Sildenafil Augments Fetal Weight and Placental Adiponectin in Gestational Testosterone-induced Glucose Intolerant Rats

Overview

Journal Toxicol Rep

Date 2021 Jul 19

PMID 34277360

Authors

Emmanuel Damilare Areola

Ifeoluwa Jesufemi Adewuyi

Taofeek Olumayowa Usman

Godsgift Tamunoibuomi

Lucy Kemi Arogundade

Barakat Olaoye

Deborah Damilayo Matt-Ojo

Abdulrazaq Olatunji Jeje

Adewumi Oluwafemi Oyabambi

Enoch Abiodun Afolayan

Lawrence Aderemi Olatunji

Affiliations

Soon will be listed here.

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; ) 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.

References

Kanova N, Bicikova M . Hyperandrogenic states in pregnancy. Physiol Res. 2010; 60(2):243-52. DOI: 10.33549/physiolres.932078. View

Ramirez C, Nian H, Yu C, Gamboa J, Luther J, Brown N . Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. J Clin Endocrinol Metab. 2015; 100(12):4533-40. PMC: 4667163. DOI: 10.1210/jc.2015-3415. View

Usman T, Areola E, Badmus O, Kim I, Olatunji L . Sodium acetate and androgen receptor blockade improve gestational androgen excess-induced deteriorated glucose homeostasis and antioxidant defenses in rats: roles of adenosine deaminase and xanthine oxidase activities. J Nutr Biochem. 2018; 62:65-75. DOI: 10.1016/j.jnutbio.2018.08.018. View

Gillis E, Mooney J, Garrett M, Granger J, Sasser J . Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt-Sensitive Rat. Hypertension. 2016; 67(3):647-53. PMC: 4752413. DOI: 10.1161/HYPERTENSIONAHA.115.06071. View

Alahakoon T, Medbury H, Williams H, Lee V . Lipid profiling in maternal and fetal circulations in preeclampsia and fetal growth restriction-a prospective case control observational study. BMC Pregnancy Childbirth. 2020; 20(1):61. PMC: 6993402. DOI: 10.1186/s12884-020-2753-1. View

Bergmann R, Bergmann K, Dudenhausen J . Undernutrition and growth restriction in pregnancy. Nestle Nutr Workshop Ser Pediatr Program. 2008; 61:103-21. DOI: 10.1159/000113181. View

Rodway G, Lovelace A, Lanspa M, McIntosh S, Bell J, Briggs B . Sildenafil and Exercise Capacity in the Elderly at Moderate Altitude. Wilderness Environ Med. 2016; 27(2):307-15. DOI: 10.1016/j.wem.2016.01.006. View

SYBULSKI S . Testosterone metabolism by rat placenta. Steroids. 1969; 14(4):427-40. DOI: 10.1016/s0039-128x(69)80005-x. View

Sir-Petermann T, Hitchsfeld C, Maliqueo M, Codner E, Echiburu B, Gazitua R . Birth weight in offspring of mothers with polycystic ovarian syndrome. Hum Reprod. 2005; 20(8):2122-6. DOI: 10.1093/humrep/dei009. View

10.

Qiao L, Wattez J, Lee S, Guo Z, Schaack J, Hay Jr W . Knockout maternal adiponectin increases fetal growth in mice: potential role for trophoblast IGFBP-1. Diabetologia. 2016; 59(11):2417-2425. PMC: 5042853. DOI: 10.1007/s00125-016-4061-x. View

11.

Mills V, Plows J, Zhao H, Oyston C, Vickers M, Baker P . Effect of sildenafil citrate treatment in the eNOS knockout mouse model of fetal growth restriction on long-term cardiometabolic outcomes in male offspring. Pharmacol Res. 2018; 137:122-134. DOI: 10.1016/j.phrs.2018.09.023. View

12.

Romo A, Carceller R, Tobajas J . Intrauterine growth retardation (IUGR): epidemiology and etiology. Pediatr Endocrinol Rev. 2009; 6 Suppl 3:332-6. View

13.

Akinola L, Poutanen M, Peltoketo H, Vihko R, Vihko P . Characterization of rat 17 beta-hydroxysteroid dehydrogenase type 1 gene and mRNA transcripts. Gene. 1998; 208(2):229-38. DOI: 10.1016/s0378-1119(97)00669-0. View

14.

Radulescu L, Munteanu O, Popa F, Cirstoiu M . The implications and consequences of maternal obesity on fetal intrauterine growth restriction. J Med Life. 2013; 6(3):292-8. PMC: 3806033. View

15.

Tapanainen P, Bang P, Wilson K, Unterman T, Vreman H, Rosenfeld R . Maternal hypoxia as a model for intrauterine growth retardation: effects on insulin-like growth factors and their binding proteins. Pediatr Res. 1994; 36(2):152-8. DOI: 10.1203/00006450-199408000-00004. View

16.

Tebay L, Robertson H, Durant S, Vitale S, Penning T, Dinkova-Kostova A . Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med. 2015; 88(Pt B):108-146. PMC: 4659505. DOI: 10.1016/j.freeradbiomed.2015.06.021. View

17.

Jia H, Guo Z, Yao Y . PDE5 inhibitor protects the mitochondrial function of hypoxic myocardial cells. Exp Ther Med. 2019; 17(1):199-204. PMC: 6307451. DOI: 10.3892/etm.2018.6951. View

18.

Iordache A, Docea A, Buga A, Zlatian O, Ciurea M, Rogoveanu O . Sildenafil and tadalafil reduce the risk of contrast-induced nephropathy by modulating the oxidant/antioxidant balance in a murine model. Food Chem Toxicol. 2019; 135:111038. DOI: 10.1016/j.fct.2019.111038. View

19.

Groom K, McCowan L, Mackay L, Lee A, Gardener G, Unterscheider J . STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction. BJOG. 2019; 126(8):997-1006. DOI: 10.1111/1471-0528.15658. View

20.

Maliqueo M, Lara H, Sanchez F, Echiburu B, Crisosto N, Sir-Petermann T . Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2012; 166(2):151-5. DOI: 10.1016/j.ejogrb.2012.10.015. View