Neonatal metformin short exposure inhibits male reproductive dysfunction caused by a high-fat diet in adult rats

Metformin (Met) is widely used to control blood glucose levels and acts on various organs, including reproductive tissues, to improve reproductive and lifespan. This study evaluated whether neonatal Met exposure prevented male reproductive dysfunction caused by being overweight during adulthood. Ran...

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Published in:	Toxicology and applied pharmacology Vol. 429; p. 115712
Main Authors:	Vieira, Henrique Rodrigues, Gonçalves, Gessica Dutra, Alves, Vander Silva, de Melo, Milene Aparecida Bobato, Borges, Stephanie Carvalho, Klagenberg, Josana, Neves, Camila Quaglio, Previate, Carina, Saavedra, Lucas Paulo Jacinto, Siervo, Gláucia Eloisa Munhoz de Lion, Malta, Ananda, Prado, Marialba Avezum Alves de Castro, Palma-Rigo, Kesia, Buttow, Nilza Cristina, Fernandes, Glaura Scantamburlo Alves, Mathias, Paulo Cezar de Freitas
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 15-10-2021
Subjects:	Animals Animals, Newborn Anti-Inflammatory Agents - administration & dosage Antioxidants - administration & dosage Developmental origin of health and disease concept Diet, High-Fat - adverse effects Drug Administration Schedule Inflammation Mediators - metabolism Lactation Male Metformin - administration & dosage Metformin programs Overfeeding Oxidative stress Oxidative Stress - drug effects Rats Rats, Wistar Reproduction - drug effects Reproductive quality Testis - drug effects Testis - metabolism Testis - pathology Testis - physiopathology Testosterone - blood Oxidative stress Reproductive quality Developmental origin of health and disease concept Metformin programs Overfeeding
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Summary:	Metformin (Met) is widely used to control blood glucose levels and acts on various organs, including reproductive tissues, to improve reproductive and lifespan. This study evaluated whether neonatal Met exposure prevented male reproductive dysfunction caused by being overweight during adulthood. Randomized Wistar rat pups received an intraperitoneal injection from postnatal days (PNDs) 1 to 12of saline (Sal; 0.9% NaCl/day in 2mL/kg) or Met (100 mg/kg/day in 2 mL/kg). From PNDs 60 to 90, the animals received a regular (R; 4.5% fat; Sal R and Met R groups) or a high-fat (HF; 35% fat; Sal HF and Met HF groups) diet. At PND 90, all animals were euthanized to evaluate their biometric and reproductive parameters. The Sal and Met groups with R showed similar body weights, however, the HF diet increased the body weight in both groups. The Sal HF group showed testicular damage regarding in antioxidant status and inflammatory profile in the epididymal cauda. The HF diet reduced Leydig and Sertoli cells numbers, with lower sperm quality. The Met R animals showed positive reproductive programming, due to improved antioxidant defense, inflammatory biomarkers, and sperm morphology. Met HF prevented HF diet damage to reproductive organs and sperm morphology, but not to sperm motility. Early Met exposure positively affected the male reproductive system of adult rats, preventing reproductive HF disorders. Metformin is used to control type 2 diabetes mellitus and can act to improve metabolism and lifespan. Metformin avoidance is recommended during pregnancy, but there is no information regarding its use when breastfeeding. For the first time, we showed in this current study that metformin positively acts in the male reproductive tissues and helps involved in later life. These data showed a better antioxidant defense and anti-inflammatory profile of Metformin animals than Saline animals and might directly improve reproductive organs morphophysiology and sperm morphology. Also, the neonatal Met application programs the male reproduction to counterbalance damages from an obesogenic environment in later life. •Metformin during breastfeeding permanently improved the male reproductive system.•Metformin benefits the testicular morphophysiology.•Reproductive antioxidant and inflammatory profiles are programed by early metformin.•Metformin prevents male reproductive dysfunction from an obesogenic diet.
ISSN:	0041-008X 1096-0333
DOI:	10.1016/j.taap.2021.115712