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.
Highlights
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental toxicants found in air, water, plants, soil, and sediment in many countries
gap junctional intercellular communication (GJIC) in Response to lower molecular weight (LMW) PAHs Little cytotoxicity was observed in the C10 cells in response to either vehicle, 1- or 2-MeA treatments (Fig. 2) at doses between 25–150 mM for several time points (30 min, 1.5 and 6 h), all subsequent experiments on cell signaling were conducted at these non-cytotoxic doses and times
Since 1-MeA was shown to inhibit GJIC quickly and effectively at a concentration of 75 mM, we investigated whether this effect was reversible after removal of 1MeA and replacement with serum free media
Summary
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental toxicants found in air, water, plants, soil, and sediment in many countries. While secondhand smoke exposure has greatly decreased in the U.S, except in apartment dwellings [7], other countries, such as China, Korea, Japan, India, Russia, Poland, and Egypt are still dealing with the effects of ETS, including childhood and adult asthma, chronic obstructive pulmonary disease (COPD), and cancer, as well as other associated etiologies such as reproductive health issues [8,9,10] Both in vivo and in vitro evidence in several cell types suggests that these nongenotoxic PAHs can modulate mechanisms involved in pulmonary diseases, such as MAP kinases (MAPK), inflammatory signaling, and influence understudied signaling events such as gap junctional intercellular communication (GJIC) [11,12]
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