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Müllerian-Inhibiting Substance Inhibits Rat Leydig Cell Regeneration after Ethylene Dimethanesulphonate Ablation¹

Population Council and The Rockefeller University,³ New York, New York 10021 Pediatric Surgical Research Laboratories,⁴ Massachusetts General Hospital, Boston, Massachusetts 02114 Pediatric Endocrine Division,⁵ Duke University Medical Center, Durham, North Carolina 27710

The postnatal development of Leydig cell precursors is postulated to be controlled by Sertoli cell secreted factors, which may have a determinative influence on Leydig cell number and function in sexually mature animals. One such hormone, Mullerian inhibiting substance (MIS), has been shown to inhibit DNA synthesis and steroidogenesis in primary Leydig cells and Leydig cell tumor lines. To further delineate the effects of MIS on Leydig cell proliferation and steroidogenesis, we employed the established ethylene dimethanesulphonate (EDS) model of Leydig cell regeneration. Following EDS ablation of differentiated Leydig cells in young adult rats, recombinant MIS or vehicle was delivered by intratesticular injection for 4 days (Days 11–14 after EDS). On Days 15 and 35 after EDS (1 and 21 days post-MIS injections), endocrine function was assessed and testes were collected for stereology, immunohistochemistry, and assessment of proliferation and steroidogenesis. Although serum testosterone and luteinizing hormone (LH) were no different, intratesticular testosterone was higher on Day 35 in MIS-treated animals. At both time points, intratesticular 5-androstan-3,17ß-diol concentrations were much higher than that of testosterone. MIS-treated animals had fewer mesenchymal precursors on Day 15 and fewer differentiated Leydig cells on Day 35 with decreased numbers of BrdU+ nuclei. Apoptotic interstitial cells were observed only in the MIS-treated testes, not in the vehicle-treated group on Day 15. These data suggest that MIS inhibits regeneration of Leydig cells in EDS-treated rats by enhancing apoptotic cell death as well as by decreasing proliferative capacity.

¹ Supported by NIH grants HD36768 and HD01367 to M.M.L. and HD32588 to M.P.H. This paper was originally published online, ahead of print with the title "Müllerian-Inhibiting Substance Prevents Rat Leydig Cell Regeneration after Ethylene Dimethanesulphate Ablation."

² Correspondence: Mary M. Lee, Division of Pediatric Endocrinology, 308 Bell Building, Box 3080, Bell Research Drive, Duke University Medical Center, Durham, NC 27710. FAX: 919 684 8613; Lee00140{at}mc.duke.edu

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