Evidence remains limited regarding the cumulative multi-system health effects of nitrogen dioxide (NO2) exposure and its lag–response patterns. This study aimed to evaluate the associations between short-term NO₂ exposure and multi-system healthcare utilization, with particular emphasis on lagged effects. Daily data on ambient air pollution, meteorological factors, and healthcare utilization across multiple disease systems were collected from 2023 to 2024 in four subtropical humid monsoon cities in China. Using a time-series design, distributed lag non-linear models (DLNMs) were applied to examine lagged and exposure–response associations between short-term NO2 exposure (lag 0–7 days) and daily healthcare visits. Stratified analyses by sex, age, healthcare utilization type, and season, as well as sensitivity analyses, were conducted. Significant positive associations between NO2 exposure and healthcare utilization were consistently observed across all four cities, with relative risks (RRs) ranging from 1.016 (95

We previously found low-level heavy metals lead (Pb), cadmium (Cd), and mercury (Hg) co-exposure impairs cognition even at their respective no observed adverse effect levels. However, the underlying mechanisms and complex interactions within mixture remain poorly understood from neurobiological basis perspective. Therefore, following low-level Pb, Cd, and Hg co-exposure, we systematically investigated the effects of that on synaptic efficiency, excitation/inhibition (E/I) balance, active neurons, and cognitive behavior impairment using electrophysiology, c-Fos active neuron labeling, and cognitive behavioral tests. In vitro factorial design experiments indicated that very low-level Pb, Cd, and Hg co-exposure specifically disrupted hippocampal synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, potentially serving as a neurobiological basis for cognitive impairment following that exposure. This synaptic dysfunction may further shift E/I balance toward hyperexcitability, with increasing baseline hippocampal neuronal activity and inducing mice risk-taking behavior in resting state. Paradoxically, with mild stimulation by foot-shock, co-exposure attenuated both neuronal and behavioral responsiveness. Further analysis showed that while baseline active excitatory neurons and vGluT1 expression (particularly in dentate gyrus) were elevated, their stimulus-evoked plasticity was impaired, following low-level Pb, Cd, and Hg co-exposure. Overall, our findings suggest that AMPA receptor-associated E/I imbalance from low-level Pb, Cd, and Hg co-exposure was linked to altered neuronal activity patterns and impaired cognitive behavioral regulation. This study provides valuable insights for researchers and managers in revising safety thresholds, exploring mechanisms, and searching interventions for low-level heavy metal exposure.

It is well-known that epigenetic regulation is involved in the negative effects of environmental physical, chemical and biological factors exposures on organs. To investigate the effects and mechanisms of histone hyperacetylation caused by environmental stress on spermatogenesis, we used the histone deacetylase inhibitor Panobinostat (PANO) to establish the hyperacetylation models in mice. To investigate the effects of PANO on testicular function of male reproductive system, we conducted the evaluation of sperm quality parameters in mice. The morphological changes of testes were observed through hematoxylin and eosin (H E) staining on paraffin sections and quantified by stereological measurements after treatment to explore the cause of infertility and figure out if PANO has any effect on the reproductive system of male mice. Immunofluorescence, immunohistochemistry and immunoblotting were utilized to elucidate the impact and mechanisms of PANO treatment on spermatogenesis. RNA-seq analysis was performed on mouse testes to elucidate the underlying mechanisms of PANO. The rates of sperm survival and movement were reduced while malformation rate of sperm increased in the 34.4-day PANO group. Gene Set Enrichment Analysis (GSEA) supported the significant role of PANO in modulating cilium movement, sperm axoneme assembly and flagellated sperm motility. Numbers of MVH+ cells were decreased while the numbers of SCP3+ cells were significantly increased after PANO treatment compared to those in the control (CTL) group. The protein levels of PLZF in PANO-treated testes were dramatically reduced along with the increased distribution changes of SOX9, F4/80 protein. Further data demonstrated that PANO impeded spermiogenesis at the stage XI in the 34.4-day PANO group and enhanced the transcriptome levels of histone variants H2bc4 and H1f2. We have reported that PANO exerts a negative impact on the spermatogonial stem cell pool in mouse testes by disrupting its niche. This disruption leads to a reduction in germ cell numbers and impairs sperm function in mice, ultimately resulting in infertility. Moreover, PANO destabilizes the nucleosomes by increasing the transcriptional levels of H2bc4 and H1f2, affects the histone-to-protamine transition, and arrests spermiogenesis at the elongating spermatid stage. These findings also suggest that H2bc4 and H1f2 may be potential key biomarkers in the testis for diagnosing male infertility associated with aberrant histone hyperacetylation due to the exposure of environmental pollutants.

Lead (Pb), an ancient metallic environmental pollutant, has received widespread attention and has been strictly controlled, but current findings have found the hazards of Pb to be much higher than previously estimated. Pb exposure can lead to memory impairment. However, the underlying molecular mechanisms have not been fully elucidated. Dynamic changes in dendritic spines form the structural basis of memory, and MEF2C, a key regulator of dendritic plasticity, plays an important role in hippocampus-dependent learning and memory. This study focused on the role of ERK-induced MEF2C phosphorylation in Pb-induced learning and memory impairments. A rat model of Pb exposure from the embryo to adolescence and the model of Pb exposure in PC12 cells were established. The results showed that Pb exposure reduced the phosphorylation level of MEF2C in the rat hippocampus by affecting the expression of ERK5. In addition, it reduced the expression of MEF2C at the translation stage, which affected its transcriptional ability and led to abnormal expression of the downstream factor ARC, causing alterations in neuronal dendritic plasticity and affecting its memory ability. Further experiments showed that regulating the phosphorylation level of MEF2C could affect neurite growth in PC12 cells exposed to Pb. Our findings demonstrate that Pb exposure may contribute to memory impairment by affecting MEF2C and its phosphorylation levels, resulting in altered dendritic plasticity.

Lead (Pb), mercury (Hg), and cadmium (Cd), prevalent neurotoxic heavy metals in the environment, are commonly detected at low concentrations in the blood of the general population. Our previous studies demonstrated that Pb, Hg, and Cd mixture induced neurodevelopmental toxicity even at very low levels. However, the long-term effects of low-level Pb, Hg, Cd exposure on brain aging remain unclear. In this study, female rats were exposed to a mixture of 10 mg/L Pb(CH3COO)2, 0.05 mg/L HgCl2, and 3.5 mg/L CdCl2 via drinking water from mating until offspring weaning. Offspring continued to exposed to heavy metal mixture (3.5 mg/L Pb(CH3COO)2, 0.015 mg/L HgCl2, and 0.5 mg/L CdCl2) for 32 weeks. At 52 weeks of age, brain aging was comprehensively evaluated through behavioral testing, histopathological examination, and telomere assessment. The results revealed that prolonged low-level exposure to the Pb, Hg, and Cd mixture compromised telomeric function by shortening telomere length, inhibiting telomerase activity, and induced neuronal loss in the hippocampal CA1 and CA3 regions. Additionally, Golgi staining revealed disrupted dendritic spines in the hippocampus and altered spine-related signaling pathways (Snk-SPAR pathway). Furthermore, behavioral testing showed that exposure to this mixture impaired spatial memory and social cognition. In conclusion, prolonged exposure to low levels of Pb, Hg, and Cd accelerated brain aging by causing hippocampal telomere dysfunction, neuronal loss, dendritic degeneration, and cognitive decline in rats. These findings offer novel insights into the potential neurotoxic effects of chronic exposure to low-level of Pb, Hg, and Cd mixtures on neurological health.

Metabolic-dysfunction associated fatty liver disease (MAFLD) is a widespread chronic liver condition that has been steadily increasing among adolescents and young adults in recent years, posing a major global public health concern. This study aims to conduct an in-depth analysis of the Global Burden of Disease (GBD) 2021 data on MAFLD, focusing on prevalence, incidence, and disability-adjusted life years (DALY) for individuals aged 15-39, spanning the period from 1990 to 2021. This research examines data from the GBD study covering 1990 to 2021 to assess the prevalence, incidence, and DALYs associated with of MAFLD in adolescents and young adults aged 15-39. The analysis is broken down by socioeconomic status, geographic regions, and specific countries. Advanced statistical methods, including the estimated annual percentage change (EAPC) and Bayesian age-period-cohort (BAPC) modeling, were used to deliver the most current and thorough epidemiological assessment of MAFLD in this demographic. In 2021, the estimated global cases of non-alcoholic fatty liver disease among adolescents and young adults reached approximately 423 million, representing a 75.31% increase from 1990. The age-standardized prevalence rate (ASPR) was 14,221.32 cases per 100,000 population, and the age-standardized incidence rate (ASIR) was 977.61 cases per 100,000 population in 2021. Between 1990 and 2021, the ASPR, ASIR, age-standardized DALY rate, and age-standardized mortality rate showed a continuous upward trend, with EAPC of 0.84, 0.79, 0.65, and 0.81, respectively. Regions with Middle and Low-middle Socio-Demographic Index (SDI), as well as High-middle SDI, emerged as "hotspots" for MAFLD prevalence, particularly in North Africa, the Middle East, East Asia, and South Asia. Males exhibited higher prevalence rates compared to females, and the rates continued to increase across all adolescents and young adult age groups. By 2050, the ASPR for MAFLD among this population is projected to reach 16,101 cases per 100,000, signaling an alarming trend. Over the last 30 years, the burden of metabolic-dysfunction associated fatty liver disease has significantly increased among adolescents and young adults worldwide. To counter this rising global health concern, it is crucial to develop and implement targeted and effective interventions tailored to socio-economic settings.

Lead (Pb), mercury (Hg), and cadmium (Cd) are prevalent and persistent environmental contaminants, causing detrimental effects on millions of individuals worldwide. Our previous research demonstrated that early-life exposure to low-level Pb, Hg, and Cd mixtures may lead to cognitive impairments. However, the association and interaction among low levels of Pb, Hg, or Cd exposure remains unclear. In this study, a two-level full factorial design (5.481, 0.036, and 2.132 mg/L for Pb, Hg, and Cd respectively) was conducted to assess the interplay among maternal Pb, Hg, and Cd exposure on offspring cognition. Following exposure during pregnancy and lactation, a competitive absorption among Pb, Hg, and Cd was observed. Maternal exposure to each metal alone resulted in higher blood and brain concentrations of Pb, Hg, and Cd in offspring compared to co-exposure at equivalent levels. However, behavioral experiments conducted in the Morris water maze and novel object recognition test revealed maternal Pb, Hg, and Cd exposure synergistically impaired offspring's spatial cognition and recognition memory. Importantly, this dysfunction persisted into middle age even without exposure after adulthood. Moreover, the open field test and elevated plus maze indicated maternal low-level Pb, Hg, and Cd co-exposure triggered risk-taking behavior in weaning offspring, with a significant main effect for Pb exposure. No long-lasting effect on risk-taking behavior was detected in middle-aged offspring. Further investigation into molecular mechanisms showed that the dysregulation of corticosterone reaction and immune response might be the potential mechanism underlying Pb, Hg, and Cd co-exposure-induced cognitive impairments. Our study highlights the synergistic and long-lasting effects of multiple heavy metal exposures,underscoring the urgency to prevent exposure to metal mixtures among children and women of childbearing age.

The heavy metals lead (Pb), cadmium (Cd), and mercury (Hg) that cause neurocognitive impairment have been extensively studied. These elements typically do not exist alone in the environment; they are often found with other heavy metals and can enter the body through various routes, thereby impacting health. Our previous research showed that low Pb, Cd, and Hg levels cause neurobehavioral impairments in weaning and adult rats. However, little is known about the biomarkers and mechanisms underlying Pb, Cd, and Hg mixture-induced neurological impairments. A combined analysis of metabolomic and proteomic data may reveal heavy metal-induced alterations in metabolic and protein profiles, thereby improving our understanding of the molecular mechanisms underlying heavy metal-induced neurological impairments. Therefore, brain tissue and serum samples were collected from rats exposed to a Pb, Cd, and Hg mixture for proteomic and metabolomic analyses, respectively. The analysis revealed 363 differential proteins in the brain and 206 metabolites in serum uniquely altered in the Pb, Cd, and Hg mixture exposure group, compared to those of the control group. The main metabolic impacted pathways were unsaturated fatty acids biosynthesis, linoleic acid metabolism, phenylalanine metabolism, and tryptophan metabolism. We further identified that the levels of arachidonic acid (C20:4 n-3) and, adrenic acid (C22:4 n-3) were elevated and that kynurenic acid (KA) and quinolinic acid (QA) levels and the KA/QA ratio, were decreased in the group exposed to the Pb, Cd, and Hg mixture. A joint analysis of the proteome and metabolome showed that significantly altered proteins such as LPCAT3, SLC7A11, ASCL4, and KYAT1 may participate in the neurological impairments induced by the heavy metal mixture. Overall, we hypothesize that the dysregulation of ferroptosis and kynurenine pathways is associated with neurological damage due to chronic exposure to a heavy metal mixture.

目的 基于单细胞测序(single-cell RNA sequencing,scRNA-seq)数据再挖掘分析探讨人骨关节炎(human osteoarthritis,hOA)进展中相关基因及生物学过程变化.方法 从GEO数据库下载hOA软骨细胞scRNA-seq数据集,并使用R软件中Seurat、Monocle 2和CellCycleSoring等软件包对数据进行质量控制、标准化和归一化,并进行差异基因(特别是转录调控因子)、细胞周期及拟时轨迹分析,在此基础上对差异基因进行基因功能分析并解析涉及的生物学过程.结果 scRNA-seq数据分析表明hOA发展初期存在细胞因子的产生和一氧化氮的生物合成等,晚期则伴随血管生成、胶原纤维形成和基质破坏,而细胞炎症反应伴随整个病理过程;差异基因分析筛选出多个新的随hOA进展发生表达水平动态改变的转录调控因子,如KMT2C、EGR2和EBF1;差异基因功能分析显示hOA进展伴随着软骨细胞的代谢改变,表现为氧化磷酸化相关基因表达水平增加,而糖酵解相关基因表达水平降低.结论 基于hOA分级的软骨细胞拟时轨迹分析发现hOA进展过程中发生了包括转录调控因子在内的差异基因表达、生物学过程和细胞代谢方式的改变,可为临床开展阶段针对性临床干预和阻遏或逆转hOA进展的新疗法的开发提供了理论基础.

Exposure to essential and toxic metals occurs simultaneously as a mixture in real-life. However, there is no consensus regarding the effects of co-exposure to multiple metal(loid)s (designated hereafter metals) on blood lipid levels. Thus, blood concentrations of six human essential metals and five toxic metals in 720 general populations from southeastern China were simultaneously determined as a measure of exposure. In addition, quantile g-computation, Bayesian kernel machine regression, elastic net regression, and generalized linear model were used to investigate both the joint and individual effects of exposure to this metal mixture on human blood lipid levels. The significant positive joint effect of exposure to this metal mixture on serum total cholesterol (TC) levels, rather than on serum triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, Castelli risk index I, Castelli risk index II, atherogenic coefficient, and non-HDL-C levels, was found. In addition, the positive effect may be primarily driven by selenium (Se), lead (Pb), and mercury (Hg) exposure. In addition, on the effect of TC levels, the synergistic effect between Pb and Hg and the antagonistic effect between Se and Pb were identified. Our finding suggests that combined exposure to this metal mixture may affect human blood lipid levels. Therefore, reducing exposure to heavy metals, such as Pb and Hg, should be a priority for the general population. In addition, Se supplementation should also be considered with caution.

Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general population. Although our previous studies have demonstrated neurodevelopmental toxicity upon co-exposure to these heavy metals at these low levels, the precise mechanisms remain largely unknown. Dendritic spines are the structural foundation of memory and undergo significant dynamic changes during development. This study focused on the dynamics of dendritic spines during brain development following Pb, Cd, and Hg co-exposure-induced memory impairment. First, the dynamic characteristics of dendritic spines in the prefrontal cortex were observed throughout the life cycle of normal rats. We observed that dendritic spines increased rapidly from birth to their peak value at weaning, followed by significant pruning and a decrease during adolescence. Dendritic spines tended to be stable until their loss in old age. Subsequently, a rat model of low-dose Pb, Cd, and Hg co-exposure from embryo to adolescence was established. The results showed that exposure to low doses of heavy metals equivalent to those detected in the blood of the general population impaired spatial memory and altered the dynamics of dendritic spine pruning from weaning to adolescence. Proteomic analysis of brain and blood samples suggested that differentially expressed proteins upon heavy metal exposure were enriched in dendritic spine-related cytoskeletal regulation and axon guidance signaling pathways and that cofilin was enriched in both of these pathways. Further experiments confirmed that heavy metal exposure altered actin cytoskeleton dynamics and disturbed the dendritic spine pruning-related LIM domain kinase 1-cofilin pathway in the rat prefrontal cortex. Our findings demonstrate that low-dose Pb, Cd, and Hg co-exposure may promote memory impairment by perturbing dendritic spine dynamics through dendritic spine pruning-related signaling pathways.

Humans are commonly exposed to the representative neurotoxic heavy metals lead (Pb), cadmium (Cd), and mercury (Hg). These three substances can be detected simultaneously in the blood of the general population. We have previously shown that a low-dose mixture of these heavy metals induces rat learning and memory impairment at human exposure levels, but the pathogenic mechanism is still unclear. LIM kinase 1 (LIMK1) plays a critical role in orchestrating synaptic plasticity during brain function and dysfunction. Hence, we investigated the role of LIMK1 activity in low-dose heavy metal mixture-induced neurobehavioral deficits and structural synaptic plasticity disorders. Our results showed that heavy metal mixture exposure altered rat fear responses and spatial learning at general population exposure levels and that these alterations were accompanied by downregulation of LIMK1 phosphorylation and structural synaptic plasticity dysfunction in rat hippocampal tissues and cultured hippocampal neurons. In addition, upregulation of LIMK1 phosphorylation attenuated heavy metal mixture-induced structural synaptic plasticity, dendritic actin dynamics, and cofilin phosphorylation damage. The potent LIMK1 inhibitor BMS-5 yielded similar results induced by heavy metal mixture exposure and aggravated these impairments. Our findings demonstrate that LIMK1 plays a crucial role in neurobehavioral deficits induced by low-dose heavy metal mixture exposure by suppressing structural synaptic plasticity.

Environmental exposure to heavy metal mixture of lead (Pb), cadmium (Cd), and mercury (Hg) would induce hazardous health effects. However, there is a paucity of data on how exposure to heavy metal mixture alters the metabolic dynamics of individual metals. Considering that the dose plays a key role in determining the toxicity of heavy metals, we performed a factorial design with three heavy metals (Pb, Cd, and Hg) at low exposure levels. Female rats were exposed to Pb, Cd, and (or) Hg from successful mating until pup weaning. Their concentrations in maternal blood, breast milk, and postnatal day 0 (PND0) and PND21 offspring blood and whole brain were measured. Using ANOVA analysis, Pearson correlation, and structural equation model, we demonstrated the complex interactions among heavy metals during their absorption, mother-offspring transport, and target organ accumulation. Among all the explored samples, almost all the highest Pb, Cd, and Hg levels were observed in their respective single heavy metal exposure groups. In addition, Hg was found could antagonize the transport of Pb or Cd, when they cross the placental barrier and blood-brain barriers (BBB). However, the effect of Hg no longer presented when they are absorbed through the digestive system. The antagonistic effect of Pb on Cd was observed when they cross the placental barrier. In addition, Cd was also found to compete the transport pathway of Pb when they cross the BBB after birth. Compared to Pb and Hg, we found that the transport efficiency of Cd in the digestive system was lower, whereas the chelation of Cd by the placental barrier was better. This preliminary information may help researchers to explore the mechanism underlying the hazardous effects of heavy metal mixture exposure, or for regulatory agencies to revise guidelines for heavy metal exposure.

Contaminated water and food are the main sources of lead, cadmium, and mercury in the human body. Long-term and low-level ingestion of these toxic heavy metals may affect brain development and cognition. However, the neurotoxic effects of exposure to lead, cadmium, and mercury mixture (Pb + Cd + Hg) at different stages of brain development are rarely elucidated. In this study, different doses of low-level Pb + Cd + Hg were administered to Sprague-Dawley rats via drinking water during the critical stage of brain development, late stage, and after maturation, respectively. Our findings showed that Pb + Cd + Hg exposure decreased the density of memory- and learning-related dendritic spines in the hippocampus during the critical period of brain development, resulting in hippocampus-dependent spatial memory deficits. Only the density of learning-related dendritic spines was reduced during the late phase of brain development and a higher-dose of Pb + Cd + Hg exposure was required, which led to hippocampus-independent spatial memory abnormalities. Exposure to Pb + Cd + Hg after brain maturation revealed no significant change in dendritic spines or cognitive function. Further molecular analysis indicated that morphological and functional changes caused by Pb + Cd + Hg exposure during the critical phase were associated with PSD95 and GluA1 dysregulation. Collectively, the effects of Pb + Cd + Hg on cognition varied depending on the brain development stages.

Osteoarthritis (OA), the leading cause of disability in the elderly, still lacks effective treatment due to the unelucidated mechanisms of pathogenesis and progression. In cartilage, although the solo cell type of chondrocytes is resident, cartilage progenitor cells (CPCs) are identified. Chondrocytes in cartilage mainly utilize glycolysis because of the low oxygen tension. Until now, whether the metabolic pathway changes are associated with OA initiation or progression, as well as the biology of CPCs, remains fully clarified. By reviewing relevant literature from previous functional studies, we further mined recently published mouse and human chondrocytes single-cell RNA-sequencing datasets to explore gene expression profiles shift in OA initiation or during OA progression, regarding metabolism. In this review, we demonstrated that chondrocytes' metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) in OA initiation or during OA progression. Genes that related to OXPHOS, electron transport, mitochondrial translation, and mitochondrial respiratory chain complex assembly were upregulated in chondrocytes of injured cartilage or during OA progression. In addition, compared to OXPHOS, glycolysis facilitates CPC expansion and chondrogenic potential. The collated information suggests a potential therapeutic for OA through metabolic reprogramming of glycolysis to interrupt OA pathology and favor CPCs rejuvenation to restore healthy cartilage.

线上教学正在逐步应用到医学教学实践中.文章通过对我国医学院校线上教学中存在的问题进行梳理,发现主要问题集中在教学目标、教学设计、课程评价、教学氛围、教学方式等方面,并提出应对策略,为医学线上教学的发展和改革提供参考.

Spermatogenic regeneration is key for male fertility and relies on activities of an undifferentiated spermatogonial population. Here, a high-throughput approach with primary cultures of mouse spermatogonia was devised to rapidly predict alterations in functional capacity. Combining the platform with a large-scale RNAi screen of transcription factors, we generated a repository of new information from which pathway analysis was able to predict candidate molecular networks regulating regenerative functions. Extending from this database, the SRCAP-CREBBP/EP300 (Snf2-related CREBBP activator protein-CREB binding protein/E1A binding protein P300) complex was found to mediate differential levels of histone acetylation between stem cell and progenitor spermatogonia to influence expression of key self-renewal genes including the previously undescribed testis-specific transcription factor ZSCAN2 (zinc finger and SCAN domain containing 2). Single cell RNA sequencing analysis revealed that ZSCAN2 deficiency alters key cellular processes in undifferentiated spermatogonia such as translation, chromatin modification, and ubiquitination. In Zscan2 knockout mice, while spermatogenesis was moderately impacted during steady state, regeneration after cytotoxic insult was significantly impaired. Altogether, these findings have validated the utility of our high-throughput screening approach and have generated a transcription factor database that can be utilized for uncovering novel mechanisms governing spermatogonial functions.

The stem cell-containing undifferentiated spermatogonial population in mammals, which ensures continual sperm production, arises during development from prospermatogonial precursors. Although a period of quiescence is known to occur in prospermatogonia prior to postnatal spermatogonial transition, the importance of this has not been defined. Here, using mouse models with conditional knockout of the master cell cycle regulator Rb1 to disrupt normal timing of the quiescence period, we found that failure to initiate mitotic arrest during fetal development leads to prospermatogonial apoptosis and germline ablation. Outcomes of single-cell RNA-sequencing analysis indicate that oxidative phosphorylation activity and inhibition of meiotic initiation are disrupted in prospermatogonia that fail to enter quiescence on a normal timeline. Taken together, these findings suggest that key layers of programming are laid down during the quiescent period in prospermatogonia to ensure proper fate specification and fitness in postnatal life.