Spontaneous mutation frequency is elevated in skin of harlequin (hq)/Big Blue(R) mice

Abstract

The harlequin (hq)/Big Blue mouse is a novel model of premature ageing distinguished by a patchy coat, early-onset neurodegeneration, stress-induced heart disease and a mutation detection assay applicable to individual tissues. The hq mutation causes down-regulation of apoptosis-inducing factor and an elevation of reactive oxygen species (ROS). Neural tissues have elevated mutant frequency and early-onset degeneration. This is the first examination of mutations and histology in the skin of hq disease mice. The frequency and pattern of cII mutations in skin from adult hq disease and wild-type (WT) mice 15 days after a single intraperitoneal (i.p.) injection of paraquat (PQ; 10 mg/kg) or vehicle control (VC) were determined to assess spontaneous mutagenesis and sensitivity to an exogenous ROS-inducing mutagen. Skin of hq disease mice shows elevated levels of ROS (P < 0.001) and reduced numbers of hair follicles and associated epidermal cells (P < 0.001) compared to WT control. Acute PQ exposure did not produce detectable skin histopathology. Spontaneous and PQ-induced mutation frequency is elevated in hq skin (P = 0.03 and P = 0.01, respectively) compared to VC-treated WT mice. Despite elevated mutation frequency, mutation patterns were unaltered. Acute PQ exposure resulted in a 1.6-fold increase in mutation frequency in WT mice compared to the level of spontaneous mutations but no significant impact on mutation frequency in hq disease mice. Increased mutation frequency in skin of hq disease mice may be relevant to mechanisms underlying the patchy coat and useful as a biomarker in tests of antioxidant efficacy in preventing the hq disease phenotype. Unaltered mutation patterns with hq disease are consistent with the multiple mutation types associated with ROS. Acute PQ exposure had only subtle effects in WT mice and reduced mitochondrial complex I activity and elevated antioxidant enzyme activity in hq disease mice may lead to PQ resistance.