Considerable toxicological research on polycyclic aromatic hydrocarbons (PAHs), which are prevalent compounds in cigarette smoke that contribute to cancer, has focused on their genotoxic attributes. However, cancer is not solely the consequence of non-reversible mutagenic events but also include reversible, epigenetic events. Thus, there is a need to reassess the toxicity of PAHs at the epigenetic level. Gap junctional intercellular communication (GJIC) centrally modulates signal transduction pathways that epigenetically alters gene expression. There is considerable evidence linking abnormal regulation of GJIC with the nongenotoxic steps of tumor promotion. Mitogen activated protein kinases (MAPKs) also play a central role in cell signaling. We will use a series of environmental and tobacco smoke-relevant PAHs and determine structure-activity relationships with inter-and intracellular signaling mechanisms in pluripotent mammalian epithelial cell lines. We will specifically test the hypothesis SA#1 that phospholipases are the upstream regulators of GJIC and MAPK in response to PAHs by using specific phospholipase inhibitors and the emerging and powerful technique of silencing genes using small interfering RNA. We will use chromatography and state of the art proteomic techniques to test the hypothesis SA#2 that lipid-derived second messengers are released from the plasma membrane, and activate cell signal proteins. We will also test the hypothesis SA#3 that inhibition of GJIC and activation of MAPK by PAHs will induce mitogenesis, and block apoptosis and differentiation. We would like to note that the use of biologically active versus inactive PAH isomers for all of the aims allows us to systematically identify molecular events that are specific to the regulation of GJIC and MAPK and subtract out non-specific events. Overall, determining the effect of environmental and tobacco-relevant PAHs on key signaling events would provide invaluable mechanistically based information on the epigenetic toxicity of these compounds, thereby aiding in the development of preventative and therapeutic strategies for cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES013268-01A2
Application #
7147012
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Tyson, Frederick L
Project Start
2006-08-16
Project End
2009-06-30
Budget Start
2006-08-16
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$358,625
Indirect Cost
Name
Michigan State University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Babica, Pavel; ?tverá?ková, Lucie; Len?ešová, Zuzana et al. (2016) Chemopreventive Agents Attenuate Rapid Inhibition of Gap Junctional Intercellular Communication Induced by Environmental Toxicants. Nutr Cancer 68:827-37
Babica, Pavel; Sovadinová, Iva; Upham, Brad L (2016) Scrape Loading/Dye Transfer Assay. Methods Mol Biol 1437:133-44
Upham, Brad L; Sovadinová, Iva; Babica, Pavel (2016) Gap Junctional Intercellular Communication: A Functional Biomarker to Assess Adverse Effects of Toxicants and Toxins, and Health Benefits of Natural Products. J Vis Exp :
Babica, Pavel; Zurabian, Rimma; Kumar, Esha R et al. (2016) Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells. Toxicol Sci 153:174-85
Sovadinova, Iva; Babica, Pavel; Böke, Hatice et al. (2015) Phosphatidylcholine Specific PLC-Induced Dysregulation of Gap Junctions, a Robust Cellular Response to Environmental Toxicants, and Prevention by Resveratrol in a Rat Liver Cell Model. PLoS One 10:e0124454
Osgood, Ross S; Upham, Brad L; Hill 3rd, Thomas et al. (2014) Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure. PLoS One 8:e65150
Hill 3rd, Thomas; Osgood, Ross S; Velmurugan, Kalpana et al. (2013) Bronchoalveolar Lavage Fluid Utilized Ex Vivo to Validate In Vivo Findings: Inhibition of Gap Junction Activity in Lung Tumor Promotion is Toll-Like Receptor 4-Dependent. J Mol Biomark Diagn 5:
Upham, Brad L (2011) Role of integrative signaling through gap junctions in toxicology. Curr Protoc Toxicol Chapter 2:Unit2.18
Alpatova, Alla L; Shan, Wenqian; Babica, Pavel et al. (2010) Single-walled carbon nanotubes dispersed in aqueous media via non-covalent functionalization: effect of dispersant on the stability, cytotoxicity, and epigenetic toxicity of nanotube suspensions. Water Res 44:505-20
Bláha, Lud?k; Babica, Pavel; Hilscherová, Klára et al. (2010) Inhibition of gap-junctional intercellular communication and activation of mitogen-activated protein kinases by cyanobacterial extracts--indications of novel tumor-promoting cyanotoxins? Toxicon 55:126-34

Showing the most recent 10 out of 19 publications