Memoirs of an insult: sperm as a possible source of transgenerational epimutations and genetic instability

Abstract

Male transgenerational epigenetic effects have been discovered in the discipline of mouse radiation genetics, using genetic and non-genetic readouts. The mechanism to explain the origin of the transmission of epigenetic and genetic instability is still unknown. In a search for a hypothesis that could satisfy the data, we propose that regulation of chromosome structure in the germline, by the occupancy of matrix/scaffold associated regions, contains molecular memory function. The male germline is strikingly dynamic as to chromatin organization. This could explain why experience of irradiation stress leaves a persistent mark in the male germline only. To be installed, such memory requires both S-phase and chromatin reorganization during spermatogenesis and in the zygote, that likely also involves reorganization of loop domains. By this reorganization, another layer of information is added, needed to accommodate early embryonic development. Observations point at the involvement of DNA repair as inducer of transgenerational epigenetic modulation. Nuclear structure, chromatin composition and loop domain organization are aspects of human sperm variability that in many cases of assisted reproduction is increased due to inclusion of more incompletely differentiated/maturated sperm nuclei. Adjustment of loop domains in early embryo development can be anticipated and zygotic and cleavage stage S-phase repair activity will have to deal with potential paternal DNA lesions. Therefore, by changing male nucleus structure due to reproduction from impaired spermatogenesis, the transgenerational information content could be changed as well. We discuss aspects of male reproductive performance in the context of this hypothesis.

Direct and delayed X‐ray‐induced DNA damage in male mouse germ cells

“…The molecular mechanisms of these non-targeted effects are a matter of intensive investigation and are not fully understood. This phenomenon has also been observed in male germ cells [de Boer et al, 2010]. Spermatogonial irradiation causes delayed genomic instability in descendant sperm [Sailer et al, 1995;Haines et al, 2001Haines et al, , 2002Cordelli et al, 2003] as well as in the progeny of irradiated male parents in rodents [Baulch and Raabe, 2005;Barber and Dubrova, 2006;Barber et al, 2009] and humans [Aghajanyan et al, 2011].…”

“…Together with the neutral comet data, the g-H2AX fluorescence results indicate that double strand breaks represent an important component of delayed DNA damage. However, the specificity of these assays for DNA double strand breaks has been questioned [Calini et al, 2002;Collins et al, 2008;de Boer et al, 2010;Costes et al, 2010;Paris et al, 2011] and chromatin structural alterations and other types of DNA breaks may be an additional component of delayed radiation damage in spermatozoa.…”

“…This mark would then be recognized at later stages of spermatogenesis triggering the production of new DNA lesions. The molecular nature of this mark is still unknown but it may be epigenetic, involving DNA methylation, non-coding RNA expression or altered chromatin organization in loop domains and matrix-associated regions [Kovalchuk and Baulch, 2008;de Boer et al, 2010].…”

“…Spermatogonial irradiation causes delayed genomic instability in descendant sperm [Sailer et al, 1995;Haines et al, 2001Haines et al, , 2002Cordelli et al, 2003] as well as in the progeny of irradiated male parents in rodents [Baulch and Raabe, 2005;Barber and Dubrova, 2006;Barber et al, 2009] and humans [Aghajanyan et al, 2011]. Remodeling of chromatin domains and nuclear matrix during spermiogenesis and in the zygote has been suggested to play a role in these phenomena [de Boer et al, 2010], but how and when they operate is still unclear.…”

The X and Y chromosome in meiosis: how and why they keep silent

“…As a back-up, unrepaired damage present in postmeiotic cells may be repaired during spermiogenesis or in the zygote, 16 but such repair would be associated with an increased risk of generating mutations. Human spermatocytes also contain a silenced XY body, and meiotic arrest is a frequent cause of infertility.…”