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Reporter models for the Evaluation of Diseases involving OXidative stress

Final Report Summary - REDOX (Reporter models for the Evaluation of Diseases involving OXidative stress)

Humans are constantly exposed to a complex mixture of deleterious environmental agents including pollutants in air, water, and foods; radiation; occupational and household chemicals; and personal habits, such as smoking and drinking. Epidemiology studies have linked such exposures to the rising incidence of non-communicable diseases and behavioural problems in adulthood. (Non-communicable diseases are essentially all non-infectious diseases and include neurodegenerative conditions, such as Alzheimer’s disease, which has been described as the greatest emergency facing modern medicine.) Overall, the WHO estimates that 23% of global deaths, rising to 36% amongst children under 14 years of age, are attributable to the environment. Despite these alarming statistics, in most cases we do not understand at a mechanistic level how complex mixtures of pollutants disrupt homeostasis to exacerbate disease pathogenesis.

A leading hypothesis suggests that pollutants adversely affect human health by damaging one or more of the three major classes of biomolecules that comprise our bodies. As a rough rule, biologists refer to damage to proteins and lipids (“fats”) as oxidative stress. DNA damage is the term used to refer collectively to all damaging changes to our genetic material. Unfortunately, this hypothesis remains untested as tools to enable monitoring of oxidative stress and DNA damage in intact organisms have not been unavailable until now.

To enable oxidative stress and DNA damage to be measured in mice, a commonly used surrogate for human biology, in this work we have engineered rodents to emit light in amounts that parallel the degree of oxidative stress or DNA damage. Using these mice, we have for the first time measured stress and damage as it occurs in living animals. Not only can we measure these phenomenon, we can locate the stressed or damaged cells with exquisite resolution, determining not only the affected organ (heart, liver, brain etc) but also the affected cell types (the human lung for example is comprised of over 40 separate cell types, any one of which may be the target of a given pollutant). By monitoring affected organs and cell types, we anticipate that we will be able to predict the likely health consequences for individuals exposed to particular pollutants. We may also be able to infer whether there is likely to be adverse health consequences for the offspring of exposed individuals as we can measure damage to spermatocytes and eggs.

To give one specific example of how we have used these mice to try and improve human health, we examined how cancer therapies damage normal tissues. Doxorubicin is a drug commonly used to treat a variety of cancers, especially paediatric cancers. However, it has severe side effects, including damage to the heart, and cancer survivors who received this drug often suffer heart failure in later life. It has been commonly believed that whereas this drug causes DNA damage – but not oxidative stress – in cancer cells, it causes oxidative stress – but not DNA damage – in normal healthy tissue. This has led to the belief that if you could reduce the oxidative stress associated with this drug you might improve its safety profile while maintaining its efficacy against cancer. Our data unambiguously disprove this notion. They show increased DNA damage – but no oxidative stress – in multiple organs from mice exposed to doxorubicin. Thus the great - and unsuccessful - efforts that have been made to date to improve the safety profile of doxorubicin have likely been mis-directed at oxidative stress and should in the future focus on its ability to cause DNA damage in healthy tissue.

More generally, oxidative stress and DNA damage are believed to be ubiquitous and unavoidable feature of life, and have been linked with essentially all human maladies and the aging process itself. We believe the new mouse models developed during this project will make a major contribution to understanding human disease and aging, and will enable investigations into the possibility of intervening in the aging process itself so as to prolong human healthspan.