A free radical scavenger ameliorates teratogenic activity of a DNA hypomethylating hematological therapeutic

Sobočan, Nikola and Katušić Bojanac, Ana and Sinčić, Nino and Himelreich-Perić, Marta and Krasić, Jure and Majić, Željka and Jurić-Lekić, Gordana and Šerman, Ljiljana and Vlahović, Maja and Ježek, Davor and Bulić-Jakuš, Floriana (2019) A free radical scavenger ameliorates teratogenic activity of a DNA hypomethylating hematological therapeutic. Stem Cells and Development, 28 (11). pp. 717-733. ISSN 1547-3287

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The spin-trap free radical scavenger N-tert-butyl-a-phenylnitron (PBN) ameliorated effects of several teratogens involving reactive oxygen species (ROS). We investigated for the first time whether PBN could ameliorate teratogenesis induced by a DNA hypomethylating hematological therapeutic 5-azacytidine (5azaC). At days 12 and 13 of gestation, Fisher rat dams were pretreated by an i.v. injection of PBN (40mg/kg) and 1 h later by an i.p. injection of 5azaC (5mg/kg). Development was analyzed at gestation day 15 in embryos and day 20 in fetuses. PBN alone did not significantly affect development. PBN pretreatment restored survival of 5azaC-treated dams’ embryos to the control level, restored weight of embryos and partially of fetuses, and partially restored crownrump lengths. PBN pretreatment converted limb adactyly to less severe oligodactyly. PBN pretreatment restored global DNA methylation level in the limb buds to the control level. Cell proliferation in limb buds of all 5azaCtreated dams remained significantly lower than in controls. In the embryonic liver, PBN pretreatment normalized proliferation diminished significantly by 5azaC; whereas in embryonic vertebral cartilage, proliferation of all 5azaC-treated dams was significantly higher than in PBN-treated dams or controls. Apoptotic indices significantly enhanced by 5azaC in liver and cartilage were not influenced by PBN pretreatment. However, PBN significantly diminished ROS or reactive nitrogen species markers nitrotyrosine and 8-hydroxy-2¢deoxyguanosine elevated by 5azaC in embryonic tissues, and, therefore, activity of this DNA hypomethylating agent was associated to the activation of free radicals. That pretreatment with PBN enhanced proliferation in the liver and not in immature tissue is interesting for the treatment of 5azaC-induced hepatotoxicity and liver regeneration.

Item Type: Article
Additional Information: This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Departments: Katedra za histologiju i embriologiju
Katedra za medicinsku biologiju
Depositing User: Kristina Berketa
Status: Published
Sobočan, NikolaUNSPECIFIED
Katušić Bojanac, AnaUNSPECIFIED
Himelreich-Perić, MartaUNSPECIFIED
Jurić-Lekić, GordanaUNSPECIFIED
Šerman, LjiljanaUNSPECIFIED
Bulić-Jakuš, FlorianaUNSPECIFIED
Date: 1 June 2019
Date Deposited: 07 Jan 2020 09:10
Last Modified: 07 Jan 2020 09:10
Subjects: /
Related URLs:
URI: http://medlib.mef.hr/id/eprint/3532

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