Exposure to a mixture of heavy metals induces cognitive impairment: Genes and microRNAs involved.

Converging evidence demonstrates that microRNAs (miRNAs) play an important role in the etiology of cognitive impairment. Thus, we aim to: (i) identify the molecular mechanisms of heavy metals, particularly miRNAs involved in the development of cognitive impairment; and (ii) generate miRNA sponges to prevent them from binding with their target messenger RNAs. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org), MicroRNA ENrichment TURned NETwork (MIENTURNET, http://userver.bio.uniroma1.it/apps/mienturnet/) and the microRNA sponge generator and tester (miRNAsong, http://www.med.muni.cz/histology/miRNAsong) were used as the core data-mining approaches in the current study. We observed that lead acetate, arsenic, gold, copper, iron, and aluminum, as well as their mixtures, had significant effects on the development of cognitive impairment. Although prevalent genes obtained from investigated heavy metals of cognitive impairment were different, the "PI3K-Akt signaling pathway", "pathways of neurodegeneration-multiple diseases", "apoptosis", "apoptosis-multiple species", "p53 signaling pathway", "NF-kappa B signaling pathway", and "Alzheimer's disease pathway" were highlighted. The mixed heavy metals altered the genes BAX, CASP3, BCL2, TNF, and IL-1B, indicating the significance of apoptosis and pro-inflammatory cytokines in the pathogenesis of cognitive impairment and the possibility of targeting these genes in future neuroprotective therapy. In addition, we used a network-based approach to identify key genes, miRNAs, pathways, and diseases related to the development of cognitive impairment. We also found 16 significant miRNAs related to cognitive impairment (hsa-miR-1-3p, hsa-let-7a-5p, hsa-miR-9-5p, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-26a-5p, hsa-miR-26b-5p, hsa-miR-34a-5p, hsa-miR-101-3p, hsa-miR-106a-5p, hsa-miR-128-3p, hsa-miR-144-3p, hsa-miR-199a-3p, hsa-miR-204-5p, and hsa-miR-335-5p). Finally, we created and evaluated miRNA sponge sequences for these miRNAs in silico. Further studies, including in vivo and in vitro, are needed to assess the link between these genes, miRNAs, pathways, and cognitive impairment.