Description:
<jats:p>MeHg is a potent neurotoxin, teratogen and probable carcinogen, but the underlying mechanisms remain unclear. Although MeHg causes several types of DNA damage, the toxicological consequences of this macromolecular damage are unknown. MeHg also enhances oxidative stress, which can cause various oxidative DNA lesions that are primarily repaired by OGG1. Thus, we investigated the potential protective role of OGG1 in MeHg‐induced DNA damage using OGG1‐deficient (<jats:bold><jats:italic>Ogg1</jats:italic></jats:bold><jats:sup>−/−</jats:sup>) murine embryonic fibroblasts (<jats:bold>MEFs</jats:bold>) with impaired capacity to repair oxidatively damaged DNA. The response of wild‐type (<jats:bold>WT</jats:bold>) and <jats:italic>Ogg1</jats:italic><jats:sup>−/−</jats:sup> MEFs to low micromolar concentrations of MeHg was compared by measuring clonogenic efficiency, cell cycle arrest and generation of DNA double‐strand breaks. <jats:italic>Ogg1</jats:italic><jats:sup>−/−</jats:sup> cells exhibited greater sensitivity to MeHg than WT controls as measured by the clonogenic assay. Both WT and <jats:italic>Ogg1</jats:italic><jats:sup>−/−</jats:sup> cells underwent cell cycle arrest when exposed to MeHg; however, double‐strand break induction was exacerbated in <jats:italic>Ogg1</jats:italic><jats:sup>−/−</jats:sup> cells compared to WT controls. Thus, impaired DNA repair capacity enhances cellular sensitivity to MeHg, indicating that the genotoxic properties of MeHg may contribute to its neurotoxic effects, and that an individual's response to DNA damage may be a determinant of risk. <jats:italic>Support: CIHR doctoral scholarship (SLO); Cancer Research Society & Province of Ontario Early Researcher Award (JPM); CIHR (PGW).</jats:italic></jats:p>