Epigenetic changes in the early stage of silica-induced cell transformation

Abstract

The increasing use of nanomaterials in numerous domains has led to growing concern about their potential toxicological properties, and the potential risk to human health posed by silica nanoparticles remains under debate. Recent studies proposed that these particles could alter gene expression through the modulation of epigenetic marks, and the possible relationship between particle exposure and these mechanisms could represent a critical factor in carcinogenicity. In this study, using the Bhas 42 cell model, we compare the effects of exposure to two transforming particles, a pyrogenic amorphous silica nanoparticle NM-203 to those of the crystalline silica particle Min-U-Sil 5. Short-term treatment by Min-U-Sil 5 decreased global DNA methylation and increased the expression of the two de novo DNMTs, DNMT3a and DNMT3b. NM-203 treatment affected neither the expression of these enzymes nor DNA methylation. Moreover, modified global histone H4 acetylation status and HDAC protein levels were observed only in the Min-U-Sil 5-treated cells. Finally, both types of particle treatment induced strong c-Myc expression in the early stage of cell transformation and this correlated with enrichment in RNA polymerase II as well as histone active marks on its promoter. Lastly, almost all parameters that were modulated in the early stage were restored in transformed cells suggesting their involvement mainly in the first steps of cell transformation.

Predictive early gene signature during mouse Bhas 42 cell transformation induced by synthetic amorphous silica nanoparticles

“…Accordingly, Bhas 42 cell transformation is associated with early increased C-MYC expression, but not in the late phase of SAS-induced cell transformation as shown previously [28]. These results, among others [14,31], confirm that markers of transformation must be identified in the early steps of the processes.…”

“…Moreover, Seidel et al proposed that the transforming activity of the crystalline silica Min-U-Sil 5  in Bhas 42 cells was related to early epigenetic DNA methylation [28].…”

“…However, even though the expression of three members of the proliferin gene family, PRCl2C2,3,5, was upregulated, proliferin was revealed as a single band by western blotting. On the other hand, c-myc upregulation was also linked to C3H/10T1/2[29] and Bhas 42 cell transformation[28]. In the latter, C-MYC mRNA and protein levels increased after cell treatment with NM-203 and Min-U-Sil 5  over 2 days.…”

Genotoxic Potential of Nanoparticles: Structural and Functional Modifications in DNA

“…Thus, in vivo and in vitro studies by several researchers ( Table 3 ) provides evidence to the notion that these NPs tend to alter the epigenome in the following ways- • Alteration of global and gene-specific DNA methylation ( Pogribna and Hammons, 2021 ) • Increase phosphorylation of histone H2AX accompanied by oxidative stress ( Kopp et al, 2018 ) • Increase the acetylation of histones H3 and H4 ( Seidel et al, 2017 ) • Increase the levels of HDAC2 protein whereas decrease the levels of HDAC1 and HDAC6 proteins ( Seidel et al, 2017 ) …”

Demethylation of the NRF2 Promoter Protects Against Carcinogenesis Induced by Nano-SiO2

“…Abnormal DNA methylation occurs frequently in the process of carcinogenesis ( Miousse et al, 2018 ; Dreval et al, 2019 ), through devastating genome stability and activating aberrant transcription ( Gama-Sosa et al, 1983 ). Decreased global DNA methylation and increased expression of DNA methyltransferases (DNMTs) were demonstrated in the early stage of Nano-SiO 2 -induced malignant cellular transformation ( Seidel et al, 2017 ), indicating that DNA methylation is involved in the Nano-SiO 2 -induced carcinogenesis.…”