Repeated Exposure to Wood Smoke Alters Pulmonary Gene and Metabolic Profiles
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE237251 | GEO | 2024/06/05
REPOSITORIES: GEO
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Project description:Climate change is impacting human health through a historic rise in wildfire smoke across the United States and the world. Whereas the deleterious effects of wildfire smoke and associated air pollution on asthma outcomes are well-established epidemiologically, genetic risks and molecular mechanisms of how wildfire smoke affects asthma are unknown. This knowledge gap hinders the identification of high-risk individuals and the creation of targeted therapies or recommendations to protect these individuals. Here, we employ a genetic approach to identify common variant (minor allele frequency > 0.05) exposure-conditional genetic risk variants that localize with genomic responses to wood smoke particles (WSP), a model of wildfire smoke exposure, and associate with asthma in the Genetic Epidemiology Research on Aging (GERA) cohort. Our novel approach used nascent transcriptional signatures derived from WSP-exposed Beas-2B airway epithelial cells to reduce the genome sequence for discovery and allow a permutation-based statistical approach to identify 52 candidate SNPs. We applied biologic and bioinformatic filters to prioritize variants for direct testing of allele-dependent transcriptional regulatory function in plasmid reporters. The rs3861144 variant identified by this approach controls WSP responses of airway epithelial cells to SPRY2, which we showed is involved in mechanical injury repair in cell culture. Our results demonstrate that wildfire particulates contribute to asthma risk at the molecular level, and we have identified mechanistic targets and genetic variant candidates to apply for clinical risk prediction and development of targeted therapies for high-risk individuals.
2024-12-02 | GSE283113 | GEO
Project description:Increase in frequency and size of wildfire raises a significant public health concern due to rapid climate change. Epidemiological studies have shown that wildfire smoke exposure can increase the risk of neurological disorders. Our study aims to understand how wildfire smoke particles affect brain endothelial cells using both primary human brain microvascular endothelial cells (HBMEC) and an immortalized human cerebral microvascular endothelial cell line (hCMEC/D3). HBMEC and hCMEC/D3 were exposed to different levels of smoldering eucalyptus smoke particles (10, 30, 50 ug/mL) for 24 hr. Supernatants were collected for LDH and ELISA array, cell lysates were collected for RNAseq, and cells were fixed and stained for tight junction marker (Zonula Occludens-1, ZO-1) via ICC. Our study found that treatment to smoldering eucalyptus particles can increase inflammatory cytokine production dose-dependently in HBMECs and hCMEC/D3. Moreover, RNAseq analyses resulted in dose-dependent changes in HBMEC and hCMEC/D3 from wood smoke treatment that could be mediated via AhR and Nrf2 pathways.
2024-10-02 | GSE271935 | GEO
Project description:Repeated Exposure to Wood Smoke Alters Pulmonary Gene and Metabolic Profiles
| PRJNA994474 | ENA
Project description:Transcriptional responses to wildfire smoke, an increasingly important cause of human morbidity, are poorly understood. Here, using a combination of precision nuclear run-on sequencing (PRO-seq) and the assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify rapid and dynamic changes in transcription and chromatin structure in Beas-2B airway epithelial cells after exposure to wood smoke particles (WSP). By comparing 30 and 120 minutes of WSP exposure, we defined three distinct temporal patterns of transcriptional induction and chromatin responses to WSP. Whereas transcription of canonical targets of the aryl hydrocarbon receptor (AHR), such as CYP1A1 and AHRR, was robustly increased after 30 minutes of WSP exposure, transcription of these genes and associated enhancers returned to near baseline at 120 minutes. ChIP-qPCR assays and AHR knockdown confirmed a role for AHR in regulating these transcriptional responses, and we applied bioinformatics approaches to identify novel AHR-regulated pathways and targets including the DNA methyltransferase, DNMT3L, and its interacting factor, SPOCD1. Our analysis also defined a role for NFkB as a primary transcriptional effector of WSP-induced changes in gene expression. The kinetics of AHR- and NFkB-regulated responses to WSP were distinguishable based on the timing of both transcriptional responses and chromatin remodeling, with induction of several cytokines implicated in maintaining the NFkB response. In aggregate, our data establish a direct and primary role for AHR in mediating airway epithelial responses to WSP and identify crosstalk between AHR and NFkB signaling in controlling pro-inflammatory gene expression.
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Project description:Transcriptional responses to wildfire smoke, an increasingly important cause of human morbidity, are poorly understood. Here, using a combination of precision nuclear run-on sequencing (PRO-seq) and the assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify rapid and dynamic changes in transcription and chromatin structure in Beas-2B airway epithelial cells after exposure to wood smoke particles (WSP). By comparing 30 and 120 minutes of WSP exposure, we defined three distinct temporal patterns of transcriptional induction and chromatin responses to WSP. Whereas transcription of canonical targets of the aryl hydrocarbon receptor (AHR), such as CYP1A1 and AHRR, was robustly increased after 30 minutes of WSP exposure, transcription of these genes and associated enhancers returned to near baseline at 120 minutes. ChIP-qPCR assays and AHR knockdown confirmed a role for AHR in regulating these transcriptional responses, and we applied bioinformatics approaches to identify novel AHR-regulated pathways and targets including the DNA methyltransferase, DNMT3L, and its interacting factor, SPOCD1. Our analysis also defined a role for NFkB as a primary transcriptional effector of WSP-induced changes in gene expression. The kinetics of AHR- and NFkB-regulated responses to WSP were distinguishable based on the timing of both transcriptional responses and chromatin remodeling, with induction of several cytokines implicated in maintaining the NFkB response. In aggregate, our data establish a direct and primary role for AHR in mediating airway epithelial responses to WSP and identify crosstalk between AHR and NFkB signaling in controlling pro-inflammatory gene expression.
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Project description:Antibiotics are increasingly detected in aquatic environments, and their potential ecological risk is a concern. However, most antibiotic toxicity studies were performed with single exposure experiments. Here, we studied the effects and mechanisms of repeated clarithromycin (CLA) exposure on the algae Microcystis aeruginosa compared to the results of a single exposure. The 96-h effective concentration of CLA was 13.37 μg/L upon single exposure but was reduced to 6.90 μg/L upon repeated exposure. Single-exposure CLA inhibited algal photosynthesis by disrupting energy absorption, dissipation and trapping, reaction center activation, and electron transport, thereby inducing oxidative stress and ultrastructural damage. CLA also upregulated glycolysis, pyruvate metabolism, and the tricarboxylic acid cycle. Stronger inhibition of algal growth was observed under repeated exposure via effects on photosynthetic pigments, biosynthesis of reaction center subunits, and electron transport, inducing more substantial oxidative damage. Furthermore, repeated exposure reduced carbohydrate utilization by blocking the pentose phosphate pathway, which changed the characteristics of extracellular polymeric substances and eventually impaired algal self-defense. Risk quotients calculated from repeated exposure were higher than 1, indicating significant ecological risks. This study elucidated the severe influence of repeated antibiotic exposure on algae, providing new insights into antibiotic risk assessment.
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