In silico investigation of chemical-induced thyroid toxicity in aquatic species
The thyroid hormone system is an important and complex endocrine system. The thyroid system regulates several important physiological processes such as energy metabolism, brain growth and development, and reproduction. The system is conservative across species. Homeostasis of the system could be disrupted by certain industrial chemicals - thyroid disruption chemicals (TDCs). TDCs have been widely identified in aquatic environments and household dust. Exposures to TDCs pose potential threats to human health and ecological system. Considering the relatively high cost of wet lab experiment, it is thus critical to develop computational models for in silico identification of TDCs from industrial chemicals and environmental pollutants. In our previous studies (SNIC 2014/2-30 & SNIC 2015/7-51), 13 novel TDCs have been identified using virtual screening and their thyroid disruption activities have been confirmed using in vitro experiments. We also performed the MD simulations to explain the molecular recognition between TDCs identified and the biological targets (e.g. thryoid hormone transporter--transthyretin (TTR) and thyroid hormone receptor (THR)) and calculate the ligand binding free energy. Our studies results have been published in ACS Environmental Science & Technology and ACS Chemical Research in Toxicology. In this project, we are aimed to (1) investigate the chemical-induced thyroid disruptions in aquatic species, especially sea bream; (2) further improve the performance of the computational models by employing state-of-art techniques in molecular modeling. Sea bream are found in oceans all over the world and in all types of water temperatures. Due to their wide distribution, they are very popular fish species for eating, especially in Europe. Several classical TDCs, such as bisphenol A and OH-PCBs have been detected in sea bream at a relative high level. These TDCs could cause the developmental disorders in the fish. More importantly, the TDCs will be accumulated in the fish tissue and consumed by human. The thyroid disruption effects in fish can be used an indicator to extrapolate the adverse effects in human. The virtual screening performance of computational models can be improved using two strategies. Firstly, usage of physical based re-scoring functions, e.g. LIE and MM-GBSA. Secondly, QM calculations for truncated molecular system of interest, e.g. the ligand binding pocket. The result of this study can be used to suggest potential TDCs for further toxicological investigations. It also gives a better understanding on the molecular mechanism-of-action of chemical-induced thyroid disruption. The diverse compounds identified help us to summarize structure-activity relationships of TDCs.