Inhibition of phosphodiesterase PDE8B reduces activation of primordial follicles in mouse ovaries

TY - JOUR

T1 - Inhibition of phosphodiesterase PDE8B reduces activation of primordial follicles in mouse ovaries

AU - Madsen, Julie Feld

AU - Amoushahi, Mahboobeh

AU - Choi, Christian Posselt

AU - Bundgaard, Stine

AU - Heuck, Anders

AU - Lykke-Hartmann, Karin

PY - 2023/6

Y1 - 2023/6

N2 - In the ovaries, cyclic adenosine 3',5'-monophosphate (cAMP) is a second messenger supporting the generation of steroids. Phosphodiesterases (PDEs) are regulators of intracellular cAMP, and therefore, potential regulators of ovarian function. Interestingly, the family of PDE genes are differentially expressed in human oocytes and granulosa cells from primordial and primary follicles, suggesting diverse roles. In this study, we addressed the functions of PDE3B and PDE8B in primordial follicle regulation using inhibitors of PDE3B and PDE8B in murine ovary primary in vitro cultures. Inhibition of PDE8B in ovarian cultures prevented primordial follicle activation, while inhibition of PDE3B had no effect on follicle distribution in the ovary, under the tested conditions. As cAMP levels may increase steroid levels, we assessed the protein levels of the steroidogenic acute regulatory protein (StAR) and aromatase enzymes, and found that inhibition of PDE3B reduced StAR protein levels, whereas inhibition of PDE8 did not alter StAR expression in our murine ovary culture system conditions. Our results showed that ketotifen-induced inhibition of PDE8B can decrease primordial follicle activation, whereas we observed no effect of follicle distribution, when PDE3B was inhibited. Expression of the StaR enzyme was not altered when PDE8B was inhibited, which might reflect not sufficient inhibition by ketotifen to induce StAR alterations, or redundant mechanisms.

AB - In the ovaries, cyclic adenosine 3',5'-monophosphate (cAMP) is a second messenger supporting the generation of steroids. Phosphodiesterases (PDEs) are regulators of intracellular cAMP, and therefore, potential regulators of ovarian function. Interestingly, the family of PDE genes are differentially expressed in human oocytes and granulosa cells from primordial and primary follicles, suggesting diverse roles. In this study, we addressed the functions of PDE3B and PDE8B in primordial follicle regulation using inhibitors of PDE3B and PDE8B in murine ovary primary in vitro cultures. Inhibition of PDE8B in ovarian cultures prevented primordial follicle activation, while inhibition of PDE3B had no effect on follicle distribution in the ovary, under the tested conditions. As cAMP levels may increase steroid levels, we assessed the protein levels of the steroidogenic acute regulatory protein (StAR) and aromatase enzymes, and found that inhibition of PDE3B reduced StAR protein levels, whereas inhibition of PDE8 did not alter StAR expression in our murine ovary culture system conditions. Our results showed that ketotifen-induced inhibition of PDE8B can decrease primordial follicle activation, whereas we observed no effect of follicle distribution, when PDE3B was inhibited. Expression of the StaR enzyme was not altered when PDE8B was inhibited, which might reflect not sufficient inhibition by ketotifen to induce StAR alterations, or redundant mechanisms.

KW - 3',5'-Cyclic-AMP Phosphodiesterases/metabolism

KW - Animals

KW - Female

KW - Humans

KW - Ketotifen/metabolism

KW - Mice

KW - Oocytes

KW - Ovarian Follicle/metabolism

KW - Ovary/metabolism

KW - Phosphoric Diester Hydrolases/genetics

KW - Steroids/metabolism

KW - primordial follicle activation

KW - PDE3B

KW - StAR enzymes

KW - PDE8B

KW - 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors

UR - http://www.scopus.com/inward/record.url?scp=85166700992&partnerID=8YFLogxK

U2 - 10.1002/mrd.23699

DO - 10.1002/mrd.23699

M3 - Journal article

C2 - 37499226

SN - 1040-452X

VL - 90

SP - 378

EP - 388

JO - Molecular Reproduction and Development

JF - Molecular Reproduction and Development

IS - 6

ER -