Citation:

Thai, S., C. Jones, B. Robinette, G. Nelson, A. Tennant, H. Ren, B. Vallanat, A. Astriab Fisher, J. Ross, AND K. Kitchin. Effects of multi-walled carbon nanotubes on message and Micro-RNA in human lung BEAS-2B cells. Materials Express. American Scientific Publishers , VALENCIA, CA, 14(2):249-263, (2024). https://doi.org/10.1166/mex.2024.2620

Impact/Purpose:

The production of CNTs exceed several thousand tons per year. There are wide applications for CNTs, they are used in energy storage, automotive parts, semi-conductors, boat hulls, sporting goods, thin-film electronics and medical applications. CNTs are being highly researched as efficient drug delivery and biosensing methods for disease treatment and health monitoring. Humans are exposed CNTs through inhalation, dermal exposure, and oral exposure through contaminated food and water.             Despite the huge amount of interest and investment in MWCNTs, the toxicological and genomic impacts of these and other engineered nanoparticles are not well understood.  MWCNTs are similar to asbestos in the physical dimensions and bio-persistence and MWCNTs were found to exhibit asbestos-like pathogenicity. In our genomic and miRNA study, we examined the effects of a MWCNT and its functionalized (-OH and -COOH) counterparts.  The results showed that -OH or -COOH functionalized MWCNTs were more biologically active than the unfunctionalized parent material.  The functionalized MWCNTs induced more changes in gene/microRNAs and more signaling pathways (from mRNA IPA analysis) and signaling hubs (from Target filter analysis) than the non-functionalized MWCNT. Our study also confirmed that functionalized MWCNT are more genotoxic (DNA damage) than the unfunctionalized MWCNT using the DNA repair pathways (BER and NER) as surrogate indicators. Furthermore, we showed that -OH modified MWCNT are more potent in causing changes in DNA repair pathways than the -COOH modified MWCNT. In addition, we demonstrated that functionalized MWCNTs caused more and larger changes in expression of the inflammation related genes. This may indicate more inflammation in functionalized MWCNTs treated cells.

Description:

Multi-walled carbon nanotubes (MWCNTs) lack sufficient quality cytotoxicity, toxicity, genotoxicity and genomic data on which to make environmental and regulatory decisions. Therefore, we did a multidisciplinary in vitro study of 3 MWCNTs in human lung cells (BEAS-2B) with the following endpoints: cytotoxicity, DNA damage, reactive oxygen and nitrogen species, lipid peroxidation and mRNA and microRNA expression analyses. The MWCNTs were either unfunctionalized or functionalized with either –OH or –COOH. Doses studied ranged from 0.3 to 100 ug/ml and were exposed to a human lung cell line in vitro for 72 h., with genomic studies being done from 30 ug/ml downward. Some of the genomic pathways that were altered by MWCNT exposure were NRF2 mediated oxidative stress response, DNA damage repair, nuclear excision repair, base excision repair, mitochondrial dysfunction, oxidative phosphorylation, HIF1α signaling, unfolded protein response, protein ubiquitination, ferroptosis and sirtuin signaling pathways. The data suggested that OH functionalized MWCNT caused more and larger gene/microRNA changes, followed by COOH functionalized MWCNT and unfunctionalized MWCNT being the least biologically active. From microRNA target filter analysis, there were altered signaling hubs. MYC is the only hub that altered by all 3 MWCNTs. Signaling hubs that are common to OH and COOH functionalized MWCNTs are GRB2, AR, TP63 and AGO2. The signaling hubs that were only present in OH functionalized MWCNTs are TP53, STAT3 and BRCA1. These signaling pathways and hubs we found in vitro correlated well with the published in vivo pathological effects like oxidative stress, DNA damage, inflammation and cancer in MWCNTs treated mice.

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