Engagement of peroxisome proliferator-activated receptor gamma (PPARγ) and mammalian target of rapamycin (mTOR) in the triclosan-induced disruption of Cyp450 enzyme activity in an in vitro model of mouse embryo fibroblasts (3T3-L1).
Konrad A Szychowski, Bartosz Skóra, Anna K Wójtowicz
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引用次数: 0
Abstract
Triclosan (TCS) is commonly used worldwide due to its bactericidal and antifungal properties. There are data suggesting the involvement of aryl hydrocarbon receptors (AhR) and peroxisome proliferator-activated receptors (PPARγ). Since the effect of TCS on mouse fibroblasts has not been described so far, we decided to investigate the mechanism of action of this compound in the mouse embryonic fibroblast cell line (3T3-L1). Our results showed that high µM concentrations of TCS increased caspase-3 activity and decreased cell viability after 24-h exposure. The molecular analysis confirmed that 1 µM TCS decreased Ki67 mRNA expression and PCNA protein expression with a similar tendency to that of AhR. The analyses of mRNA levels after treatment with αNF or βNF alone and αNF in combination with TCS showed an increase in Ki67 mRNA expression. TCS alone increased AhR mRNA but had different effects on Cyp1a1 and Cyp1b1 expression. These results suggest the involvement of the PPARγ pathway in the inhibition of Cyp1b1 by TCS. After the TCS exposure, we observed a decrease in PPARγ, and this effect was enhanced in the presence of an AhR agonist and antagonist. These results support the theory about the interaction between the AhR and PPARγ pathways. In the experiments, the strongest increase in PI3K protein expression was observed in the group treated simultaneously with TCS and βNF. Changes in the PI3K level were reflected in changes in the examined mTOR protein. TCS caused a decrease in both mTOR and Cyp1b1 after 24 hours, while opposite effects were observed after 48 hours. Given the crucial role of Cyp1b1, PPARγ, and mTOR in cellular metabolism, we can conclude that TCS is able to disrupt a number of cellular processes. Our data suggest that TCS reduces the metabolism of this xenobiotic in mouse preadipocytes.
期刊介绍：
Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.
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