Toxicol In Vitro 2021 Apr 01;72:105016. doi: 10.1016/j.tiv.2020.105016.

Evaluation of a multiplexed, multispecies nuclear receptor assay for chemical hazard assessment.

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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.

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Species referenced: Xenopus laevis
Genes referenced: ar esr1 esr2 thra