Polycyclic Aromatic Hydrocarbon-Induced Signaling Events Relevant to Inflammation and Tumorigenesis in Lung Cells Are Dependent on Molecular Structure

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1-Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs.

PM2.5 exposure induces vascular dysfunction via NO generated by iNOS in lung of ApoE-/- mouse

“…Among these components of the PM2.5 in our study, Zn, Ni, Al, Pb and PAHs were all reported to activate iNOS directly [28][29][30][31][32], suggesting the direct activation of iNOS by these PM2.5 components. Especially, PAHs were verified to upregulate iNOS expression via the decrease of their DNA methylation level [33][34][35]. Indeed, our results showed that PM2.5 exposure could reduce the DNA methylation of iNOS at 0.5hr, highly supporting the potential role of PAHs in activating iNOS (Fig.…”

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

“…Studies have shown that connexins play a key role in mediating inflammation. For example, inflammation by polycyclic aromatic hydrocarbons in lung and liver epithelial cells results in the inhibition of gap junction intercellular communication through production of arachidonic acid, chemokines, TNF, and Cox-2 activation [17][18][19][20]. In activated peritoneal macrophages, inhibition Cx43 function through either pharmacologic administration or gene knockout improved survival, indicated by a reduction in cytokines during sepsis [21].…”

Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells

“…The dysregulation of GJIC by VIN was attenuated by an inhibitor of p38, which is mechanistically similar to effects induced by 1-MeA in lung but not liver epithelial cells (Osgood et al, 2013;Upham et al, 2008), or by anisomycin in WB-F344 cells (Ogawa et al, 2004). Interestingly, the effects of MXC and VIN on GJIC were prevented by an inhibitor of PC-PLC.…”

“…Also, endogenous or synthetic estrogens and androgens were found to affect GJIC and connexins not only via classical genomic mechanism (Ren et al, 2013), but also via rapid actions of non-genomic signaling (Iwase et al, 2006;Lyng et al, 2000;Pluciennik et al, 1996). GJIC thus represents a cellular event possibly altered by hormones and EDCs via different mechanisms, which might be chemical-, as well as cell type-specific (Osgood et al, 2013;Sovadinova et al, 2015). The immediate cell responses to MXC and VIN observed in this study, such as inhibition of GJIC and phosphorylation of MAPKs and Cx43, were most likely mediated by rapid mechanisms independent of ER or AR genomic signaling.…”