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Linking Coregulated Gene Modules with Polycyclic Aromatic Hydrocarbon-Related Cancer Risk in the 3D Human Bronchial Epithelium.

ABSTRACT: Exposure to polycyclic aromatic hydrocarbons (PAHs) often occurs as complex chemical mixtures, which are linked to numerous adverse health outcomes in humans, with cancer as the greatest concern. The cancer risk associated with PAH exposures is commonly evaluated using the relative potency factor (RPF) approach, which estimates PAH mixture carcinogenic potential based on the sum of relative potency estimates of individual PAHs, compared to benzo[a]pyrene (BAP), a reference carcinogen. The present study evaluates molecular mechanisms related to PAH cancer risk through integration of transcriptomic and bioinformatic approaches in a 3D human bronchial epithelial cell model. Genes with significant differential expression from human bronchial epithelium exposed to PAHs were analyzed using a weighted gene coexpression network analysis (WGCNA) two-tiered approach: first to identify gene sets comodulated to RPF and second to link genes to a more comprehensive list of regulatory values, including inhalation-specific risk values. Over 3000 genes associated with processes of cell cycle regulation, inflammation, DNA damage, and cell adhesion processes were found to be comodulated with increasing RPF with pathways for cell cycle S phase and cytoskeleton actin identified as the most significantly enriched biological networks correlated to RPF. In addition, comodulated genes were linked to additional cancer-relevant risk values, including inhalation unit risks, oral cancer slope factors, and cancer hazard classifications from the World Health Organization's International Agency for Research on Cancer (IARC). These gene sets represent potential biomarkers that could be used to evaluate cancer risk associated with PAH mixtures. Among the values tested, RPF values and IARC categorizations shared the most similar responses in positively and negatively correlated gene modules. Together, we demonstrated a novel manner of integrating gene sets with chemical toxicity equivalence estimates through WGCNA to understand potential mechanisms.

SUBMITTER: Chang Y

PROVIDER: S-EPMC8560124 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is increased emphasis on understanding cumulative risk from the combined effects of chemical and non-chemical stressors as it relates to public health. Recent animal studies have identified pulmonary inflammation as a possible modifier and risk factor for chemical toxicity in the lung after exposure to inhaled pollutants; however, little is known about specific interactions and potential mechanisms of action. In this study, primary human bronchial epithelial cells (HBEC) cultured in 3D at the air-liquid interface (ALI) are utilized as a physiologically relevant model to evaluate the effects of inflammation on toxicity of polycyclic aromatic hydrocarbons (PAHs), a class of contaminants generated from incomplete combustion of fossil fuels. Normal HBEC were differentiated in the presence of IL-13 for 14 days to induce a profibrotic phenotype similar to asthma. Fully differentiated normal and asthmatic phenotype HBEC were treated with benzo[a]pyrene (BAP; 1 – 40 ug/mL) or 1% DMSO/PBS vehicle at the ALI for 48 hrs. Cells were evaluated for cytotoxicity, barrier integrity, and transcriptional biomarkers of chemical metabolism and inflammation by quantitative PCR. Cells with the asthmatic phenotype treated with BAP show some significant (p<0.05) increase in cytotoxicity and significantly (p<0.05) decreased barrier integrity compared to normal cells. Asthmatic phenotype cells also showed increase sensitivity to BAP metabolism compared to cells with the normal phenotype. Additionally, RNA sequencing data showed that a large number of genes were uniquely significantly expressed in cells with the induced asthmatic phenotype exposed to BAP. Future studies will further explore mechanisms of toxicity from global transcriptomics and investigate the role of microRNA in mediating mechanisms of toxicity and inflammation. These data are the first to evaluate the role of combined environmental factors associated with inflammation from pre-existing disease and PAH exposure on pulmonary toxicity in a physiologically relevant human in vitro model.

Project description:BackgroundNowadays, effects of fine particulate matter (PM2.5) are well-documented and related to oxidative stress and pro-inflammatory response. Nevertheless, epidemiological studies show that PM2.5 exposure is correlated with an increase of pulmonary cancers and the remodeling of the airway epithelium involving the regulation of cell death processes. Here, we investigated the components of Parisian PM2.5 involved in either the induction or the inhibition of cell death quantified by different parameters of apoptosis and delineated the mechanism underlying this effect.ResultsIn this study, we showed that low levels of Parisian PM2.5 are not cytotoxic for three different cell lines and primary cultures of human bronchial epithelial cells. Conversely, a 4 hour-pretreatment with PM2.5 prevent mitochondria-driven apoptosis triggered by broad spectrum inducers (A23187, staurosporine and oligomycin) by reducing the mitochondrial transmembrane potential loss, the subsequent ROS production, phosphatidylserine externalization, plasma membrane permeabilization and typical morphological outcomes (cell size decrease, massive chromatin and nuclear condensation, formation of apoptotic bodies). The use of recombinant EGF and specific inhibitor led us to rule out the involvement of the classical EGFR signaling pathway as well as the proinflammatory cytokines secretion. Experiments performed with different compounds of PM2.5 suggest that endotoxins as well as carbon black do not participate to the antiapoptotic effect of PM2.5. Instead, the water-soluble fraction, washed particles and organic compounds such as polycyclic aromatic hydrocarbons (PAH) could mimic this antiapoptotic activity. Finally, the activation or silencing of the aryl hydrocarbon receptor (AhR) showed that it is involved into the molecular mechanism of the antiapoptotic effect of PM2.5 at the mitochondrial checkpoint of apoptosis.ConclusionsThe PM2.5-antiapoptotic effect in addition to the well-documented inflammatory response might explain the maintenance of a prolonged inflammation state induced after pollution exposure and might delay repair processes of injured tissues.

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Linking Coregulated Gene Modules with Polycyclic Aromatic Hydrocarbon-Related Cancer Risk in the 3D Human Bronchial Epithelium.

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