Sensitivity to potential endocrine disrupting chemicals in the environment varies across species and is influenced by sequence conservation of their nuclear receptor targets. Here, we evaluated a multiplexed, in vitro assay testing receptors relevant to endocrine and metabolic disruption from five species. The TRANS-FACTORIAL™ system of human nuclear receptors was modified to include additional species: mouse (Mus musculus), frog (Xenopus laevis), zebrafish (Danio rerio), chicken (Gallus gallus), and turtle (Chrysemys picta). Receptors regulating endocrine function and xenobiotic recognition were included, specifically: ERα, ERβ, AR, TRα, TRβ, PPARγ and PXR. The assay, ECOTOX-FACTORIAL™, was evaluated with 191 chemicals enriched with known receptor ligands. Hierarchical clustering of potency values demonstrated strong coherence of receptor families. Interspecies comparisons of responses within a receptor family showed moderate to high concordance for potencies under 50 μM. PPARγ showed high concordance between mammalian species, 89%, but only 63% between mammalian and zebrafish. For chemicals with potencies below 1 μM, concordances were 89–100% for all receptors except PXR. Concordance showed a strong positive relationship to ligand-binding domain sequence similarity and critical amino acid residues obtained by the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool. In combination with SeqAPASS, ECOTOX-FACTORIAL may provide efficient screening of important receptors to identify species of high priority for effects monitoring.

对环境中潜在的内分泌干扰化学物质的敏感性因物种而异，并受到其核受体靶标序列保守性的影响。在这里，我们评估了多重体外测定，测试与五个物种的内分泌和代谢破坏相关的受体。人类核受体的 TRANS-FACTORIAL™ 系统经过修改，包括其他物种：小鼠 ( Mus musculus )、青蛙 ( Xenopus laevis )、斑马鱼 ( Danio rerio )、鸡 ( Gallus gallus ) 和乌龟 ( Chrysemys picta )。包括调节内分泌功能和外源物质识别的受体，具体为：ERα、ERβ、AR、TRα、TRβ、PPARγ 和 PXR。该检测方法 ECOTOX-FACTORIAL™ 使用富含已知受体配体的 191 种化学物质进行了评估。效力值的层次聚类证明了受体家族的很强的一致性。受体家族内反应的种间比较显示，50 μM 以下的效力具有中等到高度的一致性。 PPARγ在哺乳动物物种之间表现出很高的一致性，为89%，但在哺乳动物和斑马鱼之间只有63%。对于效力低于 1 μM 的化学物质，除 PXR 之外的所有受体的一致性为 89-100%。一致性显示与配体结合域序列相似性和通过序列比对预测跨物种敏感性 (SeqAPASS) 工具获得的关键氨基酸残基存在很强的正相关关系。与 SeqAPASS 结合，ECOTOX-FACTORIAL 可以有效筛选重要受体，以识别影响监测的高优先级物种。