Oxidative Stress, Testicular Inflammatory Pathways, and Male Reproduction

Abstract

Inflammation is among the core causatives of male infertility. Despite male infertility being a serious global issue, "bits and pieces" of its complex etiopathology still remain missing. During inflammation, levels of proinflammatory mediators in the male reproductive tract are greater than usual. According to epidemiological research, in numerous cases of male infertility, patients suffer from acute or chronic inflammation of the genitourinary tract which typically occurs without symptoms. Inflammatory responses in the male genital system are inextricably linked to oxidative stress (OS). OS is detrimental to male fertility parameters as it causes oxidative damage to reproductive cells and intracellular components. Multifarious male infertility causative factors pave the way for impairing male reproductive functions via the common mechanisms of OS and inflammation, both of which are interlinked pathophysiological processes, and the occurrence of any one of them induces the other. Both processes may be simultaneously found in the pathogenesis of male infertility. Thus, the present article aims to explain the role of inflammation and OS in male infertility in detail, as well as to show the mechanistic pathways that link causative factors of male reproductive tract inflammation, OS induction, and oxidant-sensitive cellular cascades leading to male infertility.

Keywords: cytokines; inflammation; male infertility; oxidative stress; reactive oxygen species.

Figure 1

Inflammation and oxidative stress (OS) as core mechanisms linking common causative factors with male infertility. (A) Exogenous and endogenous factors impacting on male reproductive system via induction of OS and inflammation; (B) Effects of various causative factors mediated male reproductive disruptions mainly via oxidative damage and induction of apoptosis.

Figure 2

Cellular pathways connecting inflammation and oxidative stress (OS) in the pathogenesis of male infertility. (A) Pattern recognition receptors (PRRs) in testicular and epididymal cells are activated by inflammatory stimuli. The activated PRRs trigger downstream signalling via the Myeloid differentiation primary response (MYD88) and mitogen-activated protein (MAP) kinases pathways (IRF3); (B) These cascades activate transcription factors such as the nuclear factor kappa light chain enhancer of activated B cells (NF-kB), activator protein 1 (AP-1), and interferon regulatory factor 3 (IRF3); (C) Excess ROS production, on the other hand, can cause oxidation of membrane phospholipids and intracellular proteins, which can activate the PRRs-inflammatory pathway. Furthermore, ROS can activate the transcription factors nuclear respiratory factor (NRF) 1 and 2 via AKT (Protein Kinase B) and estrogen receptor (ESR) 1. These activated transcription factors induce the expression of inflammatory mediators such as tumour necrosis factor α (TNFα), interferons (IFNs), interleukin (IL) 1, nitric oxide (NO), and tumour growth factor (TGF) B3, which cause exaggerated inflammation and can also act as OS stimuli, creating a feedback loop. OS can also initiate apoptotic cascades by assisting the release of cytochrome-c (Cyt-c) from mitochondria.