1 February 2013: Humans are exposed to low-dose ionizing radiation (LDIR) from a number of environmental and medical sources. In addition to inducing genetic mutations, there is concern that LDIR may also alter the epigenome. Such heritable effects early in life can either be positively adaptive or result in the enhanced formation of diseases, including cancer, diabetes, and obesity. In this study, we show that LDIR significantly increases DNA methylation at the viable yellow agouti (Avy) locus in a dose- and sex-dependent manner. Moreover, maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring. Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. These findings provide the first evidence that epigenetic alterations resulting from LDIR play a role in radiation hormesis (Calabrese and Baldwin 2002; Vincent Giuliano 2012), bringing into question the assumption that every dose of radiation is harmful. Since the epigenome varies markedly between species, the effect of LDIR on the epigenome in multiple generations needs to now be defined in humans. Epidemiological data alone will no longer suffice to assess our risk to low doses of ionizing radiation from environmental and clinical exposures.