Abstract
Dexamethasone (DEX) is frequently used to treat women at risk of preterm delivery, but although indispensable for the completion of organ maturation in the fetus, antenatal DEX treatment may exert adverse sex-dimorphic neurodevelopmental effects. Literature findings implicated oxidative stress in adverse effects of DEX treatment. Purinergic signaling is involved in neurodevelopment and controlled by ectonucleotidases, among which in the brain the most abundant are ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5ʹ-nucleotidase (e5ʹNT/CD73), which jointly dephosphorylate ATP to adenosine. They are also involved in cell adhesion and migration, processes integral to brain development. Upregulation of CD39 and CD73 after DEX treatment was reported in adult rat hippocampus. We investigated the effects of maternal DEX treatment on CD39 and CD73 expression and enzymatic activity in the rat fetal brain of both sexes, in the context of oxidative status of the brain tissue. Fetuses were obtained at embryonic day (ED) 21, from Wistar rat dams treated with 0.5 mg DEX/kg/day, at ED 16, 17, and 18, and brains were processed and used for further analysis. Sex-specific increase in CD39 and CD73 expression and in the corresponding enzyme activities was induced in the brain of antenatally DEX-treated fetuses, more prominently in males. The oxidative stress induction after antenatal DEX treatment was confirmed in both sexes, although showing a slight bias in males. Due to the involvement of purinergic system in crucial neurodevelopmental processes, future investigations are needed to determine the role of these observed changes in the adverse effects of antenatal DEX treatment.
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Funding
This work was supported by the Ministry of Education, Science and Technological Development, the Republic of Serbia, contract No. 451-03-9/2021-14/200007 and 451-03-9/2021-14/200178 and the University of Defense (grant number MFVMA/04/19–21). J.S. received support from the Natural Sciences and Engineering Research Council of Canada (NSERC; RGPIN-2016–05867).
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Danijela Laketa, Nadezda Nedeljkovic, Milica Manojlovic – Stojanoski, Irena Lavrnja, and Jean Sévigny contributed to study conception and design. Material preparation, data collection, and analysis were performed by Danijela Laketa, Milica Manojlovic-Stojanoski, Irena Lavrnja, Ivana Stevanovic, Svetlana Trifunovic, Natasa Ristic, and Natasa Nestorovic. The first draft of the manuscript was written by Danijela Laketa and all authors commented on previous version of the manuscript. All authors read and approved the final manuscript.
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The Ethical Committee for the Protection of Welfare of Experimental Animals of the Institute for Biological Research “Sinisa Stankovic” Belgrade, Serbia approved all animal experiments (Application No.02- 12/13) following the Directive on the protection of animals used for experimental and other scientific purposes (2010/63/EU) and results reported in compliance with the ARRIVE.
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Supplementary Fig. 1 Assessment of antibody specificity. Low- and high-power magnification micrographs, respectively, of consecutive coronal cross-section at the septal region of rat fetal brain from control animals, obtained after incubation with (a,b) rN1-6L(I4,I5) pre-immune serum, (c,d) NTPDase1/CD39 rN1-6L(I4,I5) antibody, (e,f) rNu-8L(I4,I5) pre-immune serum and (g,h) e5ʹNT/CD73 rNu-8L(I4,I5) antibody, counterstained with hematoxylin. Incubation with pre-immune sera was performed under the same conditions as those used for corresponding antibodies. Sections incubated with pre-immune sera are devoid of any reaction.; (i) immunoblot of brain tissue preparations obtained by chemiluminescent detection, using X-ray films of blotted membrane probed with rN1-6L(I4,I5) pre-immune serum, under same conditions as those used for corresponding anti-CD39 antibody, described in the Methods section. Cf, Cm – control female, and male fetuses, respectively; Df, Dm – DEX-treated female and male fetuses, respectively. Supplementary file1 (DOCX 5320 KB)
10571_2021_1081_MOESM2_ESM.tif
Supplementary Fig. 2 Diagram showing the number of animals used in the experiments within the present study. In our experimental conditions, between 8-12 fetuses were obtained from every pregnant dam, out of which for both sexes, 1 fetus was used for immunohistochemical analysis (3 in total), 1 for RT-PCR analysis, and 3 were pooled for crude membrane fraction and whole-brain tissue homogenate isolation. The symbols ♀ and ♂ denote females and males, respectively. Cf, Cm – control female, and male fetuses, respectively; Df, Dm – DEX-treated female and male fetuses, respectively. Supplementary file2 (TIF 792 KB)
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Manojlovic-Stojanoski, M., Lavrnja, I., Stevanovic, I. et al. Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 in the Rat Fetal Brain. Cell Mol Neurobiol 42, 1965–1981 (2022). https://doi.org/10.1007/s10571-021-01081-8
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DOI: https://doi.org/10.1007/s10571-021-01081-8