Sildenafil augments fetal weight and placental adiponectin in gestational testosterone-induced glucose intolerant rats

Emmanuel Damilare Areola; Ifeoluwa Jesufemi Adewuyi; Taofeek Olumayowa Usman; God'sgift Tamunoibuomi; Lucy Kemi Arogundade; Barakat Olaoye; Deborah Damilayo Matt-Ojo; Abdulrazaq Olatunji Jeje; Adewumi Oluwafemi Oyabambi; Enoch Abiodun Afolayan; Lawrence Aderemi Olatunji

doi:10.1016/j.toxrep.2021.06.011

Sildenafil augments fetal weight and placental adiponectin in gestational testosterone-induced glucose intolerant rats

Toxicol Rep. 2021 Jun 30:8:1358-1368. doi: 10.1016/j.toxrep.2021.06.011. eCollection 2021.

Affiliations

¹ HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.
² Cardiovascular Unit, Department of Physiology, College of Health Sciences, Osun State University, Osogbo, Nigeria.
³ Department of Pathology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.

Abstract

Testosterone induces intra-uterine growth restriction (IUGR) with maternal glucose dysregulation and oxidant release in various tissues. Adiponectin, which modulates the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is expressed in the placenta and affects fetal growth. Sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), used mainly in erectile dysfunction has been widely studied as a plausible pharmacologic candidate in IUGR. Therefore, the present study sought to determine the effect of PDE5i on placental adiponectin/Nrf2 pathway in gestational testosterone-induced impaired glucose tolerance and fetal growth. Fifteen pregnant Wistar rats were allotted into three groups (n = 5/group) receiving vehicles (Ctr; distilled water and olive oil), testosterone propionate (Tes; 3.0 mg/kg; sc) or combination of testosterone propionate (3.0 mg/kg; sc) and sildenafil (50.0 mg/kg; po) from gestational day 14-19. On gestational day 20, plasma and placenta homogenates were obtained for biochemical analysis as well as fetal biometry. Pregnant rats exposed to testosterone had 4-fold increase in circulating testosterone compared with control (20.9 ± 2.8 vs 5.1 ± 1.7 ng/mL; p < 0.05) whereas placenta testosterone levels were similar in testosterone- and vehicle-treated rats. Exposure to gestational testosterone caused reduction in fetal and placental weights, placental Nrf2 and adiponectin. Moreover, impaired glucose tolerance, elevated plasma triglyceride-glucose (TyG) index, placental triglyceride, total cholesterol, lactate, malondialdehyde and alanine aminotransferase were observed in testosterone-exposed rats. Treatment with sildenafil improved glucose tolerance, plasma TyG index, fetal and placental weights and reversed placental adiponectin in testosterone-exposed pregnant rats without any effect on placental Nrf2. Therefore, in testosterone-exposed rats, sildenafil improves impaired glucose tolerance, poor fetal outcome which is accompanied by augmented placental adiponectin regardless of depressed Nrf2.

Keywords: Adiponectin; Androgen; Placental inefficiency; Poor fetal outcome; Pregnancy.