Methylmercury (MeHg), a potent neurotoxic substance, causes adverse health outcomes by modulating metabolites through altered gut microbiota patterns. Among the many metabolites, neurotransmitters play a particularly important role in the nervous system and behavior. Resveratrol (RSV) has been investigated as an antiaging, antioxidant, anti‐inflammatory, and neuroprotective agent. The current study evaluated that RSV is protective of neurodevelopmental toxicity induced by MeHg and further explored the underlying mechanisms. Sprague–Dawley rats were treated with 1.2 mg/kg/d of MeHg, and the effects were evaluated after supplementation with RSV (20 mg/kg/d). The results indicated that MeHg had adverse effects on early neurodevelopmental indicators in the experimental group offspring as compared to control pups. Interestingly, RSV significantly improved the MeHg‐induced delays in the neurobehavioral reflexes and reduced the total mercury (THg) concentration in the colons of the offspring rats. In agreement, RSV administration improved the gut microbiota diversity and structure by increasing the abundance of probiotics and upregulating the expression of tight junction proteins. It also ameliorated the MeHg‐induced abnormalities in the expression profiles of neurotransmitters. Furthermore, eight key bacteria that were strongly linked with the neurotransmitters and neuroreflex parameters were identified. Taken together, these results demonstrate that RSV treatment effectively reduces the occurrence of neurodevelopmental toxicity caused by perinatal MeHg exposure by modulating the intestinal flora and neurotransmitter metabolism. These findings provide a new therapeutic approach for treating MeHg‐induced neurotoxicity.The cover image is based on the Research Article Resveratrol alleviates perinatal methylmercury‐induced neurobehavioral impairments by modulating the gut microbiota composition and neurotransmitter disturbances by Fang Chen et al., https://doi.org/10.1002/tox.23973.

Methylmercury (MeHg) is a hazardous substance that has unique neurodevelopmental toxic effects. However, its molecular alteration profile, sensitive response biomarkers, and mechanism of neuronal injury remain largely unknown. Here, the effects of intrauterine methylmercury chloride (low-, medium- and high-dose groups: 0.6 mg/kg/d, 1.2 mg/kg/d, 2.4 mg/ kg /d, respectively) exposure on learning and memory were assessed in offspring rats by behavioral tests, pathological analysis and hippocampal proteomic analysis. The results suggested that intrauterine MeHg exposure impairs spatial learning and memory and leads a significant reduction in the number and dispersion scattered arrangement in the hippocampus of offspring. Furthermore, in the tandem mass tag-based proteomics analysis, compared with the control group, a total of 74 differentially expressed proteins (DEPs) were found in the MeHg exposure groups; specifically, 32 down-regulated and 42 up-regulated proteins were identified. In addition, the pathways enrichment analysis indicated that these DEPs are implicated in several biological processes, such as synaptic plasticity and energy metabolism, as well as various molecular functional categories. Simultaneously, MeHg reduced the postsynaptic density, diminished the active zone, amplified the synaptic cleft and changed the synaptic interface of pyramidal cells. Western blot analysis further revealed that MeHg significantly reduced the levels of Forkhead box protein (FOXP2), Synaptophysin (SYP) and Postsynaptic density protein 95 (PSD-95), and down-regulated the N-methyl-D-aspartate receptor 1 (NMDAR1), N-methyl-D-aspartate receptor 2 A (NR2A) and N-methyl-D-aspartate receptor 2B (NR2B). In general, from a functional perspective, most overlapping proteins were related to NMDA receptor-mediated glutamatergic signaling, which is an excitotoxicity mechanism known to influence learning and memory. These discoveries contribute to our understanding of the relationship between MeHg and cognitive deficits and provide insight into the protein mediators of this relationship and possible prospective early biomarkers.

Compelling evidence has demonstrated that arsenic (As) exposure is associated with kidney injuries. Given that inflammatory responses and immune imbalances are the root causes of several kidney diseases, this study investigated the potential mechanisms underlying NLRP3 inflammasome activation in As-induced kidney injury. A rat model of sub-chronic As exposure was established via oral administration of NaAsO₂. The results revealed that urinary β-2-microglobulin (β2-MG), N-acetyl-β-D-glucosidase (NAG) and albumin (ALB) were increased in the As-exposed group, reflecting kidney impairment. Moreover, significant glomerular vacuole-like changes, tubular dilatation and inflammatory cell infiltration were observed. Meanwhile, the expression levels of neutrophil gelatinase-associated lipocalin (NGAL), IL-1β and IL-18 were enhanced in the kidney tissues of As-treated rats. Further, increased expression of NLRP3, ASC and caspase-1, which are NLRP3 inflammasome-associated proteins, were observed in the kidney tissues of rats in the As-treated groups. The expression levels of the NLRP3 upstream regulators C/EBPβ and TFAM were also elevated. These findings suggest that sub-chronic As exposure triggers inflammatory responses in rat kidney tissue and impairs kidney function. The underlying mechanisms may be related to the C/EBPβ–TFAM pathway and activation of the NLRP3 inflammasome pathway.

Developmental exposure to arsenic (As) has been linked to irreversible adverse health outcomes in offspring. However, the underlying molecular mechanisms remain a mystery. Here, maternal mice were exposed to As via drinking water. Subsequently, the hippocampi of their offspring were collected at different developmental stages to explore the dynamic changes during hippocampal maturation and the effects of As. Time-series RNA-seq analysis revealed a significant temporal correlation between As neurodevelopmental toxicity and the mRNA expression profile of the hippocampal region during critical postnatal developmental windows. Further, downregulation of genes associated with neurogenesis and telomere maintenance was observed. Notably, dynamic changes in hippocampal telomeres were observed in response to As exposure, with critically shortened telomeres inhibiting neural stem cells (NSCs) proliferation, impairing neuroblast maturation, and reducing the number and size of neurospheres. Additionally, the populations of BrdU⁺ and MAP2⁺ cells were decreased while GFAP⁺ cells were increased, indicating a decline in NSCs stemness. Furthermore, As exposure significantly impaired dendritic complexity in the hippocampus of mice, altered dendritic spine morphology, and disrupted synaptic ultrastructure, ultimately leading to cognitive impairment. These findings highlight the importance of analyzing telomere dynamics in environmental toxicology and offer insights into the neurotoxic mechanisms of maternal As on offspring development.