JAK/STAT and TGF-ß activation as potential adverse outcome pathway of TiO2NPs phototoxicity in Caenorhabditis elegans

Abstract

Titanium dioxide nanoparticles (TiO2NPs) are widely used nanoparticles, whose catalytic activity is mainly due to photoactivation. In this study, the toxicity of TiO2NPs was investigated on the nematode Caenorhabditis elegans, with and without UV activation. Comparative analyses across the four treatments revealed that UV-activated TiO2NPs led to significant reproductive toxicity through oxidative stress. To understand the underlying molecular mechanism, transcriptomics and metabolomics analyses were conducted, followed by whole-genome network-based pathway analyses. Differential expression analysis from microarray data revealed only 4 DEGs by exposure to TiO2NPs alone, compared to 3,625 and 3,286 DEGs by UV alone and UV-activated TiO2NPs, respectively. Pathway analyses suggested the possible involvement of the JAK/STAT and TGF-ß pathways in the phototoxicity of TiO2NPs, which correlated with the observation of increased gene expression of those pathways. Comparative analysis of C. elegans response across UV activation and TiO2NPs exposure was performed using loss-of-function mutants of genes in these pathways. Results indicated that the JAK/STAT pathway was specific to TiO2NPs, whereas the TGF-ß pathway was specific to UV. Interestingly, crosstalk between these pathways was confirmed by further mutant analysis. We consider that these findings will contribute to understand the molecular mechanisms of toxicity of TiO2NPs in the natural environment.

In vitro evaluation of the toxicity and underlying molecular mechanisms of Janus Fe3O4‐TiO2 nanoparticles in human liver cells

“…14 It is considered that NPs at different sizes and chemical compositions first act on the mitochondria of redox organelles in cells, which can increase the production of ROS or interfere with the cells antioxidant defense mechanisms. 15,16 Interestingly, although the toxicity of single Fe 3 O 4 NPs or TiO 2 NPs [17][18][19] has been widely studied, the toxicity evaluation of the Janus Fe 3 O 4 -TiO 2 NPs is still lacking. Due to the promising multifunctional properties of Janus Fe 3 O 4 -TiO 2 NPs in cancer diagnosis and treatment, the toxicity as well as the underlying mechanism of this material should be evaluated to obtain a baseline for its bioapplication in the future.…”

Quo Vadis Caenorhabditis elegans Metabolomics—A Review of Current Methods and Applications to Explore Metabolism in the Nematode

“…Multivariate methods can identify relationship patterns between metabolites by clustering and correlation analysis. Widely used chemometric methods such as principal component analysis (PCA), hierarchical cluster analysis (HCA), or orthogonal projection to latent structure with discriminant analysis (OPLS-DA) have been applied [ 88 , 101 , 102 ].…”

Organoid Technology: A Reliable Developmental Biology Tool for Organ-Specific Nanotoxicity Evaluation

“…The multi-arrayed mechanisms of nanotoxicity induce alterations in morphological attributes, cell viability, functional parameters, gene expression profile, proteomic and metabolomic profile, signaling pathways, etc ( Gioria et al, 2016 ; Kim et al, 2017 ; Carrow et al, 2018 ; Zheng et al, 2018 ; Hufnagel et al, 2020 ). Nanotoxicity varies considerably depending upon the employed organoid model, age of the organoid or spheroid, and type of NP as well as its dose, route, and duration of exposure ( Figure 1 ; Henriksen-Lacey et al, 2016 ; Wu et al, 2017 ; Eilenberger et al, 2019 ; Poli et al, 2020 ).…”