Nonmammalian nuclear receptors: Evolution and endocrine disruption
J. W. Thornton
Center for Ecology and Evolutionary Biology, University
of Oregon, Eugene, OR 97403-5289, USA
Abstract: Most research to identify endocrine-disrupting chemicals
and their impacts has relied on mammalian models or in vitro systems
derived from them. But nuclear receptors (NRs), the proteins that transduce
hydrophobic hormonal signals and are major mediators of endocrine disruption,
emerged early in animal evolution and now play biologically essential
roles throughout the Metazoa. Nonmammalian vertebrates and invertebrates,
many of which are of considerable ecological, economic, and cultural
importance, are therefore potentially subject to endocrine disruption
by synthetic environmental pollutants.
Are methods that rely solely on mammalian models adequate to predict
or detect all chemicals that may disrupt NR signaling? Regulation of
NRs by small hydrophobic molecules is ancient and evolutionarily labile.
Within and across genomes, the NR superfamily is very diverse, due to
many lineage-specific gene and genome duplications followed by independent
divergence. Receptors in nonmammalian species have in many cases evolved
unique molecular and organismal functions that cannot be predicted from
those of their mammalian orthologs. Endocrine disruption is therefore
likely to occur throughout the metazoan kingdom, and a significant number
of the thousands of synthetic chemicals now in production may disrupt
NR signaling in one or more nonmammalian taxa. Many of these endocrine
disruptors will not be detected by current regulatory/scientific protocols,
which should be reformulated to take account of the diversity and complexity
of the NR gene family.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
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