Abstract
Triclosan (TCS) is an antimicrobial agent that is used extensively in personal care and in sanitising products. A number of studies have shown the presence of TCS in different human tissues such as blood, adipose tissue, the liver, brain as well as in breast milk and urine. N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are widely expressed in the central nervous system and which play key roles in excitatory synaptic transmission. There is, however, no data on the involvement of NMDAR subunits in the apoptotic and neurotoxic effects of TCS. Our experiments are the first to show that TCS used at environmentally relevant concentrations evoked NMDA-dependent effects in neocortical neurons in primary cultures, as MK-801, an uncompetitive NMDA receptor antagonist, reduced the levels of TCS-induced ROS production as well as caspase-3 activity and LDH release. TCS caused a decrease in protein expression of all the studied NMDA receptor subunits (GluN1, GluN2A, GluN2B) that were measured at 3, 6 and 24 h post-treatment. However, at 48 h of the experiment, the level of the GluN1 subunit returned to the control level, and the levels of the other subunits showed a tendency to increase. In TCS-treated neocortical cells, protein profiles of NMDAR subunits measured up to 24 h were similar to mRNA expression of GluN1 and GluN2A, but not to GluN2B mRNA. In this study, cells transiently transfected with GluN1, GluN2A or GluN2B siRNA exhibited reduced levels of LDH release, which suggests the involvement of all of the studied NMDAR subunits in the neurotoxic action of TCS. According to our data, GluN1 and GluN2A were mainly responsible for neuronal cell death as evidenced by neutral red uptake, whereas GluN2A was involved in TCS-induced caspase-3-dependent apoptosis. We suggest that TCS-evoked apoptosis and neurotoxicity could be related to transient degradation of NMDAR subunits in mouse neurons. Furthermore, recycling of NMDAR subunits in response to TCS is possible. Because transfections with specific siRNA did not completely abolish the effects of TCS as compared to cells transfected with negative siRNA in this study, other NMDAR-independent mechanisms of TCS action are also possible.
Highlights
Triclosan (IUPAC name: 5-chloro-2-(2,4-dichlorophenoxy)phenol; CAS number: 3380-34-5) (TCS) is an antimicrobial agent that is commonly used worldwide
Our experiments are the first to show that TCS used at environmentally relevant concentrations activated caspase-3 and stimulated Reactive oxygen species (ROS) production as well as lactate dehydrogenase (LDH) release in neocortical neurons in primary cultures
Cells transiently transfected with GluN1, GluN2A or GluN2B siRNA exhibited reduced levels of LDH release, which suggests the involvement of all of the studied N-Methyl-D-aspartate receptors (NMDARs) subunits in the neurotoxic action of TCS
Summary
Triclosan (IUPAC name: 5-chloro-2-(2,4-dichlorophenoxy)phenol; CAS number: 3380-34-5) (TCS) is an antimicrobial agent that is commonly used worldwide. Due to both its anti-bacterial and anti-mould properties, it is added to a wide range of personal care and sanitising products as well as to household items or medical devices [1,2,3,4,5]. A number of studies have revealed the presence of TCS in human tissues, such as in fat, the liver, brain and in blood or breast milk [9,10,11,12]. Alarming concentrations of TCS have been detected in fish (13–88 ng/g) and human (0.23 ng/g) brains [10, 13]. Only a few papers have examined the TCS mechanism of action in neuronal cells [14,15,16]
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