vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ18.355vavilov-1451Research ArticleРЕПРОДУКТИВНЫЕ ТЕХНОЛОГИИPHYSIOLOGICAL GENETICSТканеспецифичные эффекты бенз[а]пирена и ДДТ на профиль экспрессии микроРНК у самок крысTissue-specific effects of benzo[a]pyrene and DDT on microRNA expression profile in female ratsУшаковД. С.UshakovD. S.

Новосибирск

Novosibirsk

d.ushackov@gmail.comКалининаТ. С.KalininaT. S.

Новосибирск

Novosibirsk

ДорожковаА. С.DorozhkovaA. S.

Новосибирск

Novosibirsk

ОвчинниковВ. Ю.OvchinnikovV. Y.

Новосибирск

Novosibirsk

ГуляеваЛ. Ф.GulyaevaL. F.

Новосибирск

Novosibirsk

Научно-исследовательский институт молекулярной биологии и биофизики; Новосибирский государственный педагогический университетРоссияInstitute of Molecular Biology and Biophysics; Novosibirsk State Pedagogical University,Russian FederationНаучно-исследовательский институт молекулярной биологии и биофизики; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Molecular Biology and Biophysics; Novosibirsk State UniversityRussian FederationНаучно-исследовательский институт молекулярной биологии и биофизикиРоссияInstitute of Molecular Biology and BiophysicsRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics SB RASRussian FederationНаучно-исследовательский институт молекулярной биологии и биофизики; Новосибирский государственный педагогический университет; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Molecular Biology and Biophysics; Novosibirsk State Pedagogical University; Novosibirsk State UniversityRussian Federation201807042018222248255Copyright © Ушаков Д.С., Калинина Т.С., Дорожкова А.С., Овчинников В.Ю., Гуляева Л.Ф., 20182018Ушаков Д.С., Калинина Т.С., Дорожкова А.С., Овчинников В.Ю., Гуляева Л.Ф.Ushakov D.S., Kalinina T.S., Dorozhkova A.S., Ovchinnikov V.Y., Gulyaeva L.F.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/1451

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. Отчасти эти нарушения могут быть опосредованы активацией ядерных рецепторов, приводящей к активации экспрессии генов и микроРНК, участвующих в процессах злокачественной трансформации клеток. Поэтому целью данной работы было исследовать цепь событий «введение ксенобиотика – активация рецептора – повышение экспрессии микроРНК – понижение экспрессии гена-мишени» в качестве одного из ключевых факторов развития канцерогенеза. С помощью методов in silico проведен анализ генома крыс для поиска микроРНК, находящихся под регуляцией АhR (арил-гидрокарбонового рецептора) и CAR (конститутивного андростанового рецептора), активируемых под действием Б(а)П и ДДТ соответственно. В частности, miR-3577 и -193b были отобраны в качестве потенциально регулируемых CAR; miR-207 – как кандидат на микроРНК, находящийся под регуляцией AhR. Результаты исследования показали, что введение ДДТ и Б(а)П вызывало тканеспецифичное изменение экспрессии микроРНК и их генов-хозяев в случае как острого, так и хронического введений ксенобиотиков. Для подтверждения эффектов ксенобиотиков на экспрессию микроРНК мы также оценили уровень мРНК генов PTPN6, EIF3F, Cbx7 и Dicer1, потенциально являющихся мишенями miR-193b, -207 и -3577. Исследование показало высокую связь экспрессии генов-мишеней и микроРНК, однако точный характер этих изменений зависел от типа ткани, времени после введения и дозы ксенобиотика.

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.

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The authors declare that there are no conflicts of interest present.