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The retinoic acid receptor (RAR) in molluscs: Function, evolution and endocrine disruption insights

André, Ana, Ruivo, Raquel, Fonseca, Elza, Froufe, Elsa, Castro, L. Filipe C., Santos, Miguel M.
Aquatic toxicology 2019 v.208 pp. 80-89
endocrine-disrupting chemicals, gain-of-function mutation, humans, isomers, ligands, loss-of-function mutation, molluscs, pesticides, phylogeny, reporter genes, retinoic acid, retinoic acid receptors, signal transduction, transcription (genetics), transcriptional activation
Retinoid acid receptor (RAR)-dependent signalling pathways are essential for the regulation and maintenance of essential biological functions and are recognized targets of disruptive anthropogenic compounds. Recent studies put forward the inability of mollusc RARs to bind and respond to the canonical vertebrate ligand, retinoic acid: a feature that seems to have been lost during evolution. Yet, these studies were carried out in a limited number of molluscs. Therefore, using an in vitro transactivation assay, the present work aimed to characterize phylogenetically relevant mollusc RARs, as monomers or as functional units with RXR, not only in the presence of vertebrate bone fine ligands but also known endocrine disruptors, described to modulate retinoid-dependent pathways. In general, none of the tested mollusc RARs were able to activate reporter gene transcription when exposed to retinoic acid isomers, suggesting that the ability to respond to retinoic acid was lost across molluscs. Similarly, the analysed mollusc RAR were unresponsive towards organochloride pesticides. In contrast, transcriptional repressions were observed with the RAR/RXR unit upon exposure to retinoids or RXR-specific ligands. Loss-of-function and gain-of-function mutations further corroborate the obtained results and suggest that the repressive behaviour, observed with mollusc and human RAR/RXR heterodimers, is possibly mediated by ligand biding to RXR.