vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ15.063vavilov-438Research ArticleМОДЕЛИРОВАНИЕ ПАТОЛОГИЙMODELING OF DISORDERS AND EXPERIMENTAL TREATMENTКорреляция чувствительности к гепатоканцерогенезу, индуцированному введением орто-аминоазотолуола, со степенью активации сигнальных путей Ahr и Car у мышейCorrelation of susceptibility to ortho-aminoazotolueneinduced hepatocarcinogenesis with Car and Ahr signaling pathway activation in miceБагинскаяН. В.BaginskayaN. V.bagin@bionet.nsc.ruКашинаЕ. В.KashinaE. V.ШаманинаМ. Ю.ShamaninaM. Yu.ИльницкаяС. И.IlnitskayaS. I.КалединВ. И.KaledinV. I.МордвиновВ. А.MordvinovV. A.mordvin@bionet.nsc.ruФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск, РоссияРоссияInstitute of Cytology and Genetics SB RAS, Novosibirsk, RussiaRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск, Россия Федеральное государственное бюджетное научное учреждение «Научно-исследовательский институт молекулярной биологии и биофизики», Новосибирск, РоссияРоссияInstitute of Cytology and Genetics SB RAS, Novosibirsk, Russia Institute of Molecular Biology and Biophysics, Novosibirsk, RussiaRussian Federation201501122015194474479Copyright © Багинская Н.В., Кашина Е.В., Шаманина М.Ю., Ильницкая С.И., Каледин В.И., Мордвинов В.А., 20152015Багинская Н.В., Кашина Е.В., Шаманина М.Ю., Ильницкая С.И., Каледин В.И., Мордвинов В.А.Baginskaya N.V., Kashina E.V., Shamanina M.Y., Ilnitskaya S.I., Kaledin V.I., Mordvinov V.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/438

Орто-аминоазотолуол (ОАТ) является сильным гепатоканцерогеном для большинства линий мышей. Ранее было показано, что введение ОАТ активирует в печени этих животных арил-гидрокарбоновый рецептор (Ahr) и конститутивный рецептор андростанов (Car). Оба эти рецептора принимают непосредственное участие в процессе гепатоканцерогенеза. В данной работе были исследо- ваны влияние хронического введения ОАТ на уровни экспрессии мРНК Ahr, Car и их генов-мишеней Cyp1a1 и Cyp2b10, а также корреляция их экспрессии со степенью воспалительной реакции у линий мышей DD/He (DD) и CC57BR/Mv (BR), контрастных по чувствительности к гепатоканцерогенезу. Самцам мышей обеих линий в течение 2 мес. четырехкратно вводили масляный раствор ОАТ в дозе 225 мг/кг веса тела. Контрольные животные получали эквивалентное количество растворителя. Мышей забивали через 1 и 4 сут после последнего введения ОАТ. Экспрес­сию генов в печени определяли методом ПЦР в реальном вре­мени. Степень воспалительной реакции оценивали в те же сроки по концентрации фактора некроза опухоли альфа (ФНОα) в сыво­ротке крови. У резистентных мышей BR введение ОАТ инду­ци­ровало более выраженное и длительное повышение уров­ня экспрессии мРНК Cyp1a1, свидетельствующее о преимущест­венной активации Ahr у этих животных. В то же время у мышей чувствительной линии DD наблюдалось более выраженное повышение уровня экспрессии Cyp2b10, что указывает на преимущественную активацию Car. Также у мышей линии DD, в отличие от BR, наблюдалась сильная и длительная воспалительная реакция в ответ на введе­ние ОАТ. Полученные результаты дают основания полагать, что преобладание активации сигнального пути Ahr над активацией сигнального пути Car может быть фактором резистентности к ОАТ-индуцированному гепатоканцерогенезу.

Ortho-aminoazotoluene (OAT) is a potent hepatocarcinogen for most strains of mice. It has previously been shown that OAT application activates the aryl hydrocarbon receptor (Ahr) and the constitutive androstane receptor (Car) in the mouse liver. Both of these receptors are directly involved in the process of hepatocarcinogenesis. In this study, we investigated the effect of chronic OAT administration on the mRNA expression levels of Ahr, Car and their target genes Cyp1a1 and Cyp2b10 in the liver of DD/He (DD) and CC57BR/Mv (BR) mouse strains contrasting in sensitivity to hepatocarcinogenesis. The inflammatory response of these strains was also studied. Male mice of both strains received OAT oil solution at the dose of 225 mg/kg body weight four times within two months. Control animals received the equivalent solvent amount. Mice were sacrificed on days 1 and 4 after the last OAT administration. Gene expression levels in the liver were determined by real-time PCR. The inflammatory response was evaluated by serum concentration of tumor necrosis factor alpha (TNF-alpha). In resistant BR mice, OAT induced a pronounced and prolonged increase in Cyp1a1 mRNA, showing primarily Ahr activation, while the DD strain displayed a more pronounced elevation of Cyp2b10 expression, indicative of Car activation. In addition, a strong inflammatory response to OAT was recorded in DD mice but not in BR. It is assumed that the prevalence of Ahr signaling pathway activation over Car signaling pathway activation is a factor of resistance to OAT-induced hepatocarcinogenesis.

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