Triclosan-Evoked Neurotoxicity Involves NMDAR Subunits with the Specific Role of GluN2A in Caspase-3-Dependent Apoptosis

Konrad Szychowski , Agnieszka Wnuk , J. Rzemieniec , Małgorzata Kajta , Teresa Leszczyńska , Anna Wójtowicz

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.
Author Konrad Szychowski (DoAS / DoAB)
Konrad Szychowski,,
- Department of Animal Biotechnology
, Agnieszka Wnuk
Agnieszka Wnuk,,
-
, J. Rzemieniec
J. Rzemieniec,,
-
, Małgorzata Kajta
Małgorzata Kajta,,
-
, Teresa Leszczyńska (FoFT / DoHN)
Teresa Leszczyńska,,
- Department of Human Nutrition
, Anna Wójtowicz (FoAS / DoAB)
Anna Wójtowicz,,
- Department of Animal Biotechnology
Journal seriesMolecular Neurobiology, ISSN 0893-7648, e-ISSN 1559-1182, (N/A 100 pkt)
Issue year2019
Vol56
No1
Pages1-12
Publication size in sheets0.55
Keywords in EnglishGluN1; GluN2A; GluN2B; NMDA; ROS; Triclosan
ASJC Classification2804 Cellular and Molecular Neuroscience
DOIDOI:10.1007/s12035-018-1083-z
URL https://link.springer.com/article/10.1007%2Fs12035-018-1083-z
Internal identifierWHiBZ/2019/6
Languageen angielski
LicenseJournal (articles only); author's original; Uznanie Autorstwa (CC-BY); after publication
Score (nominal)100
Score sourcejournalList
Publication indicators WoS Citations = 5; Scopus SNIP (Source Normalised Impact per Paper): 2017 = 0.993; WoS Impact Factor: 2018 = 4.586 (2) - 2018=4.643 (5)
Citation count*
Additional fields
FinansowanieThis study was supported by Polish National Science Center under grant no. 2014/13/N/NZ4/04809.
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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