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Diseases Associated with Oxidative Stress
Compelling evidence exists that oxidative stress is an important contributing factor for numerous diseases
and pathologies. Atherosclerosis, for example, is a disease of the arteries characterized by the thickening
of the vessel walls; it is a major contributor to heart attacks and stroke, which are the leading causes of
death in the United States and Europe. The causes and progression of the disease are complex and not
fully understood, but ample evidence implicates ROS and RNS as important components (Halliwell and
Gutteridge, 1999; Harrison et al., 2003). Also, chronic inflammatory diseases such as arthritis are
generally believed to be in part caused by ROS produced by activated phagocytes at inflamed sites, in
part an autoimmune response (Closa and Folch-Puy, 2004). The brain is considered particularly prone
to oxidative stress due to its high rate of oxidative metabolism, presence of autooxidizable neurotrans-
mitters (dopamine and norepinephrine), high levels of highly unsaturated fatty acids, relatively modest
antioxidant defenses, and presence of cytochrome P450s (Halliwell and Gutteridge, 1999). Neurodegen-
erative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are
believed to be in part due to ROS, although precise mechanisms remain unresolved (Anderson, 2004).
Cancer encompasses a diverse set of diseases with a complex etiology and has been studied extensively
in fishes as well as humans. Considerable evidence supports a role for ROS and other free radicals in
tumor initiation, promotion, and progression (Klaunig et al., 1998); relevant studies in fish models are
described in Chapter 12.
In addition to these and other diseases, an important pathology closely associated with oxidative stress
is referred to as ischemia-reperfusion tissue injury. Ischemia refers to a loss of blood flow to a tissue, a
key consequence of which is hypoxia. Hypoxia can result from atherosclerosis, physical tissue damage,
surgical procedures, and depletion of environmental O . The effects of hypoxia are variable, depending
2
on severity, time course, and tissue involved and can range from mild and reversible to irreversible tissue
damage to death. A somewhat paradoxical aspect of ischemia is that sometimes tissue injury coincides
with reperfusion (i.e., restoration of blood flow and normoxia) (Halliwell and Gutteridge, 1999). This
injury is associated with oxidative stress due to cellular changes such as ATP depletion and enhanced
ROS generation via the xanthine oxidase system (McCord, 1987) and altered mitochondrial enzyme
activities (Powell and Jackson, 2003). Evidence also suggests that an environmental analogy to this
phenomenon may occur in some aquatic systems such as shallow lakes and estuaries that display marked
diurnal and seasonal fluctuations in dissolved oxygen levels (Hermes-Lima and Zenteno-Savin, 2002;
Hochachka et al., 1996).

Aging and Oxidative Stress
The processes that govern the aging process and determine the limits of lifespan of organisms have been
the subject of debate and research for many years. Considerable evidence supports an important role for
oxidative stress in these phenomena, although other factors are likely involved (Beckman and Ames,
1998; Finkel and Holbrook, 2000). Supporting evidence for the free-radical theory of aging includes the
increased accumulation of oxidized proteins, lipids, and DNA with age; increased lifespan in organisms
engineered to overexpress antioxidant enzymes (e.g., CuZnSOD and GR) in some studies; and increased
lifespan associated with caloric restriction (which reduces mitochondrial production of ROS, a key
component of this theory). As described earlier, ROS modulates several cellular signaling pathways,
including stress-responsive pathways considered adaptive to oxidative stress. The responsiveness of some
pathways, such as heat shock proteins, appears to decline with age. Fish display a range of patterns with
respect to aging, including rapid senescence in some salmonids, and may provide useful models for
ageing research.

Chemicals and Oxidative Stress

Numerous chemicals including natural products, drugs and environmental contaminants have been shown
to impact organismal health via, at least in part, oxidative stress. Some better understood examples,
largely from mammalian studies, are noted in the following text.