Identification of key pathways and genes in the progression of silicosis based on WGCNA.

Silicosis, induced by inhaling silica particles in workplaces, is one of the most common occupational diseases. The prognosis of silicosis and its consequent fibrosis is extremely poor due to limited treatment modalities and lack of understanding of the disease mechanisms. In this study, a Wistar rat model for silicosis fibrosis was established by intratracheal instillation of silica (0, 50, 100 and 200 mg/mL, 1 mL) with the evidence of Hematoxylin and Eosin (HE) and Masson staining and the expressions of inflammatory and fibrotic proteins of rats' lung tissues. RNA of lung tissues of rats exposed to 200 mg/mL silica particles and normal saline for 14 d and 28 d was extracted and sequenced to detect differentially expressed genes (DEGs) and to identify silicosis fibrosis-associated modules and hub genes by Weighted gene co-expression network analysis (WGCNA). Predictions of gene functions and signaling pathways were conducted using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. In this study, it has been demonstrated the promising role of the Hippo signaling pathway in silicosis fibrosis, which will be conducive to elucidating the specific mechanism of pulmonary fibrosis induced by silica and to determining molecular initiating event (MIE) and adverse outcome pathway (AOP) of silicosis fibrosis.

The role of HMGB1 on SiC NPs-induced inflammation response in lung epithelial-macrophage co-culture system.

In recent years, carbonized silicon nanoparticles (SiC NPs) have found widespread scientific and engineering applications, raising concerns about potential human health risks. SiC NPs may induce pulmonary damage through sustained inflammatory responses and oxidative stress, with unclear toxicity mechanisms. This study uses an in vitro co-culture model of alveolar macrophages (NR8383) and alveolar epithelial cells (RLE-6TN) to simulate the interaction between airway epithelial cells and immune cells, providing initial insights into SiC NP-triggered inflammatory responses. The research reveals that increasing SiC NP exposure prompts NR8383 cells to release high mobility group box 1 protein (HMGB1), which migrates into RLE-6TN cells and activates the receptor for advanced glycation end-products (RAGE) and Toll-like receptor 4 (TLR4). RAGE and TLR4 synergistically activate the MyD88/NF-κB inflammatory pathway, ultimately inducing inflammatory responses and oxidative stress in RLE-6TN cells, characterized by excessive ROS generation and altered cytokine levels. Pretreatment with RAGE and TLR4 inhibitors attenuates SiC-induced HMGB1 expression and downstream pathway proteins, reducing inflammatory responses and oxidative damage. This highlights the pivotal role of RAGE-TLR4 crosstalk in SiC NP-induced pulmonary inflammation, providing insights into SiC NP cytotoxicity and nanomaterial safety guidelines.

Chronic Lead Exposure in Adult Mice: Associations with miR-671/CDR1as Regulation, NF-κB Signaling, and Alzheimer's Disease-like Pathology.

Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), ß-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-ß (Aß), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis.

Investigating the relationship of co-exposure to multiple metals with chronic kidney disease: An integrated perspective from epidemiology and adverse outcome pathways.

Systematic studies on the associations between co-exposure to multiple metals and chronic kidney disease (CKD), as well as the underlying mechanisms, remain insufficient. This study aimed to provide a comprehensive perspective on the risk of CKD induced by multiple metal co-exposures through the integration of occupational epidemiology and adverse outcome pathway (AOP). The study participants included 401 male mine workers whose blood metal, ß2-microglobulin (ß2-MG), and cystatin C (Cys-C) levels were measured. Generalized linear models (GLMs), quantile g-computation models (qgcomp), least absolute shrinkage and selection operator (LASSO), and bayesian kernel machine regression (BKMR) were utilized to identify critical nephrotoxic metals. The mean concentrations of lead, cadmium, mercury, arsenic, and manganese were 191.93, 3.92, 4.66, 3.11, 11.35, and 16.33 µg/L, respectively. GLM, LASSO, qgcomp, and BKMR models consistently identified lead, cadmium, mercury, and arsenic as the primary contributors to kidney toxicity. Based on our epidemiological analysis, we used a computational toxicology method to construct a chemical-genetic-phenotype-disease network (CGPDN) from the Comparative Toxicogenomics Database (CTD), DisGeNET, and GeneCard databases, and further linked key events (KEs) related to kidney toxicity from the AOP-Wiki and PubMed databases. Finally, an AOP framework of multiple metals was constructed by integrating the common molecular initiating events (reactive oxygen species) and KEs (MAPK signaling pathway, oxidative stress, mitochondrial dysfunction, DNA damage, inflammation, hypertension, cell death, and kidney toxicity). This is the first AOP network to elucidate the internal association between multiple metal co-exposures and CKD, providing a crucial basis for the risk assessment of multiple metal co-exposures.