Serum-borne factors alter cerebrovascular endothelial microRNA expression following particulate matter exposure near an abandoned uranium mine on the Navajo Nation

Abstract

Background: Commercial uranium mining on the Navajo Nation has subjected communities on tribal lands in the Southwestern United States to exposures from residual environmental contamination. Vascular health effects from these ongoing exposures are an active area of study. There is an association between residential mine-site proximity and circulating biomarkers in residents, however, the contribution of mine-site derived wind-blown dusts on vascular and other health outcomes is unknown. To assess neurovascular effects of mine-site derived dusts, we exposed mice using a novel exposure paradigm, the AirCARE1 mobile inhalation laboratory, located 2 km from an abandoned uranium mine, Claim 28 in Blue Gap Tachee, AZ. Mice were exposed to filtered air (FA) (n = 6) or concentrated ambient particulate matter (CAPs) (n = 5) for 2 wks for 4 h per day. Results: To assess miRNA differential expression in cultured mouse cerebrovascular cells following particulate matter (PM) exposure (average: 96.6 ± 60.4 μg/m 3 for all 4 h exposures), the serum cumulative inflammatory potential (SCIP) assay was employed. MiRNA sequencing was then performed in cultured mouse cerebrovascular endothelial cells (mCECs) to evaluate transcriptional changes. Results indicated 27 highly differentially expressed (p < 0.01) murine miRNAs, as measured in the SCIP assay. Gene ontology (GO) pathway analysis revealed notable alterations in GO enrichment related to the cytoplasm, protein binding and the cytosol, while significant KEGG pathways involved pathways in cancer, axon guidance and Wnt signaling. Expression of these 27 identified, differentially expressed murine miRNAs were then evaluated in the serum. Nine of these miRNAs (~30%) were significantly altered in the serum and 8 of those miRNAs demonstrated the same directional change (either upregulation or downregulation) as cellular miRNAs, as measured in the SCIP assay. Significantly upregulated miRNAs in the CAPs exposure group included miRNAs in the let-7a family. Overexpression of mmu-let-7a via transfection experiments, suggested that this miRNA may mediate mCEC barrier integrity following dust exposure.

CRISPR/Cas9-Mediated Whole Genomic Wide Knockout Screening Identifies Specific Genes Associated With PM2.5-Induced Mineral Absorption in Liver Toxicity

“…Previous studies have shown that major heavy metals of PM 2.5 potentially accumulate in the liver (Li et al, 2015), whereas genes associated with transportation of toxic chemicals (metals and minerals) in PM 2.5 may play an important role in apoptosis and damage of liver cells (Figure 6). Notably, our KEGG analysis revealed several pathways associated with PM 2.5 resistance, namely the insulin signaling pathway, phosphatidylinositol signaling system, adrenergic signaling in cardiomyocytes, gastric acid secretion, and inflammatory mediator regulation of TRP channels, consistent with previous studies (Xu Z. et al, 2019;Sanchez et al, 2020;Zheng et al, 2020). One of the most significant pathway was that regulating mineral absorption, which comprised several genes including ATP1A2, SLC6A19, MT1M, TRPV6, and ATP1B2, indicating that the absorption of metals by the liver is essential for PM 2.5 toxicity.…”

Regulatory roles of three miRNAs on allergen mRNA expression in Tyrophagus putrescentiae

“…These were considered as candidate novel miRNAs when the flank 80‐nt sequences (from genome locations) were successfully predicated to contain hairpin RNA structures by using RNAfold software (http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi). 23–26 …”

“…These were considered as candidate novel miRNAs when the flank 80-nt sequences (from genome locations) were successfully predicated to contain hairpin RNA structures by using RNAfold software (http://rna.tbi.univie.ac.at/cgi-bin/RNAWe bSuit e/RNAfo ld.cgi). [23][24][25][26] The expression levels of miRNA for each mite stage and sample were calculated. The miRNA differential expression levels (as represented by normalized deep-sequencing counts) were compared across samples/groups by chi-squared test, with a significance threshold of p < .01.…”

Potential Early Effect Biomarkers for Ambient Air Pollution Related Mental Disorders

“…Circulating miRNAs have been used as effective diagnostic and therapeutic biomarkers for patients [134,136]. Significant changes in cellular murine miRNA expression have been found after exposure to ambient PM near an abandoned uranium mine, and miRNAs from cerebrovascular endothelial cells show similarity to serum-derived miRNAs [137]. Additionally, exosomes are a class of extracellular vesicles derived from endocytosis, abundant in miRNAs, released by cells, and accessible in biofluids, such as saliva, urine, and plasma.…”