Cell toxicity of methacrylate monomers—The role of glutathione adduct formation

Abstract

Polymer-based dental restorative materials are designed to polymerize in situ. However, the conversion of methacrylate monomer to polymer is never complete, and leakage of the monomer occurs. It has been shown that these monomers are toxic in vitro; hence concerns regarding exposure of patients and dental personnel have been raised. Different monomer methacrylates are thought to cause toxicity through similar mechanisms, and the sequestration of cellular glutathione (GSH) may be a key event. In this study we examined the commonly used monomer methacrylates, 2-hydroxyethylmethacrylate (HEMA), triethylenglycol-dimethacrylate (TEGDMA), bisphenol-A-glycidyl-dimethacrylate (BisGMA), glycerol-dimethacrylate (GDMA) and methyl-methacrylate (MMA). The study aimed to establish monomers' ability to complex with GSH, and relate this to cellular toxicity endpoints. Except for BisGMA, all the monomer methacrylates decreased the GSH levels both in cells and in a cell-free system. The spontaneous formation of methacrylate-GSH adducts were observed for all methacrylate monomers except BisGMA. However, we were not able to correlate GSH depletion and toxic response measured as SDH activity and changes in cell growth pattern. Together, the current study indicates mechanisms other than GSH-binding to be involved in the toxicity of methacrylate monomers.

Cell toxicity of 2‐hydroxyethyl methacrylate (HEMA): the role of oxidative stress

“…Arguing this, we did not observe increased cell death when extending the BSO exposure time to 48 h (data not shown). The previously reported lack of correlation between glutathione depletion and cell viability after exposure to different methacrylate monomers also suggests additional toxic mechanisms of at least some methacrylates.…”

Activation of the Nrf2-regulated antioxidant cell response inhibits HEMA-induced oxidative stress and supports cell viability

“…The high levels of Nrf2 in HEMA-exposed cells are most likely the result of the inhibited proteasomal degradation of Nrf2 rather than a transcriptional activation immediately after exposure of cells to the monomer due to oxidized SH-groups in Keap1 and Nrf2 acting as a post-translational mechanism of stabilization [18]. Yet, activation of Nrf2 through the covalent binding of the electrophilic methacrylate group in HEMA to nucleophilic thiol groups in a Nrf2-Keap1 complex cannot be ruled out at present since binding of monomers to the SH-group of glutathione in particular has also been reported [36]. Noteworthy is that the amount of Nrf2 remained constant in cell nuclei after various exposure periods, indicating maximal stabilization of the protein in the presence of HEMA, and a slight decrease in the Nrf2 levels in the cytosol may be a consequence of its translocation to the nucleus.…”

“…The crucial role of the non-enzymatic antioxidant glutathione (GSH) for the generation of oxidative stress in monomer-exposed cell cultures has been previously revealed [17,35,36]. Here we hypothesized that an unambiguous influence of GSH on the formation of a specific type of ROS not investigated so far might lead to specific therapeutic options.…”

Feasibility and Biocompatibility of 3D‐Printed Photopolymerized and Laser Sintered Polymers for Neuronal, Myogenic, and Hepatic Cell Types

“…Cytotoxic effects of methacrylate monomers and oligomers have been previously reported in the literature. This is attributed to the induction of apoptosis, genotoxicity, and cell cycle arrest . Further work has speculated that such toxicity may also be related to the generation of reactive oxygen species (ROS) within cell cultures .…”