Background: Overexposure to manganese (Mn) can lead to
neurodegenerative damage, resulting in manganism with similar syndromes to
Parkinson’s disease (PD). However, little is known about changes in
transcriptomics induced by the toxicological level of Mn. In this study, we
conducted RNA-seq to explore the candidate genes and signaling pathways included
by Mn in human SH-SY5Y neuroblastoma cells. Methods: The differentially
expressed genes (DEGs) between the Mn-treated group and the control group were
screened, and weighted gene co-expression network analysis (WGCNA) was employed
to identify hub genes. Then, pathway enrichment analyses for those candidate
genes were performed in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and
Genomes (KEGG). We further validated the concentration- and time-response effects
of Mn exposure (0–500 M, 3–12 h) on mitochondrial
unfolded protein response (UPR) by real-time quantitative reverse
transcription PCR (qRT-PCR). Results: The results showed 179
up-regulated differentially expressed genes (DEGs) and 681 down-regulated DEGs
after Mn exposure. Based on the intersection of DEGs genes and hub genes, 73 DEGs
were related to neurotoxicity. The comprehensive pathway analysis showed Mn had
widespread effects on the mitogen-activated protein kinase (MAPK) signaling
pathway, unfolded protein response, longevity regulating pathway, inflammatory
bowel disease, and mitophagy signaling pathway. After Mn exposure, the
expressions of activating transcription factor 3 (ATF3) and C-C motif chemokine
ligand 2 (CCL2) increased, while the expressions of C/EBP homologous protein
(CHOP), caseinolytic protease P (CLPP), and Lon protease 1 (LONP1) decreased in a
concentration- and time-dependent manner. Conclusions: Overall, our
study suggests that UPR is a new sight in understanding the mechanism of
Mn-induced neurotoxicity.