Developmental origins of male subfertility: role of infection, inflammation, and environmental factors

Abstract

Male gamete development begins with the specification of primordial cells in the epiblast of the early embryo and is not complete until spermatozoa mature in the epididymis of adult males. This protracted developmental process involves extensive alteration of the paternal germline epigenome. Initially, epigenetic reprogramming in fetal germ cells results in removal of most DNA methylation, including parent-specific epigenetic information. The germ cells then establish sex-specific epigenetic information through de novo methylation and undergo spermatogenesis. Chromatin in haploid germ cells is repackaged into protamines during spermiogenesis, providing further widespread epigenetic reorganization. Finally, after fertilization, epigenetic reprogramming in the preimplantation embryo is necessary for regaining totipotency. These events provide substantial windows during which epigenetic errors either may be corrected or may occur in the germline. There is now increasing evidence that environmental factors such as exposure to toxicants, the parents' and individual's diet, and even infectious and inflammatory events in the male reproductive tract may influence epigenetic reprogramming. This, together with other damage inflicted on the germline chromatin, may result in negative consequences for fertility and health. Large epidemiological birth cohort studies have yielded insight into possible causative environmental factors. Together with experimental animal studies, a clearer view of environmental impacts on fetal development and their intergenerational and even transgenerational effects on reproductive health has emerged and is reviewed in this article.

Adrenomedullin protects Leydig cells against lipopolysaccharide-induced oxidative stress and inflammatory reaction via MAPK/NF-κB signalling pathways

“…Leydig cells, located within the interstitial compartment of the testes, mainly contributed to androgen synthesis and secretion and play an important role in testicular development, normal masculinisation, spermatogenesis maintenance and general male fertility 2 . Infections and inflammation of the male reproductive tract are well-known etiological factors of male subfertility or infertility 3 . In an infected reproductive tract, the innate immune system recruits phagocytic cells and effector molecules to the site of infection by releasing a battery of cytokines and other inflammatory mediators that remarkably affect subsequent events 4 .…”

In search of new paradigms for epididymal health and disease: innate immunity, inflammatory mediators, and steroid hormones

“…Despite the increasing prevalence and serious threat of epididymitis to men's health, these pivotal questions are only beginning to be answered. One major hurdle in the search for molecular signatures of epididymitis is that performing epididymal biopsies puts the patient at high risk for systemic infections, epididymal duct rupture, and development of anti‐sperm auto‐antibodies (Schagdarsurengin et al ., ). When epididymitis specimens from human patients have become available, clinical data have mostly been restricted to epididymis histopathological analyses that often indicate classical signs of chronic inflammation and steady‐state dysfunction, such as fibrotic remodeling, luminal obstruction, and damage to epithelial and smooth muscle layers (Lang et al ., ; Michel et al ., ).…”

From Superficial Damage to Invasion of the Nucleosome: Ranking of Morbidities by the Biosemiotic Depth Hypothesis

“…Whenever during the normal course of development, the self is attacked by one or more disease agents that are regarded by the body's immune defense systems as capable of rapidly replicating so as to present a potentially mortal threat, provided authorization is granted in consultation with the body's own DNA, the self can perform something resembling mobilization for global warfare through the littleunderstood MHC/HLA III which interacts with classes I and II (and also the still higher and even less understood MHC/HLA IV [219]). When authorized, the complement cascade, in ways not yet well understood, can develop and equip defenses involving all three classes of MHC/HLA along with an enhanced capacity for rapid clearing of destroyed pathogens and debris from collateral damage after the conclusion of something like a global emergency mobilization [220].…”