Genistein decreases androgen biosynthesis in rat Leydig cells by interference with luteinizing hormone-dependent signaling

• Published in: Toxicology letters Vol. 184; no. 3; pp. 169 - 175
• Main Authors: Hancock, Karen D., Coleman, Elaine S., Tao, Ya-Xiong, Morrison, Edward E., Braden, Tim D., Kemppainen, Barbara W., Akingbemi, Benson T.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 10.02.2009; Elsevier
• Subjects: Adenylyl Cyclases - metabolism; Animals; Biological and medical sciences; Cells, Cultured; Cholera Toxin - pharmacology; Colforsin - pharmacology; Cyclic CMP - analogs & derivatives; Cyclic CMP - pharmacology; Dose-Response Relationship, Drug; Down-Regulation; Endocrine Disruptors - toxicity; Enzyme Activators - pharmacology; Epidermal Growth Factor - metabolism; Genistein - toxicity; Leydig cells; Leydig Cells - drug effects; Leydig Cells - enzymology; Leydig Cells - metabolism; Luteinizing Hormone - metabolism; Male; Medical sciences; Phytoestrogens; Protein Kinase Inhibitors - pharmacology; Quinazolines; Rats; Rats, Long-Evans; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - metabolism; Receptors, LH - drug effects; Receptors, LH - metabolism; Signal Transduction - drug effects; Steroid hormones; Testicular interstitial cells; Testosterone - biosynthesis; Toxicology; Tyrphostins - pharmacology; Phytoestrogens; Steroid hormones; Testicular interstitial cells; Leydig cells; Rat; Genistein; Biosynthesis; Testicle; Isoflavone derivatives; Flavonoid; Leydig cell; Phytoestrogen; Signal transduction; Polyphenol; Luteinizing hormone; Hormonodependence; Androgen; Tyrosine kinase inhibitor; Steroid hormone; Rodentia; Interference; Gonadotropin; Male genital system; Interstitial cell; Vertebrata; Mammalia; Adenohypophyseal hormone; Decrease; Animal; Phenols; Phytohormone; Sex steroid hormone
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2008.11.005

Testicular Leydig cells express estrogen receptors and are the predominant source of the male sex steroid hormone testosterone (T). Previous studies demonstrated that genistein acts through estrogen receptors in Leydig cells. In the present study, pre-treatment of Leydig cells isolated from 35 day-old male Long Evans rats with the epidermal growth factor receptor (EGFR) kinase inhibitor AG 1478 abrogated genistein inhibition of T biosynthesis. Also, incubation of Leydig cells in culture medium containing epidermal growth factor (EGF) decreased T secretion (control: 255 ± 16; EGF: 190 ± 17 ng/10 6 cells, 24 h) ( P < 0.05). However, T secretion by genistein-treated Leydig cells (0.1 nM, 10 μM; 24 h) was rescued by post-treatment incubation with forskolin (control: 275 ± 28 versus 325 ± 35; 780 ± 85; ng/10 6 cells, 3 h) and dibutyryl cyclic adenosine 3′-5′-monophosphate (dbcAMP) (control: 370 ± 65 versus 580 ± 75; 2500 ± 200; ng/10 6 cells, 3 h) ( P > 0.05). Furthermore, post-treatment incubation with cholera toxin, an activator of G proteins, caused genistein-treated Leydig cells to produce similar T amounts as untreated control (control: 55 ± 5 versus 52 ± 2 and 47 ± 4; ng/10 6 cells, 3 h) ( P > 0.05). These observations imply that genistein action interferes with coupling of transmembrane luteinizing hormone receptors (LHR) with G proteins. Uncoupling of LHR from G proteins adversely affects adenylate cyclase function and impacts LH-dependent stimulation of Leydig cells. These findings have implications for testicular steroidogenesis in individuals exposed to genistein and soy-based products.