Abstract
Disruption of nuclear receptors, a transcription factor superfamily regulating gene expression in animals, is one proposed mechanism through which pollution causes effects in aquatic invertebrates. Environmental pollutants have the ability to interfere with the receptor’s functions through direct binding and inducing incorrect signals. Limited knowledge of invertebrate endocrinology and molecular regulatory mechanisms, however, impede the understanding of endocrine disruptive effects in many aquatic invertebrate species. Here, we isolated three nuclear receptors of the Pacific oyster, Crassostrea gigas: two isoforms of the retinoid X receptor, CgRXR-1 and CgRXR-2, a retinoic acid receptor ortholog CgRAR, and a peroxisome proliferator-activated receptor ortholog CgPPAR. Computer modelling of the receptors based on 3D crystal structures of human proteins was used to predict each receptor’s ability to bind to different ligands in silico. CgRXR showed high potential to bind and be activated by 9-cis retinoic acid and the organotin tributyltin (TBT). Computer modelling of CgRAR revealed six residues in the ligand binding domain, which prevent the successful interaction with natural and synthetic retinoid ligands. This supports an existing theory of loss of retinoid binding in molluscan RARs. Modelling of CgPPAR was less reliable due to high discrepancies in sequence to its human ortholog. Yet, there are suggestions of binding to TBT, but not to rosiglitazone. The effect of potential receptor ligands on early oyster development was assessed after 24h of chemical exposure. TBT oxide (0.2μg/l), all-trans retinoic acid (ATRA) (0.06 mg/L) and perfluorooctanoic acid (20 mg/L) showed high effects on development (>74% abnormal developed D-shelled larvae), while rosiglitazone (40 mg/L) showed no effect. The results are discussed in relation to a putative direct (TBT) disruption effect on nuclear receptors. The inability of direct binding of ATRA to CgRAR suggests either a disruptive effect through a pathway excluding nuclear receptors or an indirect interaction. Our findings provide valuable information on potential mechanisms of molluscan nuclear receptors and the effects of environmental pollution on aquatic invertebrates.
Highlights
One specific mechanism through which endocrine disrupting pollutants can affect wildlife is the disruption of gene expression regulation by interfering with the function of nuclear receptors
The genomic DNA data of each receptor was used as template for sequencing the full coding DNA sequences (CDS) of three oyster Nuclear receptors (NR) and their isoforms
The in silico 3D models for CgRXR and CgRAR were successfully created based on crystal structures of human homolog NRs bound to specific ligands
Summary
One specific mechanism through which endocrine disrupting pollutants can affect wildlife is the disruption of gene expression regulation by interfering with the function of nuclear receptors. Nuclear receptors (NR) are ligand binding transcription factors in metazoan species, regulating the transcription of many fundamental genes involved in development, reproduction and homeostasis. These receptors bind to specific response elements in a gene promotor sequence [1] and function either as monomers, homodimers, or heterodimers [2]. Xenobiotic agonists of NRs are commonly cited as a key mode of action in events of endocrine disruption [3, 4]
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