Influences of flavones on cell viability and cAMP-dependent steroidogenic gene regulation in MA-10 Leydig cells

Testicular Leydig cells are major contributors of androgen synthesis and secretion, which play an important role in testis development, normal masculinization, maintenance of spermatogenesis, and general male fertility. The rate-limiting step in testosterone biosynthesis involves the transfer of cholesterol to the mitochondrial inner membrane by the steroidogenic acute regulatory (Star) protein, a critical factor in steroid hormone biosynthesis. Once inside the mitochondria, cholesterol is metabolized by the steroidogenic enzyme Cyp11a1 to pregnenolone, which is further converted to testosterone by the action of other steroidogenic enzymes. Interestingly, the Star protein level declines during Leydig cell aging, resulting in defective mitochondrial cholesterol transfer and lower testosterone production. It is possible to delay the age-related decline in testosterone production by increasing Star and/or Cyp11a1 gene expression using supplementation with flavonoids, a group of polyphenolic compounds widely distributed in fruits and vegetables. In this study, we examined whether the distribution of hydroxyl groups among flavones could influence their potency to stimulate steroidogenesis within Leydig cells. Low levels of apigenin, luteolin, chrysin, and baicalein (10 mu M) stimulated cAMP-dependent Star, Cyp11a1, and Fdx1 promoters' activation and may increase steroidogenesis within Leydig cells. Indeed, luteolin effectively increased cAMP-dependent accumulation of progesterone from MA-10 Leydig cells, possibly through activation of Star and Fdx1 transcription. Thus, dietary luteolin could be potentially effective to maintain steroid production within aging males.