-related genes (Sox2, Sox3 and Sox19a), concomitantly with a marked decline in the transcription of DNA methylation genes, including Dnmt1, Dnmt3a1, Dnmt3b1, Dnmt3b2 and Dnmt3b4. Overall, our findings demonstrated that NOR-N exposure could induce apoptosis, developmental neurotoxicity and aberrant DNA methylation in zebrafish larvae. These findings provide insights to guide the safe application of NOR-N in aquaculture and support the assessment of its potential ecological risks to aquatic ecosystems.

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.

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.

Methylmercury (MeHg) is a global environmental pollutant notorious for its developmental neurotoxicity. Although many mechanisms of MeHg toxicity have been proposed, the precise molecular pathways remain incompletely understood. This study integrated population and cell models and utilized high-throughput transcriptomic screening of umbilical cord blood (UCB) and neuronal samples to identify differentially expressed genes associated with MeHg exposure. Subsequently, in vitro validation of the key mechanisms was performed. Omics data showed that differentially expressed genes in UCB from MeHg exposure are linked to mitophagy. Additionally, transcriptome sequencing of primary hippocampal neurons revealed the potential effects of MeHg on energy metabolism, indicating a mitochondrial mechanism that requires further investigation. Further in vitro mechanistic studies revealed that SIRT3/AMPK, key mediators of PINK1-dependent mitophagy, were activated by MeHg exposure. Notably, when PC12 cells were exposed to MeHg, SIRT3 was upregulated compensatorily. Our findings support a model in which MeHg-induced SIRT3 upregulation facilitates AMPKα (Thr172) phosphorylation via LKB1, suggesting that this pathway is associated with mitophagy activation, as evidenced by increased Beclin1 expression, LC3II/I conversion, and decreased p62 levels. Mitophagy was initiated as a defense response to remove damaged mitochondria and exogenous toxicants. Nevertheless, such successive cellular responses exacerbated mitochondrial stress, resulting in neuronal damage and synaptic underfeeding. Together, these results offer novel mechanistic insights into how SIRT3/AMPK-mediated mitophagy coordination regulates MeHg-induced neurotoxicity, providing potential therapeutic targets for developmental neurological disorders.

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.

Valproic acid (VPA), a commonly used treatment for epilepsy and psychiatric disorders, is associated with neurodevelopmental toxicity and an elevated risk of autism spectrum disorder (ASD). This study investigates the protective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR) agonist, against VPA-induced neurotoxicity in zebrafish larvae. Zebrafish embryos were exposed to VPA (50, 75, 100 μM) from 0.5-h postfertilization (hpf) to 120 hpf, with or without RGZ cotreatment. VPA exposure significantly reduced locomotor activity, evidenced by decreased swimming distance and velocity, and disrupted neurotransmitter homeostasis, with elevated norepinephrine and L-glutamic acid levels. Transcriptomic analysis and qRT-PCR revealed that VPA downregulated PPAR pathway genes (ppara, pparg, pck1, and fabp1), while RGZ cotreatment partially restored locomotor activity, normalized neurotransmitter levels, and rescued PPAR pathway gene expression. These findings demonstrate that RGZ mitigates VPA-induced neurotoxicity by activating PPAR signaling, restoring metabolic balance, and improving motor function, suggesting PPAR agonists as potential therapeutic agents for VPA-induced neurotoxicity and ASD-related deficits.

Human cell-based assays for neurotoxicity (NT) and developmental neurotoxicity (DNT) have reached a high level of readiness, but some tests require improvements in the specificity and sensitivity at which mitochondrial toxicants are detected. This study aimed to optimize the PeriTox assay, which uses peripheral neurons (PNs) and predicts the potential of chemicals to trigger peripheral neuropathies. By introducing a glucose-to-galactose switch in the medium composition, cells were forced to rely on mitochondrial respiration. Using pre-differentiated PNs cultured in either glucose (Glc) or galactose (Gal), we observed no major differences in baseline phenotype, gene expression, neurite outgrowth, or total ATP content. However, a marked metabolic shift was confirmed by the increased oxygen consumption in Gal conditions. Based on measurements of neurite growth and ATP levels, Gal-adapted neurons showed a heightened sensitivity, up to 7500-fold, to a range of mitochondrial respiratory chain (MRC) inhibitors. The sensitivity shift was high for inhibitors of MRC complexes I and III and modest or absent for unrelated compounds such as proteasome inhibitors or cytoskeletal poisons. For complex I-III inhibitors, the enhanced detection of mitochondrial neurotoxicants was coupled with a more accurate distinction between cytotoxic and neurite-specific effects, i.e., an improved assay specificity. In conclusion, our study on 39 compounds suggests that running the PeriTox assay in galactose increases its sensitivity and specificity for several mitochondrial toxicants, while no general disadvantages or shortcomings were observed. The modified version (PeriTox-M) may increase the performance of in vitro test batteries for scientific and regulatory applications.

Sevoflurane exposure in juvenile causes persistent learning and memory impairment via inducing endoplasmic reticulum stress in caenorhabditis elegans and mice.

Development of a multiplexed, high content imaging-based assay for assessing chemical effects on proliferation and apoptosis in human neural progenitor cells.

Placental transfer efficiency of metals and its association with cognitive development in offspring: Roles of placental inflammatory cytokines and oxidative stress markers.

Oxidative stress and retinal damage induced by cobalt chloride in Drosophila melanogaster: Insights into cone cell susceptibility and stress gene responses.

Prenatal BPB/BPAF exposure induces depression-like behavior in male mice offspring via compound-specific transcriptional dysregulation and neurodevelopmental pathway alterations.