Page 588 - The Toxicology of Fishes

568 The Toxicology of Fishes

present in humans but not the primitive fish sea lamprey (Pancer et al., 2004). The overall homology is
sufficient, however, for the authors to suggest that it is an ancestral CD4-like gene. Future work might
potentially involve an investigation into the expression of CD4-like genes in fish displaying normal,
adenoma, and carcinoma phenotypes to determine if it is indeed involved in modulating the progression
stage of the carcinogenesis process. It is only a matter of time before recent advances in -omics
technologies highlight the involvement of CD4 and other immune response elements in modulating
cancer in fish.

Environmental Factors

All fishes live in water, which, as a universal solvent, brings them into direct contact with a variety of
waterborne substances, many of which are anthropogenic contaminants. In addition, fishes are exposed
through diet to substances that are not readily soluble in water but have been accumulated within the
tissues of the organisms on which fish feed. Fishes have also developed a variety of physiological
adaptations to poikilothermy, where body temperature is dependent on ambient temperature, and unique
morphologic adaptations to aquatic life, largely in response to the high density and low compressibility
of water. Some fishes produce large eggs that can be easily examined and manipulated outside the body,
and some demonstrate what researchers using mammalian models might call “unusual” reproductive
strategies, such as the physical transition of some female wrasses (family Labridae) to the role of
dominant male when the need arises. Other fishes undergo radical physiological adaptations associated
with life-stage transitions, exemplified by the metamorphosis of the lamprey (Petromyzon marinus) and
the process of smoltification, an array of morphologic, physiologic, and behavior adaptations for ocean
life that occurs among most salmonids. In searching for an ideal mammalian experimental model,
researchers often try to identify animals that express disease processes homologous to those seen in
humans. The same strategy has been applied to fish models to variable extent; however, fish may prove
to be better models in many circumstances, not due to their similarity with humans or other mammals
but precisely due to their differences. This can be further amplified when one considers the ability of
environmental factors to modulate carcinogenesis.

Complex Mixtures
Complex mixtures are an important factor, especially when we deal with field studies and when extracts
of environmental media (sediment and industrial mixtures) are used (Fabacher et al., 1991; Metcalfe
and Sonstegard, 1985). An excellent example of complex mixtures was provided by Gardner et al. (1998).
A chronic 6-month carcinogenicity bioassay was conducted on-site in a mobile biomonitoring facility
using medaka in an initiation–promotion protocol, with DEN as the initiator and trichloroethylene (TCE)-
contaminated groundwater as the promoter. TCE (reagent-grade) was added to carbon-filtered ground-
water to simulate concentrations found in contaminated groundwater. Although the filtered water with
TCE showed no promotional effects, a tumor-promoting effect was seen in the unfiltered groundwater
after initiation with DEN. This implies that substances in the groundwater and not detected by chemical
analysis were working to promote DEN carcinogenesis.

Complicated Exposure Regimes
Field investigations are difficult to interpret in part due to complicated exposure regimes, the environ-
mentally realistic scenario. Variations in metal content in surface waters, with higher levels being present
during rainy seasons, represent a portion of the complexities with fieldwork. This could lead to differences
in tumor incidence due to promotional effects related to formation of active oxygen intermediates.
Intermittent exposures may lead to variations in the promotion or inhibition of earlier initiated carcino-
genic processes and thereby lead to errors in the potential for fish living at a particular site to develop
tumors. With methylazoxymethanol acetate (MAM) exposure, a similar incidence of liver tumors (i.e.,
nearly 100%) was found after a long-time exposure to a low level (0.1 ppm for 120 days) and after a
short exposure to a high level (10 ppm for 1 hour) of the initiating carcinogen (Aoki and Matsudaira,
1984). Dose-dependent enhancement and inhibition of the tumorigenic process were reviewed earlier.