The impact of animal models on translating male infertility research from bench to bedside: a narrative review.

Abstract

Male infertility (MI) represents a complex clinical issue affecting millions of couples worldwide. Its diverse etiologies and incompletely elucidated mechanisms limit the development of effective therapeutic strategies. Animal models, serving as a bridge between basic research and clinical practice, play an indispensable role in simulating the pathophysiological processes of human MI, deciphering key underlying mechanisms, and screening and evaluating potential therapeutic agents. This review systematically summarizes the various animal models employed in MI research, including chemically induced models (e.g., using tripterygium glycosides or cyclophosphamide), endocrine-disrupting agent-induced models (e.g., using Bisphenol A (BPA) or finasteride), and physically induced models (e.g., via heat stress or experimental varicocele). We focus on elucidating the core pathological mechanisms these models recapitulate, encompassing oxidative stress, inflammatory responses, novel cell death pathways such as apoptosis, pyroptosis, and ferroptosis, as well as endocrine disruption of the hypothalamic-pituitary-gonadal (HPG) axis. Through an in-depth analysis of the characteristics of each model, associated signaling pathways-including the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, and the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, and identified pharmacological targets, this article aims to provide insights into the complex etiology of human MI and offer a crucial theoretical foundation and experimental framework for the development and translation of novel mechanism-based therapeutics.