a-high-throughput-screening-approach-for-evaluating-binding-affinity

A High-Throughput Screening Approach for Evaluating the Binding Affinity of Environmental Pollutants to Nuclear Receptors

Increasing levels of compounds have been detected in the environment, causing widespread pollution and posing risks to human health. However, despite ...

Qingdao University

Toxicity and risk priority ranking of chemicals are crucial to management and decision-making. In this work, we develop a new mechanistic ranking approach of toxicity and risk priority ranking for polybrominated diphenyl ethers (PBDEs) based on receptor-bound concentration (RBC). Based on the binding affinity constant predicted using molecular docking, internal concentration converted from human biomonitoring data via PBPK model, and the receptor concentration derived from the national center for biotechnology information (NCBI) database, the RBC of 49 PBDEs binding to 24 nuclear receptors were calculated. 1176 RBC results were successfully obtained and analyzed. High brominated PBDEs, including BDE-201, BDE-205, BDE-203, BDE-196, BDE-183, BDE-206, BDE-207, BDE-153, BDE-208, BDE-204, BDE-197, and BDE-209, exerted more potent than low brominated congeners (BDE-028, BDE-047, BDE-099, and BDE-100) at the same daily intake dose in terms of toxicity ranking. For risk ranking, with human biomonitoring serum data, the relative RBC of BDE-209 was significantly greater than that of any others. For receptor prioritization, constitutive androstane receptor (CAR), retinoid X receptor alpha (RXRA), and liver X receptor alpha (LXRA) may be the sensitive targets for PBDEs to trigger effects in the liver. In summary, high brominated PBDEs are more potent than low brominated congeners, thus, besides BDE-047 and BDE-099, BDE-209 should be priority controlled. In conclusion, this study provides a new approach for toxicity and risk ranking of groups of chemicals, which can readily be used for others.

Toxicity and risk priority ranking of polybrominated diphenyl ethers (PBDEs): A relative receptor-bound concentration approach.

Fine particulate matter (PM)-induced metabolic disorders have attracted increasing attention, however, the underlying molecular mechanism of PM2.5-induced hepatic bile acid disorder remains unclear. In this study, we investigated the effects of PM components on the disruption of bile acid in hepatocytes through farnesoid X receptor (FXR) pathway. The receptor binding assays showed that PM extracts bound to FXR directly, with half inhibitory concentration (IC) value of 21.7 μg/mL. PM extracts significantly promoted FXR-mediated transcriptional activity at 12.5 μg/mL. In mouse primary hepatocytes, we found PM extracts (100 μg/mL) significantly decreased the total bile acid levels, inhibited the expression of bile acid synthesis gene (Cholesterol 7 alpha-hydroxylase, Cyp7a1), and increased the expression of bile acid transport genes (Multidrug resistance associated protein 2, Abcc2; and Bile salt export pump, Abcb11). Moreover, these alterations were significantly attenuated by knocking down FXR in hepatocytes. We further divided the organic components and water-soluble components from PM, and found that two components bound to and activated FXR, and decreased the bile acid levels in hepatocytes. In addition, benzo[a]pyrene (B[a]P) and cadmium (Cd) were identified as two bioactive components in PM-induced bile acid disorders through FXR signaling pathway. Overall, we found PM components could bind to and activate FXR, thereby disrupting bile acid synthesis and transport in hepatocytes. These new findings also provide new insights into PM-induced toxicity through nuclear receptor pathways.

Lanchao Sun

School of Public Health

Qingdao University

A High-Throughput Screening Approach for Evaluating the Binding Affinity of Environmental Pollutants to Nuclear Receptors

Lanchao Sun

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Qingdao University

A High-Throughput Screening Approach for Evaluating the Binding Affinity of Environmental Pollutants to Nuclear Receptors

School of Public Health