Early-Life Exposure to Paraquat Aggravates Sex-Specific and Progressive Abnormal Non-Motor Neurobehavior in Aged Mice.

Early-life exposure to environmental neurotoxicants is known to have lasting effects on organisms. In this study, we aim to investigate the impacts of PQ exposure during early developmental stages and adult re-challenge in aged mice on non-motor neurobehavior. Two mouse models, which were exposed once during early life stage and re-exposure at adulthood, were created to explore the long-term effects of PQ on non-motor neurobehavior. As the results showed, early-life exposure to PQ caused impairment in working memory and cognitive ability in aged male mice, but not in female mice, exhibiting a sex-specific impairment. Moreover, male mice that were re-challenged with PQ at adulthood following early-life exposure also exhibited non-motor neurobehavioral disorders. Notably, re-exposure to PQ exacerbated neurobehavioral disorders and anxiety levels compared to single exposure during different life stages. Collectively, early-life exposure to PQ can result in irreversible impairments in non-motor neurobehavior and increase susceptibility to subsequent insults in male mice, but not in female mice, suggesting greater sensitivity in male rodents to PQ-induced non-motor neurobehavioral deficits.

Paraquat-induced neurogenesis abnormalities via Drp1-mediated mitochondrial fission.

Neurogenesis is a fundamental process in the development and plasticity of the nervous system, and its regulation is tightly linked to mitochondrial dynamics. Imbalanced mitochondrial dynamics can result in oxidative stress, which has been implicated in various neurological disorders. Paraquat (PQ), a commonly used agricultural chemical known to be neurotoxic, induces oxidative stress that can lead to mitochondrial fragmentation. In this study, we investigated the effects of PQ on neurogenesis in primary murine neural progenitor cells (mNPCs) isolated from neonatal C57BL/6 mice. We treated the mNPCs with 0-40 µM PQ for 24 h and observed that PQ inhibited their proliferation, migration, and differentiation into neurons in a concentration-dependent manner. Moreover, PQ induced excessive mitochondrial fragmentation and upregulated the expression of Drp-1, p-Drp1, and Fis-1, while downregulating the expression of Mfn2 and Opa1. To confirm our findings, we used Mdivi-1, an inhibitor of mitochondrial fission, which reversed the adverse effects of PQ on neurogenesis, particularly differentiation into neurons and migration of mNPCs. Additionally, we found that Mito-TEMPO, a mitochondria-targeted antioxidant, ameliorated excessive mitochondrial fragmentation caused by PQ. Our study suggests that PQ exposure impairs neurogenesis by inducing excessive mitochondrial fission and abnormal mitochondrial fragmentation via oxidative stress. These findings identify mitochondrial fission as a potential therapeutic target for PQ-induced neurotoxicity. Further research is needed to elucidate the underlying mechanisms of mitochondrial dynamics and neurogenesis in the context of oxidative stress-induced neurological disorders.

Single-cell transcriptomic analysis reveals the adverse effects of cadmium on the trajectory of neuronal maturation.

Cadmium (Cd) is an extensively existing environmental pollutant that has neurotoxic effects. However, the molecular mechanism of Cd on neuronal maturation is unveiled. Single-cell RNA sequencing (scRNA-seq) has been widely used to uncover cellular heterogeneity and is a powerful tool to reconstruct the developmental trajectory of neurons. In this study, neural stem cells (NSCs) from subventricular zone (SVZ) of newborn mice were treated with CdCl2 for 24 h and differentiated for 7 days to obtain neuronal lineage cells. Then scRNA-seq analysis identified five cell stages with different maturity in neuronal lineage cells. Our findings revealed that Cd altered the trajectory of maturation of neuronal lineage cells by decreasing the number of cells in different stages and hindering their maturation. Cd induced differential transcriptome expression in different cell subpopulations in a stage-specific manner. Specifically, Cd induced oxidative damage and changed the proportion of cell cycle phases in the early stage of neuronal development. Furthermore, the autocrine and paracrine signals of Wnt5a were downregulated in the low mature neurons in response to Cd. Importantly, activation of Wnt5a effectively rescued the number of neurons and promoted their maturation. Taken together, the findings of this study provide new and comprehensive insights into the adverse effect of Cd on neuronal maturation.

Toxicity of metal-based nanoparticles: Challenges in the nano era.

With the rapid progress of nanotechnology, various nanoparticles (NPs) have been applicated in our daily life. In the field of nanotechnology, metal-based NPs are an important component of engineered NPs, including metal and metal oxide NPs, with a variety of biomedical applications. However, the unique physicochemical properties of metal-based NPs confer not only promising biological effects but also pose unexpected toxic threats to human body at the same time. For safer application of metal-based NPs in humans, we should have a comprehensive understanding of NP toxicity. In this review, we summarize our current knowledge about metal-based NPs, including the physicochemical properties affecting their toxicity, mechanisms of their toxicity, their toxicological assessment, the potential strategies to mitigate their toxicity and current status of regulatory movement on their toxicity. Hopefully, in the near future, through the convergence of related disciplines, the development of nanotoxicity research will be significantly promoted, thereby making the application of metal-based NPs in humans much safer.

Cadmium inhibits neural stem/progenitor cells proliferation via MitoROS-dependent AKT/GSK-3ß/ß-catenin signaling pathway.

Cadmium (Cd) is a toxic heavy metal widely found in the environment. Cd is also a potential neurotoxicant, and its exposure is associated with impairment of cognitive function. However, the underlying mechanisms by which Cd induces neurotoxicity are unclear. In this study, we investigated the in vitro effect of Cd on primary murine neural stem/progenitor cells (mNS/PCs) isolated from the subventricular zone. Our results show that Cd exposure leads to mNS/PCs G1/S arrest, promotes cell apoptosis, and inhibits cell proliferation. In addition, Cd increases intracellular and mitochondrial reactive oxygen species (ROS) that activates mitochondrial oxidative stress, decreases ATP production, and increases mitochondrial proton leak and glycolysis rate in a dose-dependent manner. Furthermore, Cd exposure decreases phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3 beta (GSK3ß) in mNS/PCs. In addition, pretreatment mNS/PCs with MitoTEMPO, a mitochondrial-targeted antioxidant, improves mitochondrial morphology and functions and attenuates Cd-induced inhibition of mNS/PCs proliferation. It also effectively reverses Cd-induced changes of phosphorylation of AKT and the expression of ß-catenin and its downstream genes. Taken together, our data suggested that AKT/GSK3ß/ß-catenin signaling pathway is involved in Cd-induced mNS/PCs proliferation inhibition via MitoROS-dependent pattern.

Multiple Spontaneous Visceral Arterial Dissections in a Patient With Tolosa-Hunt Syndrome on Corticosteroid Therapy.

Multiple spontaneous visceral arterial dissections are an infrequent occurrence. The etiology, risk factors and natural history of these dissections have not been elucidated, and the optimal therapeutic strategy has not been established. We report a rare case of multiple spontaneous visceral arterial dissections involving the celiac artery, splenic artery, superior mesenteric artery, and right renal artery in a patient with Tolosa-Hunt syndrome on short-term corticosteroid therapy. The patient was subjected to conservative treatment and endovascular repair, achieving good clinical and radiological outcomes during the long-term follow-up period.

Single-cell RNA sequencing of mouse neural stem cell differentiation reveals adverse effects of cadmium on neurogenesis.

Cadmium (Cd) is a toxic heavy metal and widely exists in the environment. Extensive studies have revealed that Cd exposure can elicit neurotoxicity and potentially interfere with neurogenesis. However, underlying mechanisms by which Cd exposure affects neurogenesis remain unclear. In this study, we performed single-cell RNA sequencing (scRNA-seq) of the differentiated mixture from neonatal mouse Neural Stem Cells (mNSCs) that were exposed to Cd for 24 h and differentiated for 7 days. Our results showed that Cd exposure led to an increase in the differentiation of NSCs into astrocytes while a decrease into neurons. Besides, Cd induced subtype-specific response and dysregulated cell-to-cell communication. Collectively, our scRNA-seq data suggested that Cd had toxic effects on NSCs differentiation at the single-cell level, which offered insight into the potential molecular mechanism of Cd on neurogenesis. Furthermore, our findings provided a new method for assessing the neurodevelopmental toxicity of environmental pollutants.

N-acetylcysteine alleviated paraquat-induced mitochondrial fragmentation and autophagy in primary murine neural progenitor cells.

The developing brain is uniquely vulnerable to toxic chemical exposures. Studies indicate that neural stem cell (NSC) self-renewal is susceptible to oxidative stress caused by xenobiotics. However, the impact of antioxidants on NSC self-renewal and the potential mechanisms remain elusive. In this study, primary murine neural progenitor cells (mNPCs) from the subventricular zone were used as a research model. In addition, paraquat (PQ) was used to elicit oxidative stress and N-acetylcysteine (NAC) was used as a powerful antioxidant. mNPCs were treated with 80 µm PQ for 24 hours with or without 4 hours of NAC pretreatment. Our results showed that PQ treatment increased intracellular reactive oxygen species production, decreased cell viability and DNA synthesis, and promoted cell apoptosis. Meanwhile, pretreatment with NAC alleviated PQ-induced cytotoxicity in mNPCs. To elucidate the mechanisms further, we found that NAC pretreatment prevented PQ-induced reactive oxygen species production, mitochondrial fragmentation and autophagy in mNPCs. NAC-pretreated cells showed increased anti-apoptotic protein Bcl-2 and decreased pro-apoptotic protein Bax expression. Similarly, NAC pretreatment increased p-mTOR and decreased LC3B-II protein expression. Moreover, NAC decreased mitophagy related mRNA Pink1 and Parkin expression. Taken together, our results suggested that the antioxidant NAC treatment significantly attenuated PQ-induced mNPC self-renewal disruption through decreasing autophagy and salvaging mitochondrial morphology. These findings revealed a potential mechanism for neurological treatment relating to antioxidant and suggested potentially relevant implications for PQ-related neurodegenerative disorders. Thus, our study also provided insight into therapeutic strategies for the neurotoxic effects of oxidative stress-associated toxicants.

Modification of Wnt signaling pathway on paraquat-induced inhibition of neural progenitor cell proliferation.

Paraquat (PQ) is an agricultural chemical used worldwide. As a potential neurotoxicant, PQ adversely affects neurogenesis and inhibits proliferation of neural progenitor cells (NPCs). However, the molecular mechanistic insights of PQ exposure on NPCs remains to be determined. Herein, we determine the extent to which Wnt/ß-catenin signaling involved in the inhibition effect of PQ on mouse NPCs from subventricular zone (SVZ). NPCs were treated with different concentrations of PQ (40, 80, and 120 µM). PQ exposure provoked oxidative stress and apoptosis and PQ inhibited cell viability and proliferation in a concentration-dependent manner. Significantly, PQ exposure altered the expression/protein levels of the Wnt pathway genes in NPCs. In addition, PQ reduced cellular ß-catenin, p-GSK-3ß, and cyclin-D1 and increased the radio of Bax/Bcl2. Further, Wnt pathway activation by treatment with LiCl and Wnt1 attenuated PQ-induced inhibition of mNPCs proliferation. Antioxidant (NAC) treatment alleviated the inhibition of PQ-induced Wnt signaling pathway. Overall, our results suggest significant inhibitory effects of PQ on NPCs proliferation via the Wnt/ß-catenin signaling pathway. Interestingly, our results implied that activation of Wnt/ß-catenin signaling pathway attenuated PQ-induced autophagic cell death. Our results therefore bring our understanding of the molecular mechanisms of PQ-induced neurotoxicity.