CIMAR/CIIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Avenida General Norton de Matos s/n, 4450-208, Matosinhos, Portugal; FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal; ICBAS - Institute of biomedical Sciences Abel Salazar, University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313, Porto, Portugal.
CIMAR/CIIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Avenida General Norton de Matos s/n, 4450-208, Matosinhos, Portugal.
Aquat Toxicol. 2019 Mar;208:80-89. doi: 10.1016/j.aquatox.2019.01.002. Epub 2019 Jan 7.
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.
视黄酸受体 (RAR) 依赖性信号通路对于调节和维持基本的生物学功能至关重要，并且是人为干扰化合物的公认靶标。最近的研究提出，软体动物 RAR 不能结合并响应经典的脊椎动物配体视黄酸：这一特征似乎在进化过程中丢失了。然而，这些研究仅在少数几种软体动物中进行。因此，本研究使用体外转录激活测定法，旨在表征与进化相关的软体动物 RAR，无论是单体形式还是与 RXR 形成功能单位，不仅存在脊椎动物骨钙配体，还存在已知的内分泌干扰物，这些物质被描述为调节视黄酸依赖性途径。一般来说，当暴露于视黄酸异构体时，测试的软体动物 RAR 都不能激活报告基因转录，这表明响应视黄酸的能力在软体动物中已经丢失。同样，分析的软体动物 RAR 对有机氯农药没有反应。相比之下，在暴露于视黄醇或 RXR 特异性配体时，RAR/RXR 单位会发生转录抑制。功能丧失和功能获得突变进一步证实了这些结果，并表明与软体动物和人类 RAR/RXR 异二聚体观察到的抑制行为可能是通过配体与 RXR 的结合介导的。
