Early-life manganese (Mn) overexposure induces cognitive flexibility impairments by disrupting hippocampal neurogenesis and decreasing neural stem cells (NSCs) differentiation into neuroblasts. CDC25B is a key regulator required for both the cell cycle and NSCs differentiation. However, the association between energy metabolism conversion and Mn-related hippocampal neurogenesis malfunction, and whether this malfunction is caused by Cdc25b mRNA decay, remains unclear. This study utilized C57BL/6 mouse offspring and applied single-cell RNA sequencing to investigate the link between Mn-induced cognitive impairment and early-life neurogenesis disruption. The results showed that 1.1 mg/kg/day Mn exposure significantly impaired cognitive flexibility. This impairment was associated with disrupted NSCs differentiation into neuroblasts. Subsequently, we used primary NSCs to examine whether disrupted energy metabolism conversion affected METTL3-mediated Cdc25b mRNA decay. Aligned with this hypothesis, NSCs exposed to 50 μM Mn showed an unsuccessful transition from glycolysis to OXPHOS and an elevated METTL3-dependent Cdc25b m6A modification, which led to reduced mRNA stability. In conclusion, Mn-associated inhibition of energy metabolism conversion in NSCs interrupts the CDC25B-regulated NSCs differentiation into neuroblasts in hippocampal neurogenesis.

Manganese (Mn) overexposure induces neurocognitive deficits associated with hippocampal neuronal injury and neuroinflammation, but the cellular mechanisms underlying Mn-induced hippocampal damage remain incompletely understood. Microglial pyroptosis may amplify neuroinflammation and contribute to secondary neuronal injury; however, its involvement in Mn neurotoxicity and modulation by melatonin (Mel) remain unclear. This study investigated the protective role of Mel against Mn-induced neurological deficits using C57BL/6 mice in vivo and SIM-A9 microglial cells in vitro. Mn exposure impaired learning and memory and promoted hippocampal neuronal injury, accompanied by increased NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptotic signaling in hippocampal microglia. Mel attenuated microglial pyroptosis and neuronal injury without substantially reducing Mn levels in the hippocampus, blood, or urine. Mn disrupted the thioredoxin (Trx)/thioredoxin-interacting protein (TXNIP) redox axis and enhanced TXNIP-NLRP3 interaction. Txnip overexpression strengthened this interaction and weakened the protective effect of Mel on microglial pyroptosis. Furthermore, Mel enhanced Sirtuin 6 (SIRT6) activity and nuclear SIRT6 expression, reduced H3K9ac and H3K56ac enrichment at the Txnip promoter, and suppressed Mn-induced TXNIP overexpression. These findings suggest that Mel mitigates Mn-associated hippocampal neuroinflammatory injury by partially restoring SIRT6-mediated epigenetic repression of Txnip and reducing TXNIP/NLRP3-driven microglial pyroptosis.

Vibrio parahaemolyticus is a major foodborne pathogen worldwide, responsible for seafood-associated poisoning. Among its toxin genes, tdh2 is the most critical. To investigate the role of tdh2 in V. parahaemolyticus under gastrointestinal conditions, we constructed tdh2 deletion and complementation strains and compared their survival under acid (pH 3 and 4) and bile stress (2%). The results showed that tdh2 expression was significantly upregulated under cold (4 °C) and bile stress (0.9%). Survival assays and PI staining revealed that the tdh2 mutant strain (VP: △tdh2) was more sensitive to acid and bile stress than the wild-type (WT), and this sensitivity was rescued by tdh2 complementation. These findings suggest that tdh2 plays a protective role in enhancing V. parahaemolyticus tolerance to acid and bile stress. In the VP: △tdh2 strain, seven genes were significantly upregulated and six were downregulated as a result of tdh2 deletion. These genes included VPA1332 (vtrA), VPA1348 (vtrB), VP2467 (ompU), VP0301 and VP1995 (ABC transporters), VP0527 (nhaR), and VP2553 (rpoS), among others. Additionally, LC-MS/MS analysis identified 12 differential metabolites between the WT and VP: △tdh2 strains, including phosphatidylserine (PS) (17:2 (9Z,12Z) /0:0 and 20:1 (11Z) /0:0), phosphatidylglycerol (PG) (17:0/0:0), flavin mononucleotide (FMN), and various nucleotides. The protective mechanism of tdh2 may involve preserving cell membrane permeability through regulation of ompU and ABC transporters and enhancing electron transfer efficiency via regulation of nhaR. The resulting reduction in ATP, DNA, and RNA synthesis—along with changes in membrane permeability and electron transfer due to decreased FMN—likely contributed to the reduced survival of the VP: △tdh2 strain. Meanwhile, the cells actively synthesized phospholipids to repair membrane damage, leading to increased levels of PS and PG. This study provides important insights into strategies for preventing and controlling food poisoning caused by tdh+ V. parahaemolyticus.

Decabromodiphenyl ether (BDE-209), a brominated flame retardant widely used in electronics and construction materials, has garnered significant attention due to its environmental persistence and potential health hazards. However, research on the neurotoxic effects of flame retardants is limited, and the molecular mechanisms underlying BDE-209 neurotoxicity are not fully understood. Neuroinflammation, as a key pathway in the pathological progression of neurological disorders, has received extensive attention. This study aimed to elucidate the molecular mechanisms underlying BDE-209-induced neurotoxicity, with a specific focus on pyroptosis, a form of programmed cell death closely linked to neuroinflammation. Using both in vivo mouse models and in vitro HT22 hippocampal neuron cultures, we found that BDE-209 exposure caused significant cognitive deficits in mice and activated the classical pyroptosis pathway in the hippocampus. Further analysis revealed that BDE-209 activated the JAK2/STAT3 pathway and the NLRP3 inflammasome, triggering pyroptotic cell death in HT22 neurons. Remarkably, pharmacological inhibition of NLRP3 with MCC950 and blockade of JAK2/STAT3 signaling with AG490 significantly attenuated pyroptosis, highlighting the therapeutic potential of targeting these pathways. Collectively, our findings provide new insights into the neurotoxic effects of BDE-209, demonstrating that it induces NLRP3-mediated pyroptosis through the JAK2/STAT3 axis. This study enhances our understanding of BDE-209 neurotoxicity and highlights possible intervention strategies to mitigate its harmful effects.

Manganese (Mn) overexposure-induced neurocognitive abnormalities are intensively linked to hippocampal neuronal injury, but the neurotoxic mechanisms involved are ambiguous. Under various mitochondrial stress, mitochondrial stress response (MSR) is activated and plays a dual role in cells, promoting adaptive survival while also contributing to detrimental damage, depending on the severity of mitochondrial dysfunction. Excessive MSR can lead to inevitable cell death and organ damage, ultimately driving the onset and progression of numerous disorders. Yet, whether excessive MSR is implicated in Mn-induced neuronal injury remains unclear. In this study, Mn poisoning models were established in C57BL/6 mice and hippocampal primary neurons to investigate the role of excessive MSR in mitochondria-mediated neuronal apoptosis following Mn exposure. Specifically, excessive MSR triggered hippocampal neuronal mitochondrial damage and neurocognitive abnormalities, which was primarily driven by the persistent phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Furthermore, excessive acetylation of growth arrest and DNA damage-inducible protein 34 (GADD34) impaired the dephosphorylation of phospho-eIF2α by disrupting the protein phosphatase 1α/GADD34 complex in primary neurons following Mn exposure. Finally, Sirtuin 1-mediated GADD34 deacetylation facilitated the dephosphorylation of phospho-eIF2α, thus mitigating excessive MSR-triggered neuronal apoptosis and mitochondrial dysfunction. These findings underscore the critical role and complexity of excessive MSR in Mn-induced neuronal injury.

Methylmercury (MeHg) is a potent neurotoxicant with neurodevelopmental toxicity that is widely ingested into the body through drinking water and food. MeHg crosses the placental barrier and accumulates in the brain of the fetus, affecting the growth and development of the central nervous system. Although it has been demonstrated that MeHg induces neuronal calcium overload in the rat cerebral cortex, the role of calcium overload in MeHg-induced neurodevelopmental toxicity remains unclear. Here, we used ICR-pregnant mice and their resulting offspring and administered the BAPTA-AM calcium antagonist to investigate the molecular mechanisms by which MeHg exposure during gestation and lactation affects neurodevelopment. We found that exposure to MeHg during gestation and lactation resulted in developmental arrest and neurobehavioral dysfunction in the offspring, with calcium overload, disturbed mitochondrial dynamics, and apoptosis. However, the calcium overload inhibitor BAPTA-AM rescued MeHg-induced neurodevelopmental damage, attenuated the onset of calcium overload, reduced mitochondrial kinetic disturbances and apoptosis. Meanwhile, the activation of the CaM/CaMKII/DRP1 signaling pathway induced by calcium overload was inhibited, and the interaction between DRP1 and BAX was attenuated, which alleviated apoptosis to a certain extent. In summary, our study suggests that MeHg-induced calcium overload may induce disturbed mitochondrial dynamics through activation of the CaM/CaMKII/DRP1 signaling pathway, resulting in neuronal apoptosis.

Excessive exposure to manganese (Mn) through drinking water and food during pregnancy significantly heightens the likelihood of neurodevelopmental damage in offspring. Multiple studies have indicated that melatonin (Mel) may help to relieve neurodevelopmental disorders caused by Mn, but potential mechanisms underlying this effect require further exploration. Here, we utilized primary neural stem cells (NSCs) as a model to elucidate the molecular mechanism underlying the protective function of Mel on Mn-induced cell proliferation dysfunction and cycle arrest. Our results showed that Mn disrupted the cell cycle in NSCs by suppressing positive regulatory proteins (CDK2, Cyclin A, Cyclin D1, and E2F1) and enhancing negative ones (p27KIP1 and p57KIP2), leading to cell proliferation dysfunction. Mel inhibited the Mn-dependent changes to these proteins and the cell cycle through nuclear receptor-related protein 1 (Nurr1), thus alleviating the proliferation dysfunction. Knockdown of Nurr1 using lentivirus-expressed shRNA in NSCs resulted in a diminished protective effect of Mel. We concluded that Mel mitigated Mn-induced proliferation dysfunction and cycle arrest in NSCs through Nurr1.

There is substantial evidence implicating ferroptosis in the pathogenesis of Alzheimer's disease (AD), a prevalent neurodegenerative disorder. Given the rising global incidence of AD, there is a pressing need to identify drugs with enhanced efficacy and reduced side effects, which has become a worldwide objective. Due to their diverse pharmacological effects, natural substances have emerged as possible candidates. Erigeron Breviscapus (Vant.) Hand-Mazz (EBHM), a traditional Chinese medicinal plant, has been the subject of research demonstrating its beneficial therapeutic effects on cognitive impairment-related diseases, offering promising prospects for widespread application. However, it is essential to note that the extant literature on the EBHM regulation of ferroptosis treatment for AD is limited. This study utilized an integrated approach involving WGCNA, network pharmacology, molecular docking, and molecular dynamics simulations to identify the active component and four hub genes of EBHM-regulated ferroptosis treatment AD, including HSPA8, GSK3B, CTSB, and YWHAG, as well as constructing a polygenic diagnostic model with predictive value. HSPA8 and 3,4,5-tricaffeoylquinic acid (TCQA) may be the most crucial hub genes and active components of EBHM for treating AD by regulating ferroptosis, as determined by molecular docking and molecular dynamics simulations. These findings may contribute to an in-depth comprehension of the molecular mechanisms of EBHM regulation of ferroptosis for the treatment of AD, thereby shedding new light on developing effective therapeutic pharmaceuticals for AD.

Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca2+/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury.

Manganese (Mn) overexposure induces hippocampal synaptotoxicity by the accumulation of dysfunctional synaptic vesicles (SVs). Leucine-rich repeat kinase 2 (LRRK2) kinase activity is involved in regulating axonal transport (autophagosomal maturation) and lysosomal function. Nevertheless, it remains unclear whether Mn-induced synaptotoxicity is associated with the LRRK2-mediated disruption of autophagosomal maturation in axonal transport and the impairment of lysosomes in hippocampal neurons. Here, we established models of manganism in C57BL/6 mice and hippocampal neuronal HT22 cells to verify the role of LRRK2-mediated Rab10 phosphorylation in the Mn-induced dysfunction of autophagy- lysosomal fusion. Our results proved that Mn-induced the disorder of axonal transport and that lysosome impairments were associated with the increased recruitment of phospho-Rab10 at the axon and lysosomes. Next, we established Lrrk2-KD and LRRK2 kinase- specific inhibitor (GNE-0877, GNE) pre-treated HT22 cells to inhibit Lrrk2 gene expression and kinase activity, respectively. In Mn-treated Lrrk2-KD or GNE-pretreated normal neurons, our results indicated that lysosomal pH and integrity and autophagic flow were restored, indicating by decreased levels of phospho-Rab10 on lysosomes and JNK-interacting proteins (JIP4). In addition, GNE pretreatment could provide protection against Mn-induced synaptotoxicity in vivo, which was evidenced by the partial recovery in synaptic plasticity and synaptic damage. Thus, the Mn-induced abnormal activation of LRRK2 affected lysosomes and the recruitment of phospho-Rab10 by JIP4, which disrupted autophagosomal maturation in proximal axons and resulted in the hippocampal synaptic toxicity of mice.

Ethnopharmacological relevance: Realgar, the main component of which is As2S2 or As4S4 (>= 90%), is a traditional Chinese natural medicine that has been used to treat carbuncles, furuncles, snake and insect bites, abdominal pain caused by parasitic worms, and epilepsy in China for many years. Because realgar contains arsenic, chronic or excessive use of single-flavor realgar and realgar-containing Chinese patent medicine can lead to drug-induced arsenic poisoning, but the exact mechanism underlying its toxicity to the central nervous system is unclear.Aim of the study: The aim of this study was to clarify the mechanism of realgar-induced neurotoxicity and to investigate the effects of realgar on autophagy and the Keap1-Nrf2-ARE pathway.Materials and methods: We used rats treated with the autophagy inhibitor 3-methyladenine (3-MA) or adeno-associated virus (AAV2/9-r-shRNA-Sqstm1, sh-p62) to investigate realgar-induced neurotoxicity and explore the specific relationship between autophagy and the Keap1-Nrf2-ARE pathway (the Nrf2 pathway) in the cere-bral cortex. Molecular docking analysis was used to assess the interactions among the Nrf2, p62 and Keap1 proteins.Results: Our results showed that arsenic from realgar accumulated in the brain and blood to cause neuronal and synaptic damage, decrease exploratory behavior and spontaneous movement, and impair memory ability in rats. The mechanism may have involved realgar-mediated autophagy impairment and continuous activation of the Nrf2 pathway via the LC3-p62-Keap1-Nrf2 axis. However, because this activation of the Nrf2 pathway was not sufficient to counteract oxidative damage, apoptosis was aggravated in the cerebral cortex.Conclusions: This study revealed that autophagy, the Nrf2 pathway, and apoptosis are involved in realgar-induced central nervous system toxicity and identified p62 as the hub of the LC3-p62-Keap1-Nrf2 axis in the regulation of autophagy, the Nrf2 pathway, and apoptosis.

Due to continuous exposure to ultraviolet B(UVB) radiation, eye lenses are constantly subjected to oxidative stress that induces lens epithelial cell (LEC) apoptosis, which has been associated with the inactivation of Sirtuin1 (SIRT1). It is well-established that NFE2L2 has a major protective effect on UVB-induced oxidative stress and damage. However, whether UVB radiation affects oxidative/antioxidative imbalance and damages LECs by inactivating the protective NFE2L2-mediated antioxidative stress pathway through inhibition of SIRT1 is unknown. In our research, we established in vivo and in vitro UVB exposure models in Sprague Dawley rats and SRA01/04 cells, respectively, to investigate the effect of UVB radiation on the NFE2L2/ KEAP1 pathway and the role of SIRT1 in this process. The in vivo findings revealed that UVB radiation exposure decreased Sirt1 and Nfe2l2 levels, upregulated Keap1 expression, led to an oxidative/antioxidative imbalance and increased LEC apoptosis in the eye lens. Sirt1 downregulated Keap1 expression levels, but activated Nfe2l2 and its downstream target proteins. The in vitro findings showed that UVB inhibited the deacetylation of SIRT1 target proteins and increased the acetylation levels of KEAP1 and NFE2L2. We also found that UVB radiation exposure led to a significant decrease in both co-localization levels and protein interaction between SIRT1 and KEAP1. In addition, the inhibition of SIRT1 increased KEAP1 levels, inhibited the activity of NFE2L2 and decreased co- localization levels and protein interactions between NFE2L2 and KEAP1. These results suggested that UVB radiation decreased SIRT1 levels and inhibited the KEAP1/NFE2L2 pathway, thereby reducing its antioxidant effect, which might be an important mechanism of UVB-induced cataract.

Excessive exposure of children to manganese (Mn) in the environment has a bearing on developmental neurotoxicity. Although melatonin (Mel) can play a neuroprotective role by modulating the differentiation of neural stem cells (NSCs) in the developing brain, its specific mechanism under Mn overexposure remains to be explored. Here, we cultured primary NSCs as an available model to investigate the relevant molecular mechanism of Mel mitigation on Mn-induced disorder of NSCs differentiation through sirtuin 1 (SIRT1)/β-catenin pathway. It was found that Mel could facilitate the differentiation of Mn-treated NSCs into neurons. Further, our results uncovered that the pro-differentiation mechanism of Mel depended upon ascending the activity of SIRT1, thereby weakening β-catenin acetylation and increasing phosphorylation of β-catenin ser675 in the cytoplasm, which facilitates the nuclear translocation of β-catenin. Furthermore, the role of SIRT1 in Mel-mediated signal transduction was investigated through the pretreatment of NSCs using a highly specific SIRT1 inhibitor, EX527. After EX527 pretreatment, Mel could not maintain its protective effect. Overall, our results revealed that Mel could alleviate Mn-induced disorder of NSCs differentiation through the activation of the SIRT1/β-catenin pathway.

The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic reticulum and mitochondria, a dynamic balance exists between protein folding mechanisms and unfolded protein levels under normal conditions. Disruption of this balance or an accumulation of unfolded proteins in these organelles can result in stress responses and UPR. The UPR restores organelle homeostasis and promotes cell survival by increasing the expression of chaperone proteins, regulating protein quality control systems, and enhancing the protein degradation pathway. However, prolonged or abnormal UPR can also have negative effects, including cell death. Therefore, many diseases, especially neurodegenerative diseases, are associated with UPR dysfunction. Neurodegenerative diseases are characterized by misfolded proteins accumulating and aggregating, and neuronal cells are particularly sensitive to misfolded proteins and are prone to degeneration. Many studies have shown that the UPR plays an important role in the pathogenesis of neurodegenerative diseases. Here, we will discuss the possible contributions of the endoplasmic reticulum unfolded protein response (UPR er ) and the mitochondrial unfolded protein response (UPR mt ) in the development of several neurodegenerative diseases.

Methylmercury (MeHg) is a potent neurotoxicant that could induce oxidative stress and autophagy. However, the underlying mechanisms through which MeHg affects the central nervous system have not been fully elucidated, and little has been known of the interaction between oxidative stress and autophagy. Therefore, rats were administrated with different MeHg concentrations to evaluate the neurotoxic effects and autophagy in cerebral cortex. Moreover, we have investigated the neuroprotective role of N-acetyl-L-cysteine (NAC) against MeHg-induced neurotoxicity in order to estimate the regulation effects of oxidative stress on autophagy. A total of 64 rats, 40 of which were randomly divided into control and MeHg-treated (4, 8 and 12 μ mol/kg) groups. The remaining 24 rats were divided into control, NAC control (1 mmol/kg), 12 μ mol/kg MeHg, and NAC pretreatment. Administration of 12 μ mol/kg MeHg significantly increased behavioral and pathological abnormalities, and autophagy levels. In addition, the oxidative stress levels increased, together with abnormal expression of autophagy-related molecules. Pretreatment with NAC significantly prevented MeHg-induced oxidative stress and PI3K/AKT/mTOR or AMPK/TSC2/mTOR-mediated autophagy. In conclusion, the present study suggested that oxidative stress can regulate autophagy through PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways. This study provides a theoretical basis for the study and treatment of MeHg-induced neurotoxicity.

Exposure to nitrogen dioxide might potentially change the makeup and operation of gut microbes. Nitrogen dioxide data was procured from the IEU Open GWAS (N = 456 380). Subsequently, a two-sample Mendelian randomization study was executed, utilizing summary statistics of gut microbiota sourced from the most expansive available genome-wide association study meta-analysis, conducted by the MiBioGen consortium (N = 13 266). The causal relationship between nitrogen dioxide and gut microbiota was determined using inverse variance weighted, maximum likelihood, MR-Egger, Weighted Median, Weighted Model, Mendelian randomization pleiotropy residual sum and outlier, and constrained maximum likelihood and model averaging and Bayesian information criterion. The level of heterogeneity of instrumental variables was quantified by utilizing Cochran's Q statistic. The colocalization analysis was used to examine whether nitrogen dioxide and the identified gut microbiota shared casual variants. Inverse variance weighted estimate suggested that nitrogen dioxide was causally associated with Akkermansia (beta = -1.088, 95% CI: -1.909 to -0.267, P = 0.009). In addition, nitrogen dioxide presented a potential association with Bacteroides (beta = -0.938, 95% CI: -1.592 to -0.284, P = 0.005), Barnesiella (beta = -0.797, 95% CI: -1.538 to -0.055, P = 0.035), Coprococcus 3 (beta = 1.108, 95% CI: 0.048-2.167, P = 0.040), Eubacterium hallii group (E. hallii) (beta = 0.776, 95% CI: 0.090-1.463, P = 0.027), Holdemania (beta = -1.354, 95% CI: -2.336 to -0.372, P = 0.007), Howardella (beta = 1.698, 95% CI: 0.257-3.139, P = 0.021), Olsenella (beta = 1.599, 95% CI: 0.151-3.048, P = 0.030) and Sellimonas (beta = -1.647, 95% CI: -3.209 to -0.086, P = 0.039). No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. The associations of nitrogen dioxide with Akkermansia (PH4 = 0.836) and E. hallii (PH4 = 0.816) were supported by colocalization analysis. This two-sample Mendelian randomization study found that increased exposure to nitrogen dioxide had the potential to impact the human gut microbiota.

Methylmercury (MeHg) is a widely distributed environmental pollutant that can easily cross the blood-brain barrier and accumulate in the brain, thereby damaging the central nervous system. Studies have shown that MeHg-induced mitochondrial damage and apoptosis play a crucial role in its neurotoxic effects. Mitochondrial unfolded protein response (UPRmt) is indispensable to maintain mitochondrial protein homeostasis and ensure mitochondrial function, and the ATF4/CHOP axis is one of the signaling pathways to activate UPRmt. In this study, the role of the ATF4/CHOP axis-mediated UPRmt in the neurotoxicity of MeHg has been investigated by C57BL/6 mice and the HT22 cell line. We discovered that mice exposed to MeHg had abnormal neurobehavioral patterns. The pathological section showed a significant decrease in the number of neurons. MeHg also resulted in a reduction in mtDNA copy number and mitochondrial membrane potential (MMP). Additionally, the ATF4/CHOP axis and UPRmt were found to be significantly activated. Subsequently, we used siRNA to knock down ATF4 or CHOP and observed that the expression of UPRmt-related proteins and the apoptosis rate were significantly reduced. Our research showed that exposure to MeHg can over-activate the UPRmt through the ATF4/CHOP axis, leading to mitochondrial damage and ultimately inducing neuronal apoptosis.

EDITORIAL article Front. Neurosci., 27 September 2023Sec. Neurodegeneration Volume 17 - 2023 | https://doi.org/10.3389/fnins.2023.1295344

Methylmercury (MeHg) is a bio-accumulative global environmental contaminant present in fish and seafood. MeHg accumulates in the aquatic environment and eventually reaches the human system via the food chain by bio-magnification. The central nervous system is the primary target of toxicity and is particularly vulnerable during development. It is well documented that developmental MeHg exposure can lead to neurological alterations, including cognitive and motor dysfunction. Apoptosis is a primary characteristic of MeHg-induced neurotoxicity, and may be regulated by autophagic activity. However, mechanisms mediating the interaction between apoptosis and autophagy remains to be explored. Autophagy is an adaptive response under stressful conditions, and the basal level of autophagy ensures the physiological turnover of old and damaged organelles. Autophagy can regulate cell fate through different crosstalk signaling pathways. A complex interplay between autophagy and apoptosis determines the degree of apoptosis and the progression of MeHg-induced neurotoxicity as demonstrated by pre-clinical models and clinical trials. This review summarizes recent advances in the roles of autophagy and apoptosis in MeHg neurotoxicity and thoroughly explores the relationship between them. The autophagic pathway may be a potential therapeutic target in MeHg neurotoxicity through modulation of apoptosis.

Human infertility has become the third largest serious disease in the world, seriously affecting the quality of human fertility. Studies have shown that manganese (Mn) can accumulate in the testis through the blood-testicular barrier and damage the male reproductive system. However, the mechanism has not been explored clearly. Recent studies have reported that YTH domain-containing 2 (YTHDC2) can regulate reproductive function. However, none has explored the role of YTHDC2 in Mn-induced reproductive toxicity. The present study investigated whether YTHDC2/CyclinB2 (CCNB2) pathway participates in Mn-induced reproductive toxicity using Kunming mice, spermatogonia, and the seminal plasma of male workers. The mice were received intraperitoneal (i.p.) injections of 0, 12.5, 25, and 50 mg/kg MnCl2 once daily for 2 weeks. The cells were treated with 0, 100, 200 and 400 μM MnCl2 for 24 h. Here, we found that occupational Mn exposure significantly increased Mn levels in the seminal plasma of male workers, while decreased sperm density, semen quality, and the levels of YTHDC2, CCNB1, and CCNB2. We found that Mn can inhibit the YTHDC2/CCNB2 signaling pathway and block the G2/M phase of the cell cycle. Moreover, the morphology of cells and the histomorphology of mice testis were injured. Notably, over-expression (OE) of YTHDC2 increased CCNB2 levels, reduced cell cycle arrest, and improved reproductive toxicity after Mn exposure. These findings suggest that the YTHDC2/CCNB2 signaling pathway participates in Mn-induced reproductive toxicity, and OE of YTHDC2 can mitigate the toxicity of Mn.