[Effect of benzo(a)pyrene on the expression of AhR-regulated microRNA in female and male rat lungs]
- PMID: 32588828
- DOI: 10.18097/PBMC20206603224
[Effect of benzo(a)pyrene on the expression of AhR-regulated microRNA in female and male rat lungs]
Abstract
Smoking is the main risk factor for lung cancer, mainly due to presence of nitrosamines and polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BP) in tobacco smoke composition. The genotoxic effect of BP is based on the high DNA-binding ability of its metabolites, while the epigenetic effects are mediated by a change in the expression of cancer related genes or regulatory RNAs. It has been shown that women have a higher risk to develop lung cancer upon smoking rather than men. We hypothesized that crosstalk between signaling pathways activated by BP and estrogens could underlie the sex-dependent differences in miRNAs expression. To test this hypothesis, male and female rats were subjected to short-term or long-term BP exposure. Using in silico analysis, miRNAs containing the ER- and AhR-binding sites in the promoters of the genes (or host genes) were selected. During chronic exposure of BP the expression of miR-22-3p, -29a-3p, -126a-3p, -193b-5p in the lungs of male rats were significantly increased, while the level of miRNA-483-3p were decreased. Expression of miRNA-483-3p was up-regulated during chronic BP exposure in the lungs of female rats and the levels of other studied miRNAs were unchanged. In turn, changes in the expression of miRNAs were followed by changes in the expression of their target genes, including PTEN, EMP2, IGF1, ITGA6, SLC34A2, and the observed changes in female and male rat lungs were varied. Thus, our results suggest that sex-dependent epigenetic effects of BP may be based on different expression of AhR- and ER- regulated miRNAs.
Mnogochislennymi kliniko-épidemiologicheskimi issledovaniiami pokazano, chto kurenie iavliaetsia osnovnym faktorom riska razvitiia raka legkikh, glavnym obrazom, iz-za nalichiia v sostave tabachnogo dyma nitrozaminov i politsiklicheskikh aromaticheskikh uglevodorodov, v tom chisle benz[a]pirena (BP). Genotoksicheskoe deĭstvie BP zakliuchaetsia v vysokoĭ DNK-sviazyvaiushcheĭ sposobnosti ego metabolitov, v to vremia kak épigeneticheskie éffekty oposredovany izmeneniem ékspressii genov, kodiruiushchikh belki ili reguliatornye RNK. Po dannym kliniko-épidemiologicheskikh issledovaniĭ, chastota zabolevaemosti rakom legkikh u muzhchin i zhenshchin razlichaetsia. My predpolozhili, chto éto mozhet iavliat'sia sledstviem zavisimykh ot pola razlichiĭ v ékspressii mikroRNK, oposredovannykh peresecheniem signal'nykh puteĭ, aktiviruemykh BP i éstrogenami. Dlia proverki étoĭ gipotezy samtsy i samki krys byli podvergnuty ostromu ili khronicheskomu vozdeĭstviiu BP. S pomoshch'iu analiza in silico byli vybrany mikroRNK, v promotorakh genov (ili genov-khoziaev) kotorykh soderzhatsia saĭty sviazyvaniia arilgidrokarbonovogo (AhR) i éstrogenovykh (ER) retseptorov. Pri khronicheskom vozdeĭstvii BP bylo obnaruzheno, chto uroven' mikroRNK-22-3p, -29a-3p, -126a-3p, -193b-5p dostoverno uvelichivalsia v legkikh samtsov krys, togda kak uroven' mikroRNK-483-3p snizhalsia. U samok pod deĭstviem BP v legkikh uvelichivalsia uroven' mikroRNK-483-3p, a uroven' drugikh issleduemykh mikroRNK ostalsia neizmennym. V svoiu ochered', izmeneniia ékspressii mikroRNK soprovozhdalis' izmeneniem ékspressii ikh genov-misheneĭ, takikh kak PTEN, EMP2, IGF1, ITGA6, SLC34A2, prichem vyiavlennye izmeneniia otlichalis' dlia samok i samtsov krys. Takim obrazom, poluchennye nami rezul'taty pozvoliaiut predpolozhit', chto v osnove zavisimykh ot pola épigeneticheskikh éffektov BP mozhet lezhat' razlichnaia ékspressiia potentsial'no reguliruemykh AhR i ER mikroRNK.
Keywords: AhR; ER; benzo(a)pyrene; microRNA; sex differences.