In silico investigation of interspecies variation in pollutant-transthyretin interaction and TTR-mediated thyroid disruption in humans and amphibians

SNIC 2019/3-257


SNIC Medium Compute

Principal Investigator:

Patrik Andersson


Umeå universitet

Start Date:


End Date:


Primary Classification:

30303: Occupational Health and Environmental Health

Secondary Classification:

30102: Pharmacology and Toxicology




Thyroid disrupting chemicals (TDCs) are a variety of xenobiotic agents that can potentially interferes with synthesis, secretion, transport, metabolism, binding, or elimination of natural thyroid hormones (THs). Exposures to TDCs could induce severe disorders in vital physiological processes in humans and wildlife, including homeostasis, macronutrient metabolism, energy balance, brain development, and reproduction. Transthyretin (TTR), a serum TH transporter, and thyroid receptor (TR) have been reported as molecular targets of TDCs, including per and polyfluoroalkyl substances (PFASs) and hydroxylated polychlorinated biphenyls (OH-PCBs). Despite decades of efforts, design of new compound candidates as replacements for the TDCs remains a challenging scientific topic. In this study, we aim at 1) measuring the binding affinities of environmental pollutants to frog TTR, 2) crystalizing the frog TTR structures in complex with the environmental pollutants, 3) comparing/characterizing the pollutant-TTR interactions using cheminformatic tools and molecular dynamic simulations. The compounds for investigation will be selected based on the experimental TTR and TR activities data from our previous studies (Environ. Sci. Technol. 49, 16, 10099-10107; Chem. Res. Toxicol. 29, 8, 1345-1354; Environ. Sci. Technol. 50, 21, 11984-11993, Environ. Sci. Technol., 2018, 52 (20), 11865–11874) and US NIH Tox21 HTS TR assays results. The outcomes of this study will provide us 1) better understanding of the interspecies variations and differences in TTR crystal structures and pollutants-TTR interactions; 2) a linkage between pollutant-TTR interactions and their in vivo thyroid toxic adverse effects; 3) an in-silico protocol to identify environmental pollutants that potentially disrupt the thyroid system in amphibian species.