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

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.