Page 256 - The Toxicology of Fishes

236 The Toxicology of Fishes

much of the research and many of the major advances in mechanistic understanding have occurred. A
discussion of mechanistic toxicology in fish is in part a question of extrapolation of knowledge obtained
in rodent and human systems to fish. How do biochemical systems and mechanisms of toxicity in fish
compare to what has been established in mammals? Are there differences in diversity or function of
receptors and biotransformation enzymes involved in these mechanisms? Fish also have many unique
features as compared to mammals, including distinct tissues (gill), routes of exposure (aqueous), and
life history (externally developing eggs, metamorphosis). How do these influence the ability to extrapolate
from rodents, or provide opportunities for novel mechanisms to be discovered? In addition, how can
fish be used to study mechanisms involved in the effects of long-term exposure in natural setting—effects
such as environmental carcinogenicity or evolved chemical resistance?
This chapter builds on a foundation in mammalian mechanistic toxicology (Gregus and Klaassen,
2001), as well as previous general descriptions of mechanistic toxicology in aquatic systems (Di Giulio
et al., 1996; Mommsen and Moon, 2005; Schlenk and Benson, 2001) and other chapters in this book
that deal with mechanism-related topics such as biotransformation (Chapter 4), oxidative stress (Chapter
6), target-organ toxicity (Chapter 11), and biomarkers (Chapter 16). We focus on mechanisms involving
receptors and other ligand-activated transcription factors that regulate gene expression in response to
chemical exposure.
Receptors are important in mechanisms of toxicity for several reasons: (1) Numerous receptors have
been identified as targets of chemicals or are potential targets based on known ligands (Table 5.1).
Chemicals can act as receptor agonists, partial agonists, or antagonists (defined below). Although
toxicants may “mimic” the natural ligands in activating the receptor, they may do so at an inappropriate
time, in an inappropriate cell type, or in a sustained way rather than the transient stimulus that charac-
terizes most physiological ligands. (2) Receptors are involved in highly coordinated signaling pathways
with key roles in embryonic development or adult homeostasis; thus, perturbation of receptor function
can have serious and wide-ranging effects on the organism. (3) Receptors often can be activated or
inhibited by very low concentrations of chemicals (nanomolar to micromolar) and thus can be sensitive
to trace amounts of chemicals in the environment. (4) The effects of receptor activation often include
amplification of the stimulus; for example, receptors that act as transcription factors typically control
the expression of several genes, and a single activated receptor can stimulate the synthesis of multiple
transcript copies from each gene. Other receptors control ion channels or initiate kinase cascades that
similarly involve signal amplification.
To illustrate some general principles of receptor-mediated toxicity as they apply to fish, we concentrate
on the well-known mechanisms involving dioxin-like compounds acting through aryl hydrocarbon
receptors (AhRs); where appropriate, we also discuss other receptors that are targets for environmental
contaminants. Important themes in this chapter include the value of fish both as targets and models,
ligand–receptor pharmacology and its relevance to mechanisms of toxicity, and the presence in fish of
additional diversity of toxicologically relevant genes—the result of a fish-specific whole-genome dupli-
cation in a teleost ancestor.

Fish as Targets and Models

The study of mechanisms of toxicity in fish involves two distinct rationales, with fish serving both as
targets and as models. Clearly, fish are targets for environmental contaminants; some fish populations
are highly exposed to chemicals, especially in urban, industrial, or coastal sites. These fish are studied
because of concern for population-level effects (Cook et al., 2003; Nacci et al., 2002) or as sentinels for
the health of the environment. In addition, they may be subjects of research to investigate the mechanisms
involved in physiological or evolutionary adaptation to chemical exposure (Wirgin and Waldman, 2004)
(see Chapter 13). Fish also are widely (and increasingly) used as animal models in toxicological research,
with the ultimate goal of extrapolating the results to inform questions concerning the potential human
health effects of chemical exposure. Thus, research in fish toxicology involves a two-way extrapolation,
with human (and rodent) results being used to establish mechanisms of relevance to fish as targets, and
fish being used as models to address specific mechanistic questions with application to human health.