Epigenetics in radiation biology: a new research frontier

Abstract

The number of people that receive exposure to ionizing radiation (IR) via occupational, diagnostic, or treatment-related modalities is progressively rising. It is now accepted that the negative consequences of radiation exposure are not isolated to exposed cells or individuals. Exposure to IR can induce genome instability in the germline, and is further associated with transgenerational genomic instability in the offspring of exposed males. The exact molecular mechanisms of transgenerational genome instability have yet to be elucidated, although there is support for it being an epigenetically induced phenomenon. This review is centered on the long-term biological effects associated with IR exposure, mainly focusing on the epigenetic mechanisms (DNA methylation and small RNAs) involved in the molecular etiology of IR-induced genome instability, bystander and transgenerational effects. Here, we present evidence that IR-mediated effects are maintained by epigenetic mechanisms, and demonstrate how a novel, male germline-specific, small RNA pathway is posited to play a major role in the epigenetic inheritance of genome instability.

Keywords: DNA methylation; bystander effects; epigenetics; genome instability; histones; radiation; small RNAs; transgeneration effects.

FIGURE 1

The ping-pong model for piRNA amplification in mice. In mice primary processing results in sense piRNAs that preferentially associate with MILI. In prenatal testis both MILI and MIWI2 participate in the amplification cycle. MIWI2 is specifically enriched in secondary antisense piRNAs as compared to MILI. Antisense secondary piRNAs guide DNA methylation of transposable element sequences. After birth, when MIWI2 is no longer expressed, MILI is believed to continue to operate in the cycle alone. If DNA methylation of transposon sequences is impaired due to downstream mutations in methyltransferase proteins, overexpression of transposon transcripts boosts primary processing and increases the fraction of primary sense piRNAs. Adapted with permission from Aravin et al. (2008).

FIGURE 2

Anatomy and cellular associations of a murine seminiferous tubule cross section. (A) Drawing of a cross section of a mouse seminiferous tubule showing Sertoli cells dividing the germinal epithelium into basal and adluminal compartments. (B) Immuno-fluorescent picture of a seminiferous tubule from a cross section of paraffin embedded mouse testis with Mili (green) and nuclear (DAPI) stain (blue). Image taken with a laser scanning confocal microscope (×60). Seminiferous tubule labeled with relevant cell types associated with spermatogenesis: SpG, spermatogonia; SpC, spermatocyte; SpT, spermatid; SpZ, spermatozoa; SC, Sertoli cell; LC, Leydig cell.