Review A review of adaptive mechanisms in cell responses towards oxidative stress caused by dental resin monomers Stephanie Krifka a , Gianrico Spagnuolo b , Gottfried Schmalz a , Helmut Schweikl a, * a Department of Operative Dentistry and Periodontology, University Hospital Regensburg, D-93042 Regensburg, Germany b Department of Oral and Maxillofacial Science, University of Naples “Federico II”, Italy article info Article history: Received 21 February 2013 Accepted 9 March 2013 Available online xxx Keywords: Resin monomer Oxidative stress Adaptive cell response Dental composite 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 res- torations 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 observa- tions 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 de- fense 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. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Dental composite resins are prevalent materials used to aesthetically restore the structural integrity of teeth, generally impaired by caries, but also due to attrition, erosion, or fracture. Hence, diverse resinous materials are available, for instance adhe- sives (primer and bonding agents), flowable and conventional composite resins, fiber-reinforced composites or resin cements [1,2]. Their therapeutic application depends on the depth, size, and location of the existing defect from fissure sealant, caries infiltra- tion, direct and indirect restorative materials, endodontic sealer, post or retrograde root filling materials, and to luting agents for composite and ceramic restorations or orthodontic brackets [2e4]. Thus, following the revised definition of a biomaterial, dental * Corresponding author. Fax: þ49 941 944 6025. E-mail address: helmut.schweikl@klinik.uni-regensburg.de (H. Schweikl). Contents lists available at SciVerse ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.biomaterials.2013.03.019 Biomaterials xxx (2013) 1e9 Please cite this article in press as: Krifka S, et al., A review of adaptive mechanisms in cell responses towards oxidative stress caused by dental resin monomers, Biomaterials (2013), http://dx.doi.org/10.1016/j.biomaterials.2013.03.019