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

Scientific paper - Original scientific paper

• Author: Nikola Sobočan
• Author: Ana Katušić Bojanac
• Author: Nino Sinčić
• Author: Marta Himelreich-Perić
• Author: Jure Krasić
• Author: Željka Majić
• Author: Gordana Jurić-Lekić
• Author: Ljiljana Šerman
• Author: Maja Vlahović
• Author: Davor Ježek
• Author: Floriana Bulić-Jakuš
• Author's institution: University of Zagreb; School of Medicine
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences

Abstract (english)

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.

• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Published version
• Journal title: Stem Cells and Development
• Numbering: vol. 28, no. 11, pp. 717-733
• p-ISSN: 1547-3287
• DOI: https://doi.org/10.1089/scd.2018.0194
• URN:NBN: urn:nbn:hr:105:278242
• Publication: 2019-06-01
• Document URL: http://doi.org/10.1089/scd.2018.0194
• Type of resource: Text
• Access conditions: Open access
• Created on: 2024-03-28 10:30:21