Oxidative stress in disease and drug toxicity

My lab over 45 years has investigated the role of reactive oxygen species (ROS) and free radical intermediates in intrinsic disease and xenobiotic toxicity, including cancer, organ damage, developmental disorders and neurodegeneration.  Using in vitro and in vivo approaches, we have elucidated an array of molecular mechanisms underlying ROS-mediated pathologies and the determinants of risk in several animal models and humans.  The balance of multiple pathways regulating ROS formation and detoxification, and the repair of oxidatively damaged DNA, is a major determinant of risk. Even a modest imbalance among these pathways causes ROS-initiated diseases including cancer, developmental disorders and age-related neurodegeneration in the absence of environmental xenobiotics, while xenobiotic toxicity occurs at normally safe exposure levels.  The developing fetus and aging brain typically exhibit biochemical imbalances that favour ROS-mediated pathologies.  Most recently, we found that increased DNA oxidation in DNA repair-deficient fetal mice, or in fetuses exposed to the ROS-enhancing drug ethanol, causes postnatal neurodevelopmental disorders (NDDs) via non-mutational mechanisms including epigenetic changes and genome-wide transcriptional dysregulation.  NNDs in the untreated repair-deficient mouse progeny may be relevant to some components of human disorders like autism, attention-deficit/hyperactivity disorder (ADHD) and other mental disorders, while the ethanol-enhanced NDDs may be relevant to fetal alcohol spectrum disorders (FASD).  Postnatal treatment of both saline- and ethanol-exposed repair-deficient progeny with an epigenetic modifier reversed the ROS-mediated epigenetic changes, which prevented the transcriptional dysregulation and some NDDs, raising the possibility of a cure for some NDDs, rather than the current reliance on symptomatic management.