title: Aryl hydrocarbon receptor is an ozone sensor in human skin.
abstract: Ozone, one of the main components of photochemical smog, represents an important source of environmental oxidative stress to which the skin is exposed, especially during smoggy and ozone-alert days. However, very little is known about the effects of ozone exposure on human skin. Here, we used normal human epidermal keratinocytes (NHEKs) to determine the effects of attainable levels of ozone exposure on the family of cytochrome P450 (CYP) isoforms, which plays a determinant role in the biotransformation of many environmental pollutants. NHEK exposure to ozone (0.3 ppm) resulted in an increase in protein and messenger RNA (mRNA) expression of CYP1A1, CYP1A2, and CYP1B1. NHEK exposure to ozone also resulted in nuclear translocation of the aryl hydrocarbon receptor (AhR) and in phosphorylation of epidermal growth factor receptor (EGFR). The effect of ozone on events downstream of EGFR was an increased activation of phosphoinositide 3-kinase and phosphorylation of protein kinase B and mitogen-activated protein kinases. We found that AhR silencing by small interfering RNA abolished the capacity of these cells to increase the protein and mRNA expression of CYPs on ozone exposure. Thus, AhR signaling is an integral part of the induction of CYPs by ozone. These studies strongly suggest that there are toxicological consequences of ozone to human skin.
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Farrukh
authors.initials: F
authors.lastname: Afaq
authors.forename: Mohammad Abu
authors.initials: MA
authors.lastname: Zaid
authors.forename: Edward
authors.initials: E
authors.lastname: Pelle
authors.forename: Naghma
authors.initials: N
authors.lastname: Khan
authors.forename: Deeba N
authors.initials: DN
authors.lastname: Syed
authors.forename: Mary S
authors.initials: MS
authors.lastname: Matsui
authors.forename: Daniel
authors.initials: D
authors.lastname: Maes
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010126:Ozone / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D010126:Ozone; D003577:Cytochrome P-450 Enzyme System; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases