Figure 1.

Environmental agents contribute to repeat instability. In adult somatic tissue (a), researchers have provided evidence for the role of an MMR-BER hybrid pathway in responding to potassium chromate or potassium bromate exposure, thus, leading to increased oxidative damage and susceptibility to repeat expansion. Additional studies support the role of components of BER and potentially MMR pathways in responding to oxidative damage, such as that induced by exogenous hydrogen peroxide or aging, again resulting in repeat expansion. Of note, when BER pathways alone are involved in responding to oxidative damage, evidence points to repeat contractions rather than expansions. Potassium bromate is shown to affect intergenerational repeat instability in germline cells via oxidative damage. The exact pathways that mediate this form of oxidative damage remain unknown; however, evidence suggests that oxidative damage in the germline (b) promotes repeat expansion. Differences in female and male germline instability call for future studies to investigate mechanistic differences in environmentally induced repeat instability in egg and sperm. Both hydrogen peroxide and potassium bromate exposure to embryonic tissue (c) is shown to promote repeat expansion. Studies have pointed to the role of MSH2 (component of MMR pathway), as well as suggest additional, potentially hybrid pathways, involving BER and NHEJ in mediating the response to oxidative damage and facilitating repeat expansion. Further research also showed that pluripotent cells are especially susceptible to repeat instability in response to environmental exposures.