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The Society for Integrative and Comparative Biology
Xenobiotics and the Evolution of Multicellular Animals: Emergence and Diversification of Ligand-Activated Transcription Factors1
1 Department of Medicine, 0693, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0693
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Multicellular animals, which evolved about 700 to 1,000 myr ago, contain many of the genes found in yeast. Important for the evolution of multicellular animals were new pathways for intercellular signaling that regulated more complex physiological responses. Here we focus on the contribution to this process of lipophilic molecules that interact with nuclear receptors and the aryl hydrocarbon receptor, as well as enzymes that regulate the concentrations of these molecules. Both nuclear receptors and the aryl hydrocarbon receptor are found in invertebrates and vertebrates. We propose that environmental chemicals (xenobiotics) have been an important influence on the evolution of multicellular animals through a process involving the co-evolution of ligand-activated transcription factors and enzymes that detoxify xenobiotics. Indeed, this conversion of "xenobiotic swords" into "adaptive plowshares" contributed to the diverse physiology found in multicelluar animals. An important implication of this analysis is that enzymes as well as hormone receptors are vulnerable targets for endocrine disruptors. That is, some toxic chemicals act by inhibiting the enzymes that catalyze the formation or degradation of lipophilic signals, such as steroids, thus, disrupting hormone action.
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Multicellular animals appeared on earth about 700 to 1,000 million years ago (Ayala et al., 1998
; Valentine et al., 1999; Budd and Jensen, 2000). This is relatively late in the evolution of life on earth. Life in the form of single cell prokaryotes appeared on earth about 3.5 billion years ago. Eukaryotes are thought to have appeared on earth about 2 billion years ago. Although there is evidence for multicellular animals in the Vendian from 650 to 600 million years ago, it is not until the Cambrian explosion, about 550 million years ago, that we see extensive evidence for multicellular animals in the fossil record (Valentine et al., 1999; Conway Morris, 2000). Indeed, during this time most of the various invertebrate and vertebrate phyla evolved.
These data raise some interesting questions. What caused the delay of over a billion years in the evolution of multicellular animals after the evolution of single cell eukaryotes? And what are the causes of the sudden appearance of multicellular animals in the Cambrian about 550 million years ago? Regarding the latter question, one important factor was the increase in oxygen concentration in the preCambrian to levels that supported the higher metabolic activity of multicellular animals (Canfield and Teske, 1996; Knoll, 1999; Knoll and Carroll, 1999).
Also important were duplications of genes in ancestral multicellular animals because mutations in the duplicated gene could lead to the evolution of new functions that supported the increased complexity found in multicellular animals. However, in addition to individual gene duplications, there is evidence for large scale duplications either of an entire chromosome or several chromosomes prior to the Cambrian (Ohno, 1970; Holland et al., 1994; Holland, 1999). Such large scale duplications would yield complete "extra" networks of genes, which upon mutation evolved into new regulatory pathways.
Important insights into when various regulatory mechanisms arose and how they have evolved have come from the sequencing of entire genomes of eukaryotes. At the same time, some aspects of the genomic data are perplexing because they show that increased gene number by itself does not appear to correlate with animal complexity. For example, the fruitfly Drosophila melanogaster (Adams et al., 2000) and worm Caenorhabditis elegans (The C. elegans Sequencing Consortium, 1998) have about 13,500 and 18,000 genes, respectively. Yet the fly has more complex cell types and development.
A similar lack of correlation between gene size and complexity appears to be true for vertebrates. Humans have from 30,000 to 35,000 genes (International Human Genome Consortium, 2001; Venter et al., 2001; Li et al., 2001), which is at best only 2-fold more than the worm. How can we account for increased complexity found in vertebrates? Various explanations for the unexpected low gene number in humans have been proposed (International Human Genome Consortium, 2001; Venter et al., 2001; Li et al., 2001). First, gene number is not as low as it seems because from 40% to 60% of human genes are alternatively spliced. Second, human proteins contain novel combinations of domains, which allow for increased protein-protein interactions, compared to invertebrate proteins. Third, post-translational modification of proteins adds complexity. Fourth, was the evolution in vertebrates of networks of transcription factors and the genes that they regulate (Szathmary et al., 2001).
In addition, we proposed that the evolution of receptors for five different classes of steroids and of enzymes, such as steroid dehydrogenases and cytochrome P450s (P450), which regulates the concentrations of these steroids, in a protochordate and in primitive vertebrates, such as hagfish and lamprey, was important event in the evolution of complexity seen in vertebrates (Baker, 2003, 2004). In vertebrates, adrenal and sex steroids—aldosterone, cortisol, estradiol, progesterone and testosterone—regulate a wide range of physiological processes, including reproduction, development and homeostasis (Fig. 1). Receptors for these steroids are a subset of the nuclear receptor superfamily (Escriva et al., 2000; Chawla et al., 2001; Robinson-Rechavi et al., 2003), which is a large family of transcription factors, found in vertebrates and invertebrates (Escriva et al., 1997). Among the ligands that act through nuclear receptors are steroids, retinoids, thyroid hormone, bile acids, 1,25-dihydroxyvitamin D3, and ecdysone (Figs. 1, 2).
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Here we extend this model to the evolution of complexity in invertebrates by considering the co-evolution of more ancestral nuclear receptors and enzymes that convert lipophilic molecules into metabolites that interact with these nuclear receptors. We propose that both enzymes and nuclear receptors were important in the early evolution of complexity in invertebrates. Some of these enzymes and receptors were and still are important in the response to foreign chemicals in the environment, which explains, in part, the vulnerability to xenobiotics of pathways involved in the differentiation, development and reproduction of both invertebrates and vertebrates.
Although we focus on the evolution of molecules that act through nuclear receptors, and in a particular, the actions of sterols, this discussion for nuclear receptors is relevant for other ligand-activated receptors, such as the aryl hydrocarbon receptor (AhR), which also binds and responds to diverse lipophilic compounds.
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Nuclear receptors are large family of transcription factors that are regulated by small hydrophobic ligands (Escriva et al., 2000
; Chawla et al., 2001; Robinson-Rechavi et al., 2003) (Figs. 1, 2). These lipophilic ligands regulate almost all aspects of animal physiology, including homeostasis, differentiation, development, sexual maturation and the response to stress. Some nuclear receptors still do not have a known ligand that regulates their action. These receptors are called orphan receptors (Kliewer et al., 1999; Chawla et al., 2001; Gustafsson, 1999).
Nuclear receptors have a characteristic multi-domain structure in which the ligand-binding domain containing about 250 amino acids is at the carboxyl terminus and the DNA-binding domain containing about 70 amino acids is on the amino terminal side of the ligand-binding domain. When the hormone (e.g., steroid, thyroid hormone, retinoid, bile acid) binds to its nuclear receptor, the receptor undergoes a conformational change that alters its affinity for DNA and for other proteins such as co-activators and co-repressors (McKenna and O'Malley, 2000; Rosenfeld and Glass, 2001; Smith and O'Malley, 2004), leading to the transcription of genes that characterize the response to the hormone.
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NUCLEAR RECEPTORS ARE UNIQUE TO MULTICELLULAR ANIMALS |
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The highly conserved DNA-binding domain contains four cysteine residues in a characteristic motif that is diagnostic for nuclear receptors. This domain is so well conserved that it can be used to catalog the number of nuclear receptors in genomes. Searches of entire genomes of human, Fugu, C. elegans, and D. melanogaster for genes that contain this characteristic DNA-binding domain revealed that there are 48 nuclear receptors in humans, 68 in Fugu, 270 in C. elegans and 21 in D. melanogaster (Robinson-Rechavi et al., 2001
; Sluder et al., 1999; Maglich et al., 2003).
Unexpectedly, a similar search of the genome of the yeast Saccharomyces cerevisiae did not find any nuclear receptor genes (Goffeau et al., 1996). Also unexpectedly, a search of the genome of the plant Arabidopsis did not find any nuclear receptor genes (The Arabidopsis Genome Initiative, 2000). This was surprising because nuclear receptors, such as the estrogen receptor (Metzger et al., 1988) and glucocorticoid (Schena and Yamamoto, 1988) receptor, can function nicely when transfected into yeast along with a reporter gene. Similarly, the glucocorticoid receptor can function when transfected into Arabidopsis (Schena et al., 1991). This indicates that the basic machinery for transcriptional activation by nuclear receptors evolved in yeast, even if they do not contain these receptors. These genome analyses indicate that nuclear receptors arose in multicellular animals and suggest that nuclear receptors had an important role in their evolution.
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NUCLEAR RECEPTORS THAT BIND LIGANDS WITH 27 CARBONS AND THE EVOLUTION OF COMPLEX INVERTEBRATES |
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Figure 3 shows a phylogenetic tree of the ligand-binding domains of various nuclear receptors. This tree gives an insight into the evolution of ligands that regulate nuclear receptor action, which is the focus of this article. The DNA-binding domain appears to have a different evolutionary history and will not be discussed here (Baker, 2002b; Thornton et al., 2003
).
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Figure 3 shows two large groups of nuclear receptors. One group contains the adrenal and sex steroid receptors (Baker, 1997
, 2002b, 2001; Escriva et al., 2000; Thornton, 2001; Thornton et al., 2003). The ligands that bind steroid receptors contain from 18 to 21 carbon atoms (Fig. 1). Thus, far, receptors that mediate the response to adrenal and sex steroids have only been found in the vertebrate line (Thornton, 2001; Baker, 2003), which arose relatively late in the evolution of multicellular animals. Because the focus of this paper is the early evolution of ligand activation of transcription factors in multicellular animals, there only will be limited discussion of adrenal and sex steroid receptors in this paper.
The second group contains nuclear receptors that bind a diverse group of ligands (Fig. 2). This second group can be subdivided further (Fig. 3). One clade contains the 1,25-dihydroxy-vitamin D3 receptor (VDR), the ecdysone receptor (EcR), the liver X receptor (LXR), which binds oxysterols, and the farnesoid X receptor (FXR), which binds bile acids. The ligands for these receptors contain from 24 to 27 carbon atoms and are synthesized from cholesterol or from another sterol found in either plants or yeast. For example, insects do not synthesize cholesterol, which is the precursor of ecdysone, the molting hormone. Instead, insects obtain cholesterol (27 carbons) from animals. Alternatively, insects convert ergosterol (28 carbons) or stigmasterol (29 carbons), from yeast and plants (Fig. 4), respectively, to cholesterol (Svoboda, 1999; Gilbert et al., 2002). Because receptors such as EcR, VDR, FXR and LXR respond to ligands that are derived from cholesterol, we will call this group C27-nuclear receptors (C27-NR). The nodes of the branches for this part of the tree in Figure 3 indicate that the ancestors of C27-NRs are deep in the invertebrate line, which is consistent with the analysis of Escriva et al., 1997 and experimental evidence that C27-NRs are biologically active in invertebrates (Svoboda, 1999; Gilbert et al., 2002; Kurzchalia and Ward, 2003; Gissendanner et al., 2004).
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We propose that C27-NRs had an important role in the evolution of multicellular invertebrates. Important for our model is that some C27-NRs, such as LXR and FXR have low affinity and specificity for their ligands. Indeed, many ligands interact with these receptors in invertebrates and vertebrates, consistent with the function of LXR and FXR to regulate the levels of oxysterols and bile acids, respectively, as well as acting as sensors for lipophilic xenobiotics (Chawla et al., 2001
; Xie and Evans, 2001; Chiang, 2002). We propose that xenobiotic recognition in various ancient nuclear receptors and the evolution of enzymes, especially P450 enzymes, which inactivate xenobiotics, together had a major role in the transition from unicellular organisms, such as yeast (which do not contain nuclear receptors) to multicellular invertebrates.
This raises the question, analogous to the "chicken and egg" conundrum: Which came first: the C27 ligand or the receptor (Thornton, 2001; Baker, 2000a, 2004)? That is, did an organism first synthesize a ligand, for which a receptor had not yet evolved? Or did a proto-hormone receptor for a hormone evolve before the evolution of enzyme(s) necessary for synthesis of its ligand? As described below, we favor a "chicken and egg" model, with the emergence of nuclear receptors and high affinity ligands through a co-evolutionary process involving an ancestral nuclear receptor with low selectivity for a ligand and detoxification enzymes that happened to catalyze the formation of ligands with higher affinity for the proto-hormone receptor.
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P450 ENZYMES: CONVERTING XENOBIOTIC SWORDS INTO PLOWSHARES |
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We propose that early in the evolution of nuclear receptors, they had low specificity for or "fuzzy recognition" of lipophilic ligands. Indeed, it has been proposed that the ancestral nuclear receptor(s) were ligand-independent transcription factors that acquired ligand-dependence later (Escriva et al., 2000
). This evolutionary model does not exclude ancient nuclear receptors also binding more than one ligand with low affinity. Such ligands could be similar in their carbon skeleton, but differ in the number of methyl, alcohol or ketone groups that they contain. A modern example is the similar affinity of aldosterone, cortisol and corticosterone for the human MR (Arriza et al., 1987). An undesirable consequence is that various foreign chemicals also could bind to an ancestral nuclear receptor or to other cellular proteins and disrupt homeostasis, development or reproduction in the organism, even if the nuclear receptor was active in the absence of ligand.
Early in the evolution of eukaryotes, mechanisms evolved to deal with these unwanted effects of xenobiotics. A key protective system involves P450s, heme-containing enzymes, which are one of the most ancient enzyme families (Lewis and Sheridan, 2001; Danielson, 2002; Lathe, 2002; Nelson, 2003). P450s evolved through gene duplication and divergence into a diverse protein family that metabolize a wide variety of chemicals, that now have two general functions: inactivation and removal of xenobiotics and synthesis of complex organic molecules (Danielson et al., 1997; Nebert and Russell, 2002; Nelson, 2003). P450s catalyze the replacement of hydrogen in a C-H bond with a hydroxyl, which can significantly alter a chemical's affinity—either up or down—for proteins. One consequence of the addition of a hydroxyl group is to increase water solubility, which facilitates excretion from humans and other vertebrates.
However, P450s also are essential for synthesis of cholesterol and other membrane sterols (Yoshida et al., 2000; Danielson, 2002; Nebert and Russell, 2002), bile acids (Chiang, 2002) and in converting ecdysone to 20-hydroxyecdysone (Svoboda, 1999; Gilbert et al., 2002). In this case, P450s function to synthesize a molecule that is used by the organism to alter membrane properties or to act as a signal to regulate a physiological process, such as molting.
We propose that these activities of P450s are important in two "chance" events, which are not mutually exclusive, that eventually yielded nuclear receptors with more selectivity for ligands, such as steroids. First, a mutant P450 could catalyze the formation of a metabolite that had an increased affinity for an endogenous wild-type nuclear receptor. This is similar to the activation of drugs by some P450s. Organisms that metabolized either a foreign or an endogenous chemical into a biologically active molecule had a selective advantage in competition with other animals. A biological example of this process is found in modern flies, in which P450s catalyze the conversion of exogenous cholesterol to ecdysone and its subsequent conversion to 20-hydroxyecdysone, yielding a steroid that regulates molting (Svoboda, 1999; Gilbert et al., 2002).
Second, an animal contained a mutant nuclear receptor, which "by chance" had an increased affinity for a P450 metabolite. Animals with these more selective mutant receptors were able to compete for resources and to reproduce better than animals that had wild-type receptors, which fixed the mutation in the population. In both cases, P450s would catalyze the formation of ligands that would activate endogenous nuclear receptors. Co-evolution of the nuclear receptor and P450s would lead to more selective and tighter ligand-receptor complexes.
The above discussion also is relevant for other nuclear receptors. For example, retinoid X receptor (RXR) has orthologs in invertebrates, and is a co-receptor with many C27-NRs (Glass, 1994). Moreover, RXR regulates transcription of P450 enzymes and retinoids and fatty acids are metabolized by P450 enzymes. Thus, RXR was under the same selective pressures as C27-NRs.
This analysis also is relevant to the AhR, which belongs to another protein family that is found in invertebrates and vertebrates (Burbach et al., 1992; Hahn, 2002). Xenobiotics with diverse structures bind to AhR, leading to the induction of P450s, which metabolize these xenobiotics (Denison and Nagy, 2003; Mimura and Fujii-Kuriyama, 2003).
In summary, the evolution and divergence of the P450 enzyme family provided eukaryotes with a mechanism to cope with diverse lipophilic compounds that are produced by foreign organisms, as well as potentially toxic metabolites produced by the host organism. Some of these P450 metabolites interact with hydrophobic sites on proteins, including transcription factors. In some cases, these interactions provided a selective advantage to the host organism. Many of the C27 nuclear receptors respond to more than one metabolite, giving these receptors broad specificity, which increases the range of xenobiotics that can be recognized and removed (Xie and Evans, 2001; Chawla et al., 2001; Blumberg et al., 1998). This property is advantageous for preventing unwanted actions of harmful chemicals. In contrast, adrenal and sex steroid receptors have high substrate specificity and affinity for steroids, which is important in vertebrate physiology. Co-evolution of both low and high specificity nuclear receptors and P450 enzymes was an important factor in the evolution of multicellular animals.
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1 From the Symposium EcoPhysiology and Conservation: The Contribution of Endocrinology and Immunology presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 5–9 January 2004, at New Orleans, Louisiana.
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