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Receptor-Mediated Mechanisms of Toxicity 257

possess three estrogen receptor-related receptors (ERRs), fish possess up to six ERR genes (Bardet et al.,
2004; Maglich et al., 2003; Tarrant et al., 2006). The role of nuclear steroid receptors in fish endocrine
toxicology is detailed in Chapters 10 and 25. In addition, recent studies have identified membrane steroid
receptors that are not related to the nuclear receptors but rather are G-protein-coupled receptors that
mediate rapid nongenomic actions for estrogens, androgens, and progestins (Zhu et al., 2003a,b). These
receptors, which may also be targets for environmental chemicals, are also described in Chapter 10.
Other nuclear receptors of importance in toxicology include the constitutive androstane receptor (CAR)
and pregnane X receptor (PXR). The discovery of these receptors in mammals and their initial charac-
terization in fishes have illuminated a long-standing mystery in toxicology. Early studies of CYP
induction in mammals had suggested the existence of two types of responses: 3-MC type and PB type,
named after the model inducers 3-methylcholanthrene (3-MC) and phenobarbital (PB), which induce
primarily CYP1A and CYP2B, respectively. Induction of CYP1A by 3-MC was well known to occur
through the AhR, but the mechanism of PB-type induction remained elusive for many years. Interestingly,
fish display 3-MC-type but not PB-type induction (Addison et al., 1987; Ankley et al., 1987; Elskus and
Stegeman, 1989; Kleinow et al., 1990), but it was not known whether this was caused by lack of
orthologous CYP2 genes or lack of the induction mechanism (reviewed in Stegeman and Hahn, 1994).
Studies in mammals identified CAR as the transcription factor regulating CYP2 induction and PXR as
the regulator of CYP3A induction (although some functional overlap occurs between the gene targets
of these two receptors) (Handschin and Meyer, 2003). Searches of fish genome sequences and homology
cloning efforts reveal that fish possess a homolog of mammalian PXR, but CAR appears to be absent
(Maglich et al., 2003; Moore et al., 2002; Bainy and Stegeman, 2004). Evolutionary studies in a variety
of vertebrates suggest that mammalian CAR and PXR arose by a gene duplication in the mammalian
lineage (Handschin et al., 2004; Reschly and Krasowski, 2006); thus, nonmammalian PXR homologs
are related to both PXR and CAR. The zebrafish PXR has been cloned; like other vertebrate PXRs, it
has a broad ligand specificity, and it is activated by many of the known activators of mammalian PXRs
(Bainy and Stegeman, 2004; Moore et al., 2002). Currently, the role of PXR in fish toxicology is not
well understood beyond its probable function in regulating CYP3 expression. Recent studies have shown
that several compounds, including some xenoestrogens, can induce PXR expression in fish (Bresolin et
al., 2005; Meucci and Arukwe, 2006; Mortensen and Arukwe, 2006).
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with a variety of roles in
regulating lipid metabolism. PPARs have been studied extensively in mammalian systems; mammals
have three PPAR isoforms that act as heterodimers with the retinoid X receptor (RXR). PPAR ligands
include fatty acids (natural ligands), fibrate drugs, phthalate ester plasticizers, and herbicides (Grun and
Blumberg, 2006; Peraza et al., 2006). Some fish species may possess additional PPAR forms as compared
to mammals (Escriva et al., 2002; Hahn et al., 2005; Leaver et al., 2005; Maglich et al., 2003; Robinson-
Rechavi et al., 2001). As compared to mammalian PPARs, fish PPARs have added complexity in terms
of their diversity, expression patterns, and ligand specificity (M. J. Leaver, pers. commun.).
Corticosteroid receptors regulate responses to stress and salt balance, including seawater adaptation.
Fish have two glucocorticoid receptors (GRs) and a mineralocorticoid receptor, whereas mammals have
one of each (Bury et al., 2003; Greenwood et al., 2003; Maglich et al., 2003; Prunet et al., 2006; Stolte
et al., 2006). Studies in mammals suggest that GR could be directly affected by xenobiotics (Johansson
et al., 1998), but the role of fish GRs in mechanisms of toxicity is not well understood (Knudsen and
Pottinger, 1999; Vijayan et al., 2005). Evidence in fish suggests interactions between GR signaling and
other receptor-dependent signaling pathways, such as the AhR pathway (Celander et al., 1996, 1997;
DeVault et al., 1989). For a detailed description of fish corticosteroid receptors as targets for xenobiotics,
see Vijayan et al. (2005).
Other fish nuclear receptors also are potential targets for xenobiotics; these include thyroid hormone
receptors (TRs), androgen receptors (ARs), and retinoid receptors (RXRs, RORs, RARs). Thyroid
hormone receptors have important roles in metamorphosis and other developmental processes in fish
(Power et al., 2001) and thus are likely to be important targets of contaminants, through direct or indirect
mechanisms (Brown et al., 2004; Crane et al., 2005; Elsalini and Rohr, 2003; van der Ven et al., 2006).
Retinoid and androgen receptors have also been examined as targets for environmental chemicals in
fishes (Alsop et al., 2003; Hewitt et al., 2003; Makynen et al., 2000; Wells and Van Der Kraak, 2000).