title: A review of adaptive mechanisms in cell responses towards oxidative stress caused by dental resin monomers.
abstract: Dental composite resins are biomaterials commonly used to aesthetically restore the structure and function of teeth impaired by caries, erosion, or fracture. Residual monomers released from resin restorations as a result of incomplete polymerization processes interact with living oral tissues. Monomers like triethylene glycol dimethacrylate (TEGDMA) or 2-hydroxylethyl methacrylate (HEMA) are cytotoxic via apoptosis, induce genotoxic effects, and delay the cell cycle. Monomers also influence the response of cells of the innate immune system, inhibit specific odontoblast cell functions, or delay the odontogenic differentiation and mineralization processes in pulp-derived cells including stem cells. These observations indicate that resin monomers act as environmental stressors which inevitably disturb regulatory cellular networks through interference with signal transduction pathways. We hypothesize that an understanding of the cellular mechanisms underlying these phenomena will provide a better estimation of the consequences associated with dental therapy using composite materials, and lead to innovative therapeutic strategies and improved materials being used at tissue interfaces within the oral cavity. Current findings strongly suggest that monomers enhance the formation of reactive oxygen species (ROS), which is most likely the cause of biological reactions activated by dental composites and resin monomers. The aim of the present review manuscript is to discuss adaptive cell responses to oxidative stress caused by monomers. The particular significance of a tightly controlled network of non-enzymatic as well as enzymatic antioxidants for the regulation of cellular redox homeostasis and antioxidant defense in monomer-exposed cells will be addressed. The expression of ROS-metabolizing antioxidant enzymes like superoxide dismutase (SOD1), glutathione peroxidase (GPx1/2), and catalase in cells exposed to monomers will be discussed with particular emphasis on the role of glutathione (GSH), which is the major non-enzymatic antioxidant. The causal relationship between vital cell functions like the regulation of cell survival or cell death in monomer-treated cell cultures and the availability of GSH will be highlighted. We will also consider the influence of monomer-induced oxidative stress on central signal transduction pathways including mitogen-activated protein kinases (MAPK) ERK1/2, p38, and JNK as well as the stress-activated transcription factors downstream Elk-1, ATF-2, ATF-3, and cJun. Finally, we address signaling pathways originating from monomer-induced DNA damage including the activation of ATM (ataxia-telangiectasia mutated), Chk2, p53, p21, and H2AX. The understanding of the mechanisms underlying adaptive cell responses will stimulate a constructive debate on the development of smart dental restorative materials which come into contact with oral tissues and effective strategies in dental therapy.
authors.affiliation: Department of Operative Dentistry and Periodontology, University Hospital Regensburg, D-93042 Regensburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krifka
authors.forename: Gianrico
authors.initials: G
authors.lastname: Spagnuolo
authors.forename: Gottfried
authors.initials: G
authors.lastname: Schmalz
authors.forename: Helmut
authors.initials: H
authors.lastname: Schweikl
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003188:Composite Resins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D011140:Polyurethanes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000180:Acrylic Resins; C029012:Composite Dental Resin; D003188:Composite Resins; D009153:Mutagens; D011140:Polyurethanes; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D005978:Glutathione