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DNA damage is correlated with oxidative stress and is particularly frequent in the spermatozoa of sub-fertile males. The aetiology of such DNA damage is uncertain at the present time, but environmental factors and paternal age have been identified as two key contributors to the development of this pathology. Examples of environmental factors that impact upon DNA integrity in male germ cells include paternal smoking and exposure to environmental oestrogens. Our working hypothesis is that the generation of DNA damage by xenobiotics is mediated by cytochrome P450 enzymes (P450). These Phase I detoxifying enzymes can be inefficient in their metabolism of xenobiotics and as a result of uncoupling release reactive oxygen species (ROS). ROS are capable of reacting with bases to generate oxidative DNA damage. We therefore set out to characterize the P450s present in the male germline. The mouse model provides a unique experimental system to examine DNA damage as result of toxicant exposure. Round spermatids, pachytene spermatocytes and spermatogonia were individually isolated to >90% purity by density sedimentation. Subsequently, gene expression profiling was performed on RNA from these cell populations. We identified 52 cytochrome P450 (CYP) genes expressed in round spermatids. As expected, CYP51 was highly expressed in these cells. Surprisingly, CYP17A1 was also highly expressed in round spermatids. We then mined the GEO-profiles data for the expression of CYP17A1 in the mouse testis. CYP17A1 expression increased dramatically at 30 days postpartum, which is indicative of round spermatid expression. Interestingly, 6 out of the 10 CYP genes displaying the highest expression were members of the CYP2 gene family and thus likely to be associated with xenobiotic metabolism. Having characterized the CYP genes expressed we intend to utilize the P450 substrate specificities to generate predictive models of the DNA damaging potential of xenobiotics.J. E. Schjenken, R. J. Aitken and S. D. Roma

Abstracts of the 28th Annual Meeting of the United Kingdom Environmental Mutagen Soceity, August 3–5, 2005 at the University of Bradford, UK