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Association between oxidative stress, DNA damage and its cellular response in pregnant women and newborns at different hyperglycemia levels

Grant number: 11/18240-2
Support type:Regular Research Grants
Duration: January 01, 2012 - June 30, 2014
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Iracema de Mattos Paranhos Calderon
Grantee:Iracema de Mattos Paranhos Calderon
Home Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Assoc. researchers:Débora Cristina Damasceno ; Estela Maris Andrade Forell Bevilacqua ; Marilza Vieira Cunha Rudge ; Simone Correa da Silva

Abstract

The Group for Research on Diabetes and Pregnancy - Clinical and Experimental Investigation has developed clinical and experimental studies in this line for over 25 years. The results of such studies have characterized a group of pregnant women who, despite their normal tolerance to 100-g glucose (TTG-100g), show hyperglycemia with disorders in their glycemic profile (GP). These pregnant women have been classified as Rudge's IB Group, with mild gestational hyperglycemia. In addition to other adverse perinatal outcomes (APO) that are characteristic in the offspring of diabetic mothers, gestational hyperglycemic women have attributable risk for perinatal death that is comparable to that in the group of diabetic pregnant women (4.16% vs. 6.12%) and, for this reason, they are treated as diabetic patients. The current literature has acknowledged the fact that maternal hyperglycemia, of any intensity and regardless of a gestational diabetes diagnosis, must be controlled due to the risk for APO. This fact validates the treatment initiated over 25 years ago for Rudge's IB Group comprising women with mild gestational hyperglycemia.In studies on the factors involved in the adverse outcomes of pregnancies complicated by glycemic disorders, the results achieved by our research group show intra-uterine hypoxia and varied-intensity maternal hyperglycemia. Such association would lead to morphological and functional disorders of the placenta that are characterized by compromising the vascularization of mother-fetus exchange surfaces, increase and/or decrease in vascular proliferation markers, apoptosis increase and alterations in the cytokine profile. At the same time, our experimental results in rats with streptozotocin-induced diabetes showed other factors involved with APO. The oxidative processes mediated by free radicals and increased general DNA damage showed to be directly dependent on the maternal hyperglycemia intensity reflected in the intrauterine medium. Among other factors, hyperglycemia and inflammation produce reactive oxygen species (ROS), leading to a state of oxidative stress and the resulting damage in the DNA molecule. If cells are not capable of DNA repair, cellular mutation accumulation or cellular death will occur. The application of molecular biology tools in our studies was decisive in order to define new directions. Hence, a project by two post-doctoral students with PNPD/CAPES grants (Project PNPD n. 02597/09-8; 2010-2015), is presently being developed with the purpose to explore the route of hypoxia and placental vascularization in pregnancies complicated by diabetes and mild gestational diabetes. These studies will be complemented by the present project, with exploration of potential changes in the routes of DNA damage and repair that also result from hyperglycemia and hypoxia in the intrauterine medium of such pregnancies. In this context, the goal of the present project is to investigate the oxidative stress markers, DNA damage (nuclear and mitochondrial), DNA repair capacity and damage-activated cellular death in pregnant women with varied-intensity hyperglycemia and their offspring. The development of this project will contribute to clarify the mechanisms involved with and the resulting prevention of APR in these pregnancies, which justifies its proposition. In addition to scientific advancement, this project will consolidate a partnership that has already been initiated (PNPD/CAPES n. 02597/09-8) with researchers from the Institute of Biomedical Sciences (ICB) of São Paulo University, Professor Estela Maris Andrade Forell Bevilacqua, responsible for the Trophoblast Cytophysiology Laboratory, and Professor Carlos Frederico Martins Menck, responsible for the DNA Repair Laboratory. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MORELI, JUSCIELE B.; SANTOS, JANINE H.; LORENZON-OJEA, ALINE RODRIGUES; CORREA-SILVA, SIMONE; FORTUNATO, RODRIGO S.; ROCHA, CLARISSA RIBEIRO; RUDGE, MARILZA V.; DAMASCENO, DEBORA C.; BEVILACQUA, ESTELA; CALDERON, IRACEMA M. Hyperglycemia Differentially Affects Maternal and Fetal DNA Integrity and DNA Damage Response. International Journal of Biological Sciences, v. 12, n. 4, p. 466-477, 2016. Web of Science Citations: 6.
MORELI, JUSCIELE BROGIN; SANTOS, JANINE HERTZOG; ROCHA, CLARISSA RIBEIRO; DAMASCENO, DEBORA CRISTINA; MORCELI, GLILCIANE; RUDGE, MARILZA VIEIRA; BEVILACQUA, ESTELA; PARANHOS CALDERON, IRACEMA MATTOS. DNA Damage and Its Cellular Response in Mother and Fetus Exposed to Hyperglycemic Environment. BIOMED RESEARCH INTERNATIONAL, 2014. Web of Science Citations: 12.

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