Responses and coping methods of different testicular cell types to heat stress: overview and perspectives

Abstract

To facilitate temperature adjustments, the testicles are located outside the body cavity. In most mammals, the temperature of the testes is lower than the body temperature to ensure the normal progression of spermatogenesis. Rising temperatures affect spermatogenesis and eventually lead to a decline in male fertility or even infertility. However, the testes are composed of different cell types, including spermatogonial stem cells (SSCs), spermatocytes, spermatozoa, Leydig cells, and Sertoli cells, which have different cellular responses to heat stress. Recent studies have shown that using different drugs can relieve heat stress-induced reproductive damage by regulating different signaling pathways. Here, we review the mechanisms by which heat stress damages different cells in testes and possible treatments.

Keywords: Leydig cells; heat stress; reproduction; spermatocytes; spermatogonial stem cells.

Figure 1. Effects of heat stress in the testes

Heat stress can affect most cell types in the testis, including spermatids, spermatocytes, spermatogonial stem cells, Sertoli cells, and Leydig cells. However, heat stress has a variety of impacts on these cell types.

Figure 2. Apoptosis pathways in spermatocytes

Heat stress can induce spermatocyte damage. On one hand, BAX (pro-apoptotic protein) responds to heat stress and accumulates in the mitochondria, while BCL-2 is phosphorylated and loses activity. BAX is integrated into the outer mitochondrial membrane, causing a conformational change that releases cytochrome c into the cytoplasm. Cytochrome c interacts with APAF-1 to form a complex that activates the caspase cascade. On the other hand, heat stress connects the death receptor FAS to its ligand FASL through p53. FAS recruits FAS-related death domain (FADD) through the shared death domain (DD) to form a complex, which is bound to the caspase-8 promoter, triggering the caspase cascade. Heat stress activates spermatocyte apoptosis by directly activating the p38-MAPK signaling pathway independently of p53 signals. Finally, heat stress also inhibits DNA repair-related genes, such as Ogg1 (involved in base excision repair), Xpg (involved in nucleotide excision repair), Rad51 and Rad54 (involved in double-strand break repair) and, eventually, spermatocyte replication and meiosis separation, resulting in reproductive damage. p53 signaling plays a very important role in these genes and signaling pathways. p53 causes cell death through FAS; it also disrupts the BCL-2/BAX balance and triggers mitochondria-related apoptosis.