Thyroid-Disrupting Effects of 6:2 and 8:2 Polyfluoroalkyl Phosphate Diester (diPAPs) at Environmentally Relevant Concentrations from Integrated In Silico and In Vivo Studies

摘要

Polyfluoroalkyl phosphate esters (PAPs), a kind of poly/perfluoroalkyl substance, are used in food contact materials. Herein, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed and applied to predict the binding affinity of 6:2 and 8:2 polyfluoroalkyl phosphate diesters (diPAPs) with transthyretin (ttr) to potentially displace thyroid hormones. The predicted activity of 6:2 diPAP was higher than that of 8:2 diPAP, and both were comparable to that of perfluorobutanesulfonate, suggesting their potential endocrine disrupting effects. For verification, zebrafish embryos were incubated with 6:2 and 8:2 diPAPs at 0.5-50 ng/L for 7 days. Both diPAPs reduced total and free thyroxine (T4) and triiodothyronine (T3) levels but elevated deiodinases levels, suggesting inhibited synthesis and increased metabolism of thyroid hormones. Consistent with the results of 3D-QSAR, the efficacy of 6:2 diPAP was generally higher than that of 8:2 diPAP, which might be due to the higher binding affinities of 6:2 diPAP for thyroid hormone receptor (TR) beta and TTR, predicted by molecular docking. For both diPAPs, the decreased thyroid hormones weakened the activation of TR alpha, thus significantly reducing the TR alpha level in the intestine. The integrated results provide strong evidence of thyroid toxicities of 6:2 and 8:2 diPAPs.