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Abstract
Many xenobiotics in the human environment, such as benzo[a]pyrene (B(a)P) and dichlorodiphenyltrichloroethane (DDT), may act as non-genotoxic carcinogens through epigenetic mechanisms, including changes in microRNA expression profile. In part, such disorders can be mediated by the activation of nuclear receptors, resulting in the activation of protein coding gene expression and microRNAs involved in malignant transformation of cells. Therefore, the aim of this study was to investigate the chain of events “xenobiotic administration – receptor activation – up-regulating microRNA expression – down-regulation target genes expression” as one of the key factors in the chemically-induced carcinogenesis. Using in silico methods, an analysis of the rat genome was carried out to find microRNAs putatively regulated by AhR (aryl hydrocarbon receptor) and CAR (constitutive androstane receptor), activated by BP and DDT, respectively. In particular, miR-3577 and -193b were selected as potentially regulated CAR, miR-207 was selected as a candidate for miR under AhR regulation. The results of the study showed that the treatment of female rats with DDT and B(a)P caused a tissue-specific changes in the expression of microRNAs and host genes in both acute and chronic administration of xenobiotics. To confirm the effects of xenobiotics on the microRNA expression, we also estimated the mRNA level of PTPN6, EIF3F, Cbx7, and Dicer1 genes potentially targeting miR-193b, -207, and -3577. The study has shown a high correlation between the expression of target genes and microRNAs; however these changes depended on the tissue types, the dose and time after xenobiotic treatment.
Highlights
Многие ксенобиотики окружающей среды, такие как бенз[а]пирен (Б(а)П) и 1,1,1-трихлор-2,2-бис(4-хлорфенил) этан (ДДТ), обладают эпигенетическими механизмами повреждения клеток, приводящими к развитию канцерогенеза
One of the mechanisms of such regulation is the RNA interference between the “seed” sequence of microRNA and the 3′-end (5′-end in less rare cases) of the mRNA transcribed from the target gene
With bioinformatic analysis microRNAs whose promoters had promoters of host genes, as well as intergenic miRs were found, and their expression in different organs of female rats treated with these xenobiotics was investigated
Summary
Такие как бенз[а]пирен (Б(а)П) и 1,1,1-трихлор-2,2-бис(4-хлорфенил) этан (ДДТ), обладают эпигенетическими механизмами повреждения клеток, приводящими к развитию канцерогенеза. Transcriptional regulation includes changes in the host gene expression along with a change in intragenic miR or an independent change in miR expression having an intrinsic (intergenic) promoter In this case, the change in expression can be achieved through signaling cell cascades triggered by various stimuli, including endogenous compounds, such as, for example, hormones and xenobiotics. The activation of nuclear receptors, in cases when xenobiotics can be their ligands, with subsequent changes in the expression of target genes can be one of such mechanisms. In their turn, these genes can contain intronic (intragenic miRs), which will be co-expressed with host genes. The choice of females was due to the fact that DDT has an estrogen-like effect, so its toxic effect may be more pronounced in females
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