NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 are Upregulated in a Sex-specific fashion in the Rat Fetal Brain After Repeated Antenatal Dexamethasone Treatment

Abstract

To accelerate organ maturation and prevent complications due to preterm birth, antenatal treatment with synthetic glucocorticoids (GCs – dexamethasone or betamethasone) is usually given between the 24th and 34th week of pregnancy to women at risk of delivery within the next seven days [1]. Despite recommendations, repeat courses of antenatal GCs are frequently given, although excessive GC stimulation may exert adverse neurodevelopmental effects [1]. The purinergic system is essential for neurodevelopment [2]. Extracellular purine levels are regulated by ectonucleotidases, with ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5ʹ-nucleotidase (e5ʹNT/CD73), abundant in the CNS, which jointly hydrolyze ATP to adenosine. Both ectonucleotidases are also involved in cell adhesion and migration [3]. We aimed to explore the effects of antenatal dexamethasone (DEX) treatment on the expression and enzymatic activity of NTPDase1/e5ʹNT tandem in the rat fetal brain. Wistar rat dams were treated with 0.5 mg/kg DEX, at gestation day (GD) 16, 17, and 18. We found sex-specific male-biased upregulation of CD39 and CD73 mRNA and protein abundances, and an increase in the corresponding enzymatic activities in the rat fetal brain at GD21, induced by antenatal DEX treatment. Observed changes indicate a possible decrease in P2, and an increase in P1 purinergic receptors-mediated signaling, as well as a potential decrease in migration of progenitor cells, particularly pronounced in the brain of male fetuses. Together, sex-dependent induction of CD39 and CD73 might interfere with neurodevelopmental processes, thus contributing to adverse effects of antenatal DEX treatment, especially in males.