Page 278 - The Toxicology of Fishes

258 The Toxicology of Fishes

Neurotransmitter Receptors

Fish, like other vertebrates, possess a large variety of receptors for neurotransmitters such as GABA,
glutamate, acetylcholine, and serotonin, as well as other receptors such as ryanodine receptors. All of
these may be targets for environmental chemicals, as described in Chapters 9 and 20 and elsewhere
(Baraban et al., 2005; Carr et al., 1999; Linney et al., 2004b; Stehr et al., 2006).

Olfactory Receptors
Another group of receptors that are potential targets for xenobiotic chemicals are the chemosensory
receptors used by fish to detect small molecules (amino acids, steroids, fatty acids) in their aquatic
environment. These receptors include the classical odorant receptors (Alioto and Ngai, 2005), vomero-
nasal receptors (Hashiguchi and Nishida, 2005), and the newly identified trace amine-associated receptors
(TAARs) (Gloriam et al., 2005; Liberles and Buck, 2006). Odorant receptor gene expression changes
during the parr–smolt transformation in Atlantic salmon (Dukes et al., 2004). These receptors have been
suggested to be important in homing behavior, through imprinting on natal odor cues (Barinaga, 1999;
Dittman et al., 1997; Nevitt et al., 1994); thus, interference with olfactory function in fishes could have
long-term reproductive consequences. Few studies, however, have addressed the effect of toxicants on
olfactory receptor function. One study showed that exposure of salmon to copper interfered with the
neurophysiological response to natural odorants (Baldwin et al., 2003), illustrating the potential toxico-
logical significance of the olfactory system.

Other Xenobiotic-Activated Transcription Factors

Other ligand-activated transcription factors play important roles in mechanisms of toxicity in fish. Some
of these do not function as classically defined receptors, in that they do not exhibit high-affinity specific
binding of ligands; rather, they are activated by other types of interactions with xenobiotics. One example
of such transcription factors are those in the Cap‘n’Collar basic leucine zipper (CnC-bZIP) family,
including NRF2 (nuclear factor erythroid-derived-2 [NFE2]-related factor 2).* NRF2 and related proteins
are activated by oxidative stress and upregulate the expression of genes that are part of the antioxidant
response, including several phase II biotransformation enzymes (Nguyen et al., 2003).
Fish possess an antioxidant response that is similar, although not identical, to that of mammals, as
described in Chapter 6 and elsewhere (Carvan et al., 2001; Hahn et al., 2005). A fish NRF2 ortholog
has been identified and shown to regulate the induction of glutathione S-transferase π (GSTP), NQO1,
and gamma-glutamylcysteine synthetase (γ-GCS) after exposure of zebrafish embryos and larvae to tert-
butylhydroquinone (tBHQ) (Kobayashi et al., 2002; Suzuki et al., 2005); thus, the function and target
genes of NRF2 appear to be conserved in mammals and fishes. As with many other transcription factors,
however, the diversity of NRF2-like genes appears to be greater in fish than in mammals (Hahn et al.,
2005). Understanding the different roles of these NRF genes in the response to xenobiotic exposure is
an important goal of future research. Details concerning the mechanisms of response to oxidative stress
can be found in Chapter 6.
Another example of a nonreceptor, ligand-activated transcription factor is the metal-responsive
transcription factor (MTF-1). MTFs are zinc finger proteins that are activated (either directly or
2+
2+
indirectly) by heavy metals such as Zn and Cd , and they regulate transcription through binding to
metal-responsive elements (MREs) in the 5′-regulatory region of genes such as those encoding metal-
lothioneins (MTs) (Giedroc et al., 2001; Samson and Gedamu, 1998). MTF-1 can also be activated by
oxidative stress (Dalton et al., 1996). MTF-1 has been characterized in several fish species, and it
appears to function similarly in fish and mammals (Auf der Maur et al., 1999; Chen et al., 2002; Dalton
et al., 2000).

* NRF2 is also known as NFE2L2 (NFE2-like-2).