Abstract
Background and Objectives: Titanium dioxide nanoparticles (TiO2-NP) are important materials used in commercial practice. Reportedly, TiO2-NP exposure during pregnancy can affect the development of the central nervous system in mouse offspring; however, the underlying mechanism remains unknown. In the present study, we investigated the impact of prenatal TiO2-NP exposure on global DNA methylation and mRNA expression patterns in the brains of neonatal mice. Materials and Methods: Pregnant C57BL/6J mice were intratracheally administered a TiO2-NP suspension (100 μg/mouse) on gestational day 10.5, and brains were collected from male and female offspring at day 1 postpartum. After extraction of methylated DNA by immunoprecipitation, the DNA methylation profile was analyzed using a mouse CpG island microarray. Total RNA was obtained, and mRNA expression profiles were comprehensively assessed using microarray analysis. Results: Among genes in the CpG island microarray, DNA methylation was increased in 614 and 2,924 genes and decreased in 6,220 and 6,477 genes in male and female offspring, respectively. Combined with mRNA microarray analysis, 88 and 89 genes were upregulated (≥1.5-fold) accompanied by demethylation of CpG islands, whereas 13 and 33 genes were downregulated (≤0.67-fold) accompanied by methylation of CpG islands in male and female offspring mice, respectively. Gene Set Enrichment Analysis (GSEA) revealed that these genes were enriched in gene ontology terms related to the regulation of transcription factors, cell proliferation, and organism development. Additionally, MeSH terms related to stem cells and morphogenesis were enriched. Conclusion: Prenatal TiO2-NP exposure induced genome-wide alterations in DNA methylation and mRNA expression in the brains of male and female offspring. Based on GSEA findings, it can be speculated that prenatal TiO2-NP exposure causes adverse effects on brain functions by altering the DNA methylation state of the fetal brain, especially neural stem cells, resulting in the subsequent abnormal regulation of transcription factors that modulate development and differentiation.
Highlights
Nanomaterial research and development have gained momentum in recent years, with several new nanotechnology-based products commercially available
The results revealed that 658 and 650 mRNAs were upregulated (≥1.5-fold) in male and female offspring brains of the TiO2-H group when compared with the Sham group (Supplementary Tables S8A, S9A); in contrast, prenatal TiO2-NP exposure downregulated 482 and 409 mRNAs (≤0.67-fold) in male and female offspring brains (Supplementary Tables S8B, S9B)
We indicated that prenatal intratracheal exposure to TiO2-NP induces abnormal DNA methylation status and mRNA expression profile in the brain of mouse offspring at PND1
Summary
Nanomaterial research and development have gained momentum in recent years, with several new nanotechnology-based products commercially available. Titanium dioxide nanoparticles (TiO2-NP) are important materials used in commercial paints for buildings (Shandilya et al, 2015), cosmetics (Kaida et al, 2004), and food additives (Weir et al, 2012). As possible exposure routes for TiO2-NP, inhalation, dermal and oral exposure are the most obvious (Borm et al, 2006). Sunscreens and other cosmetics providing ultra violet protection may expose consumer lungs to TiO2-NP by inhalation because they can be available as sprayable products (Dréno et al, 2019). Titanium dioxide nanoparticles (TiO2-NP) are important materials used in commercial practice. TiO2-NP exposure during pregnancy can affect the development of the central nervous system in mouse offspring; the underlying mechanism remains unknown. We investigated the impact of prenatal TiO2-NP exposure on global DNA methylation and mRNA expression patterns in the brains of neonatal mice
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