Neonatal Metformin Administration Exerts a Suppressive Effect on Sertoli Cell Proliferation in Rats

PELLIZZARI E; DA ROS VG; RIERA MF; RINDONE GM; CAMBEROS MC; BUFFONE MG; GORGA A; GALARDO MN; MERONI SB

New Orleans

Congreso; 101st Annual Meeting Endocrine Society; 2019

Endocrine Society

Sertoli cell (SC) proliferation, a factor defining SC population size, occurs during a restricted period of time. In rats, SCs start proliferating during fetal development and undergo mitosis for up to 15 days after birth. In humans, SCs proliferate during fetal and neonatal periods for up to 6 months after birth and there is a second stage of proliferation at the onset of puberty. Metformin (MET), a first line anti-hyperglycemic agent, is used in pediatric population at ages when SCs are still proliferating. In addition to its strong anti-diabetic properties, numerous studies have demonstrated that MET has anti-proliferative activity (1). In this context, it has been demonstrated in SC cultures obtained from 8-day old rats that MET decreases FSH-stimulated SC proliferation and that this decrease is accompanied by a reduction in Cyclin D1, D2, E1 and E2 expression and an increase in cell cycle inhibitor p21Cip expression (2). The aim of this study was to analyze the potential effect of in vivo neonatal administration of Metformin on rat Sertoli cell proliferation and its impact on the spermatogenic capacity in adult animals. Male Sprague Dawley rat pups were randomly assigned at postnatal day 3 (PND3) to the following groups: MET (receiving daily 200 mg/kg MET i.p., from day 3 to 7 inclusive) and control (receiving daily sterile saline solution i.p). At PND8, SCs were isolated from a set of animals to analyze the expression of cell cycle regulators and of SC maturation markers by RT-qPCR. Another set of animals were injected with BrdU (50 mg/kg) 90 min before sacrifice to evaluate cell proliferation. Our results showed that MET group exhibited a significant decrease in BrdU incorporation in SCs compared to controls (p