title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Center, Aurora, Colorado, United States of America.
authors.forename: Ross S
authors.initials: RS
authors.lastname: Osgood
authors.forename: Brad L
authors.initials: BL
authors.lastname: Upham
authors.forename: Thomas
authors.initials: T
authors.lastname: Hill
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Helms
authors.forename: Kalpana
authors.initials: K
authors.lastname: Velmurugan
authors.forename: Pavel
authors.initials: P
authors.lastname: Babica
authors.forename: Alison K
authors.initials: AK
authors.lastname: Bauer
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000737:chemistry / Q000633:toxicity; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008168:Lung / Q000473:pathology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008970:Molecular Weight; D010766:Phosphorylation / Q000187:drug effects; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry* / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000873:Anthracenes; D018031:Connexin 43; D011084:Polycyclic Aromatic Hydrocarbons; D047428:Protein Kinase Inhibitors; C051246:1-methylanthracene; C051247:2-methylanthracene; D020928:Mitogen-Activated Protein Kinases