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Adenosine blocks hormone-induced meiotic maturation by suppressing purine de novo synthesis
1Biology Department, Marquette University, Milwaukee, Wisconsin 53233, USA. downss@Marquette.edu
Abstract:
We have examined adenosine (Ado) suppression of FSH-induced germinal vesicle breakdown (GVB) and its relationship to purine de novo synthesis. Oocyte-cumulus cell complexes (OCC) from PMSG-primed, immature mice were cultured 17-18 hr in medium containing 4 mM hypoxanthine (HX) or 300 microM dibutyryl cAMP (dbcAMP) to maintain meiotic arrest, and FSH was added to stimulate meiotic maturation. In the absence of FSH, Ado (1-250 microM) had no effect in dbcAMP-arrested oocytes but dose-dependently suppressed maturation in HX-treated oocytes. FSH-induced maturation was prevented by Ado, though more effectively in dbcAMP-supplemented cultures. Ado affected the magnitude, but not the kinetics pattern, of the response to FSH. Inosine also blocked meiotic induction, but only in dbcAMP-arrested oocytes. Purine de novo synthesis was nearly doubled in OCC by FSH treatment, and this response was completely prevented by Ado. FSH had no effect on HX salvage, although Ado reduced this activity by 98%. Inosine effects on metabolism were intermediate between the control and Ado groups. Experiments with radiolabeled energy substrates showed that Ado suppressed FSH activation of the pentose phosphate pathway but did not prevent significant activation of glycolysis or oxidation of pyruvate. Finally, in cultured follicles from primed mice, hCG-induced maturation was blocked by Ado as effectively as by the purine de novo synthesis inhibitor, azaserine. It is concluded that Ado has an inhibitory action on hormone-induced maturation that is due, at least in part, to suppression of glucose metabolism, leading to compromised purine de novo synthesis.
Insights
Adenosine (Ado) suppresses hormone-induced oocyte maturation by inhibiting purine synthesis and glucose metabolism. This research clarifies adenosine
Area of Science:
- Reproductive Biology
- Cellular Metabolism
- Molecular Endocrinology
Background:
- Oocyte maturation is a critical process in female reproduction, regulated by complex signaling pathways.
- Adenosine (Ado) is known to influence various cellular processes, but its specific role in oocyte maturation requires further elucidation.
- Purine synthesis is essential for cellular energy and nucleic acid production, impacting cell function and development.
Purpose of the Study:
- To investigate the inhibitory effect of adenosine (Ado) on follicle-stimulating hormone (FSH)-induced oocyte maturation.
- To explore the relationship between adenosine's inhibitory action and purine de novo synthesis during oocyte maturation.
- To determine the impact of adenosine on glucose metabolism pathways crucial for oocyte development.
Main Methods:
- Oocyte-cumulus cell complexes (OCC) from immature mice were cultured and treated with hypoxanthine (HX) or dibutyryl cAMP (dbcAMP) to maintain meiotic arrest.
- FSH was added to stimulate meiotic maturation, with varying concentrations of adenosine (Ado) or inosine administered.
- Purine de novo synthesis, hypoxanthine (HX) salvage, and glucose metabolism (pentose phosphate pathway, glycolysis, pyruvate oxidation) were assessed using radiolabeled substrates and inhibitors.
Main Results:
- Adenosine (Ado) dose-dependently suppressed FSH-induced oocyte maturation, particularly in hypoxanthine (HX)-treated oocytes, and also inhibited hCG-induced maturation.
- Ado completely prevented the FSH-stimulated increase in purine de novo synthesis and significantly reduced HX salvage, while also suppressing pentose phosphate pathway activation.
- Adenosine's inhibitory effect on maturation was linked to suppressed glucose metabolism, leading to compromised purine de novo synthesis, rather than direct interference with maturation kinetics.
Conclusions:
- Adenosine (Ado) exerts an inhibitory effect on hormone-induced oocyte maturation.
- This inhibition is, at least partially, mediated by the suppression of glucose metabolism, which subsequently compromises purine de novo synthesis.
- Understanding adenosine's role provides insights into the metabolic regulation of oocyte maturation and potential therapeutic targets.