Dysregulation of Gap Junction Function and Cytokine Production in Response to Non-Genotoxic Polycyclic Aromatic Hydrocarbons in an In Vitro Lung Cell Model.

Brad L. Upham,Deedee Romo,Kalpana Velmurugan,Alison K. Bauer,Lori D. Dwyer-Nield

doi:10.3390/cancers11040572

Abstract

Polycyclic aromatic hydrocarbons (PAHs), prevalent contaminants in our environment, in many occupations, and in first and second-hand smoke, pose significant adverse health effects. Most research focused on the genotoxic high molecular weight PAHs (e.g., benzo[a]pyrene), however, the nongenotoxic low molecular weight (LMW) PAHs are emerging as potential co-carcinogens and tumor promoters known to dysregulate gap junctional intercellular communication (GJIC), activate mitogen activated protein kinase pathways, and induce the release of inflammatory mediators. We hypothesize that inflammatory mediators resulting from LMW PAH exposure in mouse lung epithelial cell lines are involved in the dysregulation of GJIC. We used mouse lung epithelial cell lines and an alveolar macrophage cell line in the presence of a binary PAH mixture (1:1 ratio of fluoranthene and 1-methylanthracene; PAH mixture). Parthenolide, a pan-inflammation inhibitor, reversed the PAH-induced inhibition of GJIC, the decreased CX43 expression, and the induction of KC and TNF. To further determine the direct role of a cytokine in regulating GJIC, recombinant TNF (rTNF) was used to inhibit GJIC and this response was further enhanced in the presence of the PAH mixture. Collectively, these findings support a role for inflammation in regulating GJIC and the potential to target these early stage cancer pathways for therapeutics.

Highlights

Polycyclic aromatic hydrocarbons (PAH) are abundant toxicants in the environment, occupational settings, and in mainstream smoke, secondhand smoke (SHS), and thirdhand smoke exposures [1,2,3,4]
In the C10 the cells, PAH the mixture not cytotoxic cytotoxic up to 60 all μM, all subsequent studies done at non-cytotoxic below up to 60 μM, subsequent studies were done were at non-cytotoxic doses belowdoses
This finding is important given that the lung microenvironment is so complex, and inflammation is involved in the early stages of cancer development that is typically dependent on immune cells, the macrophages [28]

Summary

Introduction

Polycyclic aromatic hydrocarbons (PAH) are abundant toxicants in the environment (air, water, soil), occupational settings, and in mainstream smoke, secondhand (sidestream) smoke (SHS), and thirdhand smoke exposures [1,2,3,4]. In SHS, the level of 2–4 ring LMW PAHs is ~20 times that of the HMW PAHs [2] and in the Kentucky 1R1 reference cigarette smoke condensates, the methylated anthracenes (LMW PAHs) are 62 times higher than B[a]P and benzo(e)pyrene [11] Many of these LMW PAH species are considered U.S.E.P.A. priority PAHs based on their potential for human exposure and abundance at hazardous waste sites, environmental disasters (e.g., Deepwater Horizon oil spill), among others [3,18]. Our objective is to provide mechanistic-based empirical evidence to improve the assessment of health risks from LMW PAHs, and potentially identify new therapeutic targets

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Conclusion