title: In utero exposure to second-hand smoke activates pro-asthmatic and oncogenic miRNAs in adult asthmatic mice.
abstract: Exposures to environmental pollutants contribute to dysregulated microRNA (miRNA) expression profiles, which have been implicated in various diseases. Previously, we reported aggravated asthmatic responses in ovalbumin (OVA)-challenged adult mice that had been exposed in utero to second-hand smoke (SHS). Whether in utero SHS exposure dysregulates miRNA expression patterns in the adult asthma model has not been investigated. Pregnant BALB/c mice were exposed (days 6-19 of pregnancy) to SHS (10 mg/m(3)) or HEPA-filtered air. All offspring were sensitized and challenged with OVA (19-23 weeks) before sacrifice. RNA samples extracted from lung homogenates, were subjected to RNA sequencing (RNA-seq). RNA-seq identified nine miRNAs that were most significantly up-regulated by in utero SHS exposure. Among these nine, miR-155-5p, miR-21-3p, and miR-18a-5p were also highly correlated with pro-asthmatic Th2 cytokine levels in bronchoalveolar lavage fluid. Further analysis indicated that these up-regulated miRNAs shared common chromosome locations, particularly Chr 11C, with pro-asthmatic genes. These three miRNAs have also been characterized as oncogenic miRNAs (oncomirs). We cross-referenced miRNA-mRNA expression profiles and identified 16 tumor suppressor genes that were down-regulated in the in utero-exposed offspring and that are predicted targets of the up-regulated oncomirs. In conclusion, in utero SHS exposure activates pro-asthmatic genes and miRNAs, which colocalize at specific chromosome locations, in OVA-challenged adult mice. The oncogenic characteristics of the miRNAs and putative miRNA-mRNA regulatory networks suggest that the synergistic effect of in utero SHS exposure and certain adult irritants may promote an oncogenic milieu in mouse lungs via inhibition of miRNA-regulated tumor suppressor genes.
authors: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana.|Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
authors: Rui
authors: R
authors: Xiao
authors: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana.
authors: Alexandra
authors: A
authors: Noël
authors: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana.
authors: Zakia
authors: Z
authors: Perveen
authors: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana.
authors: Arthur L
authors: AL
authors: Penn
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010047:Ovalbumin / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D012680:Sensitivity and Specificity; D017423:Sequence Analysis, RNA; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D035683:MicroRNAs; D014028:Tobacco Smoke Pollution; D010047:Ovalbumin
keywords: RNA-seq; asthma; cancer; in utero; microRNA; ovalbumin; second-hand smoke