Chemical exposure generates DNA damage in the germ line, which is detrimental to the next generation. We recently established the first mouse model of chronic exposure to a xenobiotic in which we examined the impact on the male germ line. We demonstrated a dose and time-dependent increase in DNA damage in male germ cells of mice exposed to acrylamide via their drinking water (0 -10ug/ml) for 1, 3, 6, 9 and 12 months (1). Damage was first observed following 6 months of exposure at the highest doses; and after 9 months, damage was detectable at concentrations equivalent to human exposure levels.
Our current aim is to identify biomarkers of xenobiotic exposure. Array analysis was performed on testis RNA extracted from acrylamide exposed mice at the 1, 6 and 12 month time points. In total, 45 arrays were analysed with 10,238 genes demonstrating expression above background. For each time point and acrylamide dose, the differentially expressed (DE) genes were determined by pairwise comparisons with the time-matched controls. A total of 248, 865 and 180 DE genes were identified at the 1, 6 and 12 month time points respectively.
We focused on the genes displaying regulation at 6 months that were clearly associated with spermatogenesis as identified by Ingenuity Pathway Assist analysis. Confirmation of gene regulation was performed by QPCR at 6 months. We further examined gene expression in testis at 3 months and identified 6 genes (odf2, dhh, spata16, gsg, fads2, lrrc18) which were regulated at this time point. This suggested that gene regulation at earlier time points could be used as a biomarker of xenobiotic exposure prior to DNA damage being induced in the male germ line.
1. Nixon et. al. (2012) Toxicol. Sci. available online May 24, 2012