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Transcriptomic signatures in human LP9 mesothelial cells after treatment with differentially purified and surface functionalized multiwalled carbon nanotubes

: Ziemann, Christina; Reamon-Buettner, Stella Marie; Lison, D.; Brûle, Sybille van den; Bonner, J.C.; Creutzenberg, Otto H.

The Toxicologist 168 (2019), No.1, Abstract PL 3290
ISSN: 0731-9193
Society of Toxicology (Annual Meeting) <58, 2019, Baltimore/Md.>
Fraunhofer ITEM ()

Exposure to certain long and straight multiwalled carbon nanotubes (MWCNT) has been implicated in adverse biological effects, including induction of malignant mesothelioma. Besides morphology, functionalization seems to affect the toxic potential of MWCNT. The ERA-NET SIINN project ICONS (“International Collaboration On Nanotube Safety”) therefore aimed at mechanistically evaluating and ranking the pro-fibrotic and genotoxic potential of seven differentially purified (chemically or thermally) and functionalized (-COOH and -NH2), or milled MWCNT, made from one batch of industrially relevant Nanocyl NC7000 (tangled morphology). As a prerequisite, initial tests indicated sterility and lack of relevant endotoxin contamination of the materials. In a subproject performed by Fraunhofer ITEM, human peritoneal mesothelial LP9 cells (target cells for mesothelioma development) were incubated for 24 h with 5 µg/cm2 of the diverse MWCNT, followed by microarray analysis to evaluate material-specific transcriptomic signatures. In subsequent bioinformatic analyses, significant number of differentially-regulated genes (DEGs) was noted for all eight MWCNT (range: 555 to 2524 genes), with the amount of differentially-regulated genes and the observed fold-change values being strongly dependent on the MWCNT type. Interestingly, number of DEGs was about two- to five-fold higher for the surface-modified samples than for pristine Nanocyl NC7000. Furthermore, number of induced genes seemed to correlate with the cytotoxic potential of the different MWCNT (e.g. membrane damage and disturbance of the tubulin network). Comparison analyses found IL-8 signaling as the top-scoring activated canonical pathway, and a broad panel of cytokines, chemokines and growth factors as top-scoring upregulated genes in all data sets. Inflammatory response and mechanisms pertaining to carcinogenesis were shown to be significantly activated. In conclusion, surface modification of tangled MWCNT can adversely influence transcriptomic signature in primary mesothelial cells, with enhancement of the pro-inflammatory potential of pristine MWCNT. This project part was funded by the German BMBF (FKZ: 03XP0063).