Mechanistic Insights into Lead Acetate-Induced Neurotoxicity Using RNA-Seq Analysis
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ABSTRACT:
PROVIDER: PRJNA1204108 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31848306_1.fastq.gz | Fastqsanger.gz | |||
| SRR31848306_2.fastq.gz | Fastqsanger.gz |
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Project description:Lead acetate (Pb-acet) is a neurotoxicant that significantly impacts human brain development. This study used LUHMES cells, a human embryonic stem cell-derived neuronal model, to explore its molecular toxicity mechanisms. RNA sequencing (RNA-seq) showed distinct gene expression changes due to Pb-acet exposure. Principal Component Analysis (PCA) highlighted significant gene expression alterations at high toxicant concentrations (Ld10) compared to low concentrations (Ld1) and controls. Pb-acet disrupted pathways related to ribosome function and RNA splicing, and activated endoplasmic reticulum (ER) stress pathways, including PERK, ATF6, and IRE1. It also upregulated genes linked to ER-associated degradation (e.g., SVIP) and apoptosis (Bcl2 and CHOP), and disrupted the ubiquitin ligase complex, indicating impaired protein homeostasis. This study identifies ribosomal processes and ER stress pathways as potential biomarkers of Pb-acet exposure, demonstrating the utility of LUHMES cells in neurodevelopmental toxicity and environmental biomarker research.
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Project description:Heavy metal toxicity is a worldwide health problem. Lead exposure is of particular concern due to the adverse effects of low concentrations on cognitive development in children. Although the mechanism of lead neurotoxicity has been well studied, the analysis and molecular mechanism of the transgenerational effects of lead exposure-induced neurotoxicity are lacking. To address this, Drosophila, a powerful developmental animal model, was exposed to lead acetate. We found that Pb exposure during the developmental stage affected the neurodevelopment of F0 fruit flies, resulting in a loss of the correlation between the motor terminal area and muscle fiber area and the increased frequency of β-lobe midline crossing phenotype in Mushroom bodies. We also found that Pb exposure led to an increase in BRP expression, suggesting an increase in synaptic vesicle release sites and a decrease in synaptic vesicle protein SYN expression in F0 generation. This explained the results of our electrophysiological data that Pb exposure led to an increase in the amplitude of evoked excitatory junctional potential (EJP) and an increase in the frequency of spontaneous excitatory junctional potential (mEJP). Our results further confirmed that the developmental neurotoxicity of parental Pb exposure has a transgenerational effect. Neurodevelopmental defects, abnormalities in synaptic function, and repetitive behavior also were observed in the F3 offspring of F0 exposed to lead. Our Medip-seq analysis showed that Pb exposure altered the DNA methylation levels of many neurodevelopmentally associated genes (eg, hppy, nrg, baz, and spn) in the F3 offspring of the F0 generation with Pb exposure. Our findings suggest that epigenetic mechanisms may underlie the transgenerational inheritance of acquired phenotypic traits resulting from exposure to environmental factors.
2023-12-09 | GSE249281 | GEO
Project description:An oligonucleotide microarray, the HC ToxArrayTM was used to study the gene expression changes induced by lead acetate in mouse liver.
2010-07-26 | E-MEXP-2712 | biostudies-arrayexpress
Project description:Lead exposure induced transgenerational developmental neurotoxicity by altering genome methylation in Drosophila
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Project description:Background Lignocellulosic biomass is a promising renewable feedstock for biofuel production. Acetate is one of the major inhibitors liberated from hemicelluloses during hydrolysis. An understanding of the toxic effects of acetate on the fermentation microorganism and the efficient utilization of mixed sugars of glucose and xylose in the presence of hydrolysate inhibitors is crucial for economic biofuel production. Results A new microarray was designed including both coding sequences and intergenic regions to investigate the acetate stress responses of Zymomonas mobilis 8b when using single carbon sources of glucose or xylose, or mixed sugars of both glucose and xylose. With the supplementation of exogenous acetate, 8b can utilize all the glucose with a similar ethanol yield, although the growth, final biomass, and ethanol production rate were reduced. However, xylose utilization was inhibited in both media containing xylose or a mixed sugar of glucose and xylose, although the performance of 8b was better in mixed sugar than xylose-only media. The presence of acetate caused genes related to biosynthesis, the flagellar system, and glycolysis to be downregulated, and genes related to stress responses and energy metabolism to be upregulated. Unexpectedly, xylose seems to pose more stress on 8b, recruiting more genes for xylose utilization, than does acetate. Several gene candidates based on transcriptome results were selected for genetic manipulation, and a TonB-dependent receptor knockout mutant was confirmed to have a slight advantage regarding acetate tolerance. Conclusions Our results indicate Z. mobilis utilized a different mechanism for xylose utilization, with an even more severe impact on Z. mobilis than that caused by acetate treatment. Our study also suggests redox imbalance caused by stressful conditions may trigger a metabolic reaction leading to the accumulation of toxic intermediates such as xylitol, but Z. mobilis manages its carbon and energy metabolism through the control of individual reactions to mitigate the stressful conditions. We have thus provided extensive transcriptomic datasets and gained insights into the molecular responses of Z. mobilis to the inhibitor acetate when grown in different sugar sources, which will facilitate future metabolic modeling studies and strain improvement efforts for better xylose utilization and acetate tolerance.
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Project description:Quantifying impact of lead on cytokine production and gene expression in PBMCs Cells were treated with 10mkM lead acetate for one day, washed and grown in RPMI for the second day. Lead acetate was not added to matching control cells.
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Project description:75 Diosophilia Roo lines, recominant inbred lines, were raised to adulthood either on conventional diet or diet supplemented with lead acetate. Whole flies were used for RNA extraction. RNA was run on Dros Genome 2 arrays. Each line also genotyped for 88 markers; Control food consisted of standard cornmeal, agar, sugar, yeast, and 250 microM NaAc (Ashburner 1989). Lead-contaminated food consisted of standard food plus 250 microM PbAc (lead exposure at this concentration has been shown to affect locomotion in adults (Hirsch et al. 2003)). Experiment Overall Design: 75 RI lines each line treated and untreated with lead acetate
2009-06-08 | E-GEOD-11695 | biostudies-arrayexpress
Project description:Mechanistic insights into cancer drug resistance through optogenetic PI3K signaling hyperactivation
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Project description:Lead is a ubiquitous environmental and industrial pollutant. Its nonbiodegradable toxicity induces a plethora of human diseases. The current study was undertaken to purify a novel 252-kDa bioactive glycoprotein containing 1.15% carbohydrate from the edible fungus Auricularia polytricha with the ability of adsorbing lead and producing detoxification. The A. polytricha detoxifying glycoprotein (APL), which displayed unique molecular properties, was purified by ion exchange chromatography and gel filtration chromatography. For investigating the protective effects of A. polytricha, Sprague Dawley (SD) rats were divided into six groups which received daily intraperitoneal injection of lead acetate for 30 days, followed by gavage with APL (40, 80, 160 mg/kg B body weight) and EDTA (300 mg/kg body weight) for 30 days after successful establishment of an animal model of lead detoxification. The serum concentrations of lead and the liver biomarkers AST and ALT were significantly (p<0.05) improved by APL treatments, as well as treatment with the positive control EDTA. Likewise, results on lead residue showed that the clearance ratios of liver and kidney were respectively 44.5% and 18.1% at the high APL dosage, which was even better than the corresponding data for EDTA. Proteomics disclosed that 351 proteins differentially expressed due to lead exposure and the expression levels of 41 proteins enriched in the pathways mainly involved in cell detoxification and immune regulation were normalized after treatment with APL-H. Our results signify that APL may ameliorate lead-induced hepatorenal injury by positive regulation of immune processing, and suggest that APL be applied as a therapeutic intervention of lead poisoning in clinic treatment. This report represents the first demonstration of the protective action of a novel mushroom protein on lead-elicited hepatorenal toxicity.
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