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Reactive Oxygen Species and Oxidative Stress 291

TABLE 6.2
Representative List of Gene Products Induced after Exposure to Prooxidants or ROS-Generating
Chemicals in Fish Species
Induction Observed
at the Level of: Gene Refs.
mRNA GSTP Kobayashi et al. (2002)
QR1 Kobayashi et al. (2002)
GCLC Kobayashi et al. (2002)
MT Kille et al. (1992); Lange et al. (2002); Schlenk et al. (2000)
Protein GST Armknecht et al. (1998); Henson et al. (2001); Van Veld et al. (1991)
Heme oxygenase Schlenk et al. (1996)
MnSOD Meyer et al. (2003)
Metallothionein Kille et al. (1992); Pedrajas et al. (1995); Van den Hurk et al. (2000)
Activity GST Ahmad et al. (2000); Armknecht et al. (1998); Henson et al. (2001);
Stephensen et al. (2002)
UDPGT Förlin et al. (1996); Gadagbui et al. (1996); Zhang et al. (1990)
GCL Gallagher et al. (1992a); Stephensen et al. (2002)
QR1 Förlin et al. (1996); Lemaire et al. (1996); Winzer et al. (2002b)
GR Åkerman et al. (2003); Förlin et al. (1996); Meyer et al. (2003);
Stephensen et al. (2002)
GPx Meyer et al. (2003); Radi and Matkovics (1988)
Heme oxygenase Ariyoshi et al. (1990)
Note: These genes are candidates for ARE regulation; no gene has yet been conclusively demonstrated to be ARE
regulated in any fish species.

ROS-Mediated Modulation of Gene Expression: Summary

The alterations observed in eukaryotic gene regulation in response to ROS are highly complex. These
alterations in gene expression may result from interaction with pathways that normally employ ROS as
signaling molecules; antioxidant responses, including those aimed at preventing the generation of ROS,
increasing the scavenging of ROS, and repair of oxidative damage; and alterations resulting from
oxidation of transcription factors or other important cellular macromolecules. The expression of a wide
variety of genes is altered by exposure to ROS, including many genes coding for proteins that are not
typically thought of as antioxidants, but rarely involves very large changes in expression. These char-
acteristics may relate to the fact that ROS play a normal physiological role in eukaryotes, suggesting
that repressing ROS to too low of a concentration might be problematic and to the fact that the
transcription factors that mediate many of the apparently adaptive antioxidant responses are involved in
other pathways as well, suggesting that large alterations in their activity might be disruptive to other
important biological responses.

Deleterious Cellular Effects of Reactive Oxygen Species
As discussed previously, the generation of ROS is a normal consequence of aerobic life and even in
some cases a beneficial one. Aerobic organisms have evolved a complex array of antioxidant defenses
that effectively deal with typical fluxes of ROS encountered by aerobic cells. As these fluxes increase,
due to both natural phenomena (such as increased aerobic metabolism during physical exertion, sharp
rises in dissolved oxygen in aquatic environments, or pronounced inflammatory responses) as well as
unnatural variables (such as anthropogenic chemicals), cellular antioxidant capacity can be overtaxed.
As described above, through mechanisms including ROS-mediated changes in gene expression, cells
can adapt to some extent by enhancing their antioxidant capacity. Upregulation of antioxidant defenses
comprises an early response to elevated ROS fluxes; however, such fluxes can exceed even adapted