Triclosan Disrupts SKN-1/Nrf2-Mediated Oxidative Stress Response in C. elegans and Human Mesenchymal Stem Cells

Yoon, Dong Suk; Choi, Yoorim; Seok, Dong; Zhang, Peng; Choi, Sung‐Ja; Alfhili, Mohammad A.; Polli, Joseph Ryan; Pendergrass, De Qwon; Taki, Faten; Kapalavavi, Brahmam; Pan, Xiaoping; Zhang, Baohong; Blackwell, T. Keith; Lee, Jin Woo; Lee, Myon‐Hee

doi:10.1038/s41598-017-12719-3

Cited by 38 publications

(24 citation statements)

References 61 publications

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“…These pathways include Nrf2-mediated oxidative stress response, nitric oxide & hypoxia signaling, mitochondrial bioenergetic dynamics, etc. (28-31). Of note, the redox levels and pathways involved in redox signaling have not been thoroughly studied in the differentiating iPS-iCMs.…”

Section: Introductionmentioning

confidence: 99%

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Shanmugam

Crossman

Rajasingh

et al. 2019

Preprint

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Background: Reprogramming of somatic cells into pluripotent stem cells (iPSC) and subsequent differentiation into iPSC-derived cardiomyocytes (iCM) seems to be a promising strategy for cardiac regenerative therapy. However, recent failure or poor outcomes in cardiac cell therapy warrants further investigation focusing on the infarction/wound environment (site of healing) to improve the cardiac regenerative medicine. Here, using next generation sequencing (NGS), we analyzed the global transcriptome to discover the unidentified genes/pathways that are crucial for cell survival, cytoprotection and mitochondrial dynamics during the differentiation of iPSC into iCM.Methods: High throughput NGS was performed RNA from human iPSCs and iCMs (n=3/group) and analyzed the global changes in the transcriptome during differentiation. Furthermore, Ingenuity Pathway Analysis (IPA) and Gene Ontology (GO) for biological process were performed to understand the transcriptional networks that are involved during iCM differentiation. RNA-seq data were further validated by qRT-PCR analyses. Results:Global transcriptome analysis revealed that ~9,290 genes (log 2 FC >2) were significantly altered in human iCMs compared to the parent iPSCs, in which 4,784 transcripts were substantially upregulated and 4,506 transcripts were down-regulated during differentiation.GO enrichment and IPA analyses revealed the top 10 regulatory networks (i.e. hierarchical order) involved in differentiation of iCMs including cardiomyocyte remodeling, integrin-linked kinase signaling, Rho family of GTPases, etc. Surprisingly, none of the top 10 pathways listed the genes liable for redox signaling networks that are crucial for the basal cellular redox homeostasis, Nrf2-dependent antioxidant defense, mitochondrial functions and cell survival. Our deeper and unbiased analysis of this data revealed that the genes involved in above canonical signaling pathways are found in the middle of the inverted vertical cone. Of note, although these pathways are significantly altered during the differentiation (of iPS into cardiomyocytes), a majority of them are ranked low in the hierarchical list (>150). Validation of the randomly selected genes representing various pathways real-time qPCR confirmed the global transcriptome changes observed in NGS. Conclusion:We highlight the significance of Nrf2-redox and mitochondrial transcriptome during differentiation of iPSC into iCMs. Thus, targeting the redox signaling mechanisms in iCMs may enhance their efficiency for cell therapy and improved myocardial repair.180 genes were detected out of 230 genes known to constitute this pathway, whereas 58 genes were increased and 56 genes were decreased. From this list, the top 15 up and down-regulated genes were used to generate the heat-maps. A substantial list of genes were downregulated during cardiomyocyte differentiation including, MGST1, GSTM5, PRKCQ, PRKCB and PIK3R, while PIK3R5ACTA2, GSTM3, FMO1, ACTC1 and GSTA3 were increased during cardiomyocyte differentiation. RNA-seq data was valid...

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Section: Introductionmentioning

confidence: 99%

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Shanmugam

Crossman

Rajasingh

et al. 2019

Preprint

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“…This gene encodes the SKN-1 proteins, which are required for longevity and oxidative stress resistance in C. elegans [ 124 ]. There are indeed some similarities between the pattern expression of sod-1 / sod-4 and skn-1 genes after their exposure to the tested compounds ( Figure 5 ), which corresponds with the role of this gene in oxidative stress responses [ 125 ].…”

Section: Discussionmentioning

confidence: 79%

Toxic Effects of Bisphenol A, Propyl Paraben, and Triclosan on Caenorhabditis elegans

Espiñeira

Benítez

Olívero-Verbel

2018

IJERPH

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Bisphenol A (BPA) is a ubiquitous plasticizer which is absorbed by ingestion and dermal contact; propyl paraben (PPB) inhibits the microbiome and extends the shelf life of many personal care products, whereas triclosan (TCS) is commonly found in antiseptics, disinfectants, or additives. In this work, Caenorhabditis elegans was used as a biological model to assess the toxic effects of BPA, PPB, and TCS. The wild type strain, Bristol N2, was used in bioassays with the endpoints of lethality, growth, and reproduction; green fluorescent protein (GFP) transgenic strains with the hsp-3, hsp-4, hsp-16.2, hsp-70, sod-1, sod-4, cyp-35A4, cyp-29A2, and skn-1 genes were evaluated for their mRNA expression through fluorescence measurement; and quick Oil Red O (q ORO) was utilized to stain lipid deposits. Lethality was concentration-dependent, while TCS and PPB showed more toxicity than BPA. BPA augmented worm length, while PPB reduced it. All toxicants moderately increased the width and the width–length ratio. BPA and PPB promoted reproduction, in contrast to TCS, which diminished it. All toxicants affected the mRNA expression of genes related to cellular stress, control of reactive oxygen species, and nuclear receptor activation. Lipid accumulation occurred in exposed worms. In conclusion, BPA, PPB, and TCS alter the physiology of growth, lipid accumulation, and reproduction in C. elegans, most likely through oxidative stress mechanisms.

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“…In male rats, TCS exposure led to decreases in serum testosterone (T), sperm production, and male accessory gland weight (Kumar, Chakraborty, Kural, & Roy, 2009). Recent studies have also shown that TCS may interfere with thyroid hormone metabolism in humans through the activation of nuclear receptors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR) (Yoon et al, 2017). In vitro studies also confirmed that TCS exert both estrogenic and androgenic effects in assays with breast cancer cells (Clayton, Todd, Dowd, & Aiello, 2011;Gee, Taylor, & Darbre, 2008) and receptor-based bioassay screens.…”

Section: Introductionmentioning

confidence: 99%

Assessment of triclosan impact on enzymatic biomarkers in an Indian major carp, Catla catla

Hemalatha

Rangasamy

Nataraj

et al. 2019

JoBAZ

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Background: The present study was designed to determine the median lethal concentration (96-h LC50) of triclosan (TCS) and to investigate the effect of a sublethal concentrations of TCS on the activities of glutamic oxaloacetic transaminases (GOT), glutamic pyruvic transaminases (GPT), and glutathione S-transferase (GST) in the gill, liver, and muscle of an Indian major carp Catla catla. Results: In this study, static renewal procedure was followed to determine the 96 LC50 value. The results indicated that the 96-h LC50 of TCS for C. catla was 0.36 mg L −1. 1/10th, 1/25th, and 1/50th of 96-h LC50 value (0.036, 0.014, 0.007 mg L −1) were selected for sublethal studies, and the fish were examined every 5 days for 20 days. The results indicated that TCS exposure to fish at three different sublethal concentrations significantly (p < 0.05, p < 0.01) enhanced GOT, GPT, and GST enzyme activity in all the tissues with increased dose and exposure period. Conclusion: Prolonged exposure (20 days) to TCS at sublethal concentrations induces severe physiological alterations in Catla catla, and these biomarkers can be used as a mechanistic tool for evaluating the toxicity-derived alterations in fish.

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Triclosan Disrupts SKN-1/Nrf2-Mediated Oxidative Stress Response in C. elegans and Human Mesenchymal Stem Cells

Cited by 38 publications

References 61 publications

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Toxic Effects of Bisphenol A, Propyl Paraben, and Triclosan on Caenorhabditis elegans

Assessment of triclosan impact on enzymatic biomarkers in an Indian major carp, Catla catla

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