Bisphenol A Analogs Induce Cellular Dysfunction in Human Trophoblast Cells in a Thyroid Hormone Receptor-Dependent Manner: In Silico and In Vitro Analyses

Abstract

Bisphenol A (BPA) and its analogs are frequently detected in human daily necessities and environmental media. Placental thyroid hormone plays an important role in fetal development. Herein, we followed the adverse outcome pathway (AOP) to explore the toxic mechanisms of BPA and its analogs toward placental thyroid hormone receptor (TR). First, the TOX21 database was used, and the interactions between BPA analogs and the ligand-binding domains (LBDs) of two subtypes of TR (TRα and TRβ) were subjected to in silico screening using molecular docking (MD) and molecular dynamics simulation (MDS). Fluorescence spectra and circular dichroism (CD) showed that BPA and its analogs interfere with TRs as a molecular initiation event (MIE), including static fluorescence quenching and secondary structural content changes in TR-LBDs. Key events (KEs) of the AOP, including the toxicity induced in placental chorionic trophoblast cells (HTR-8/SVneo) by an inverted U-shaped dose effect and changes in ROS levels, were tested in vitro. BPA, BPB, and BPAF significantly changed the expression level of TRβ, and only BPAF significantly downregulated the expression level of TRα. In conclusion, our study contributes to the health risk assessment of BPA and its analogs regarding placental adverse outcomes (AOs).

Amino Acid Transporter as a Potential Carrier Protein for the Root-to-Shoot Translocation of Polybrominated Diphenyl Ethers in Rice

“…The binding of PBDEs to LHT might induce the conformational change of LHT and thereby affect its transcriptional and translational activity. 43 rescence, 31,32 the intensity of which is affected by the change of protein conformations. In this study, the fluorescence intensity of free LHT peaked at 324.8 and 328.2 nm at 298 and 310 K, respectively (Figures S8 and S9).…”

“…55 Specifically, the calculated K q values had an order of magnitude of 10 13 , 3 orders of the magnitude higher than the maximum scatter collision quenching constant (2.0 × 10 10 L/mol•s) for a biomacromolecule dissolved in water. 31 This excluded the possibility of dynamic quenching. Furthermore, the quenching constants of PBDEs decreased with increasing temperature, indicating that the stability of PBDE-LHT conjugates weakened at higher interaction temperatures.…”

“…Characterizing the interaction affinity between pollutants and the target macromolecules is the key to deciphering the molecular mechanisms through which pollutants interfere with target proteins and cause adverse outcomes. Conventional chemical approaches, such as fluorescence spectra, circular dichroism (CD), and sorption equilibrium studies, can uncover the quenching mechanisms, changes in secondary structures, and ligand–receptor maximal binding capacity. − Functional genomic approaches, such as CRISPR/Cas9 gene editing, can reveal the direct links between the genes of interest and the corresponding loss of function ( e.g. , increased resistance or susceptibility to the chemical exposure). − The combined use of chemical and gene editing techniques offers a comprehensive approach to examining PBDE translocation in plants, shedding light on both biological and chemical mechanisms underlying this behavior.…”

Machine Learning Model for Screening Thyroid Stimulating Hormone Receptor Agonists Based on Updated Datasets and Improved Applicability Domain Metrics

“…As shown in Figure and Figure S18, organic phosphoric acids and derivatives and phenolics were identified as main classes of TSHR agonists in the different chemical inventories. These compounds were also reported as thyroid disruptors in previous studies. , Totally, the classifier identified 90 TSHR agonist classes, which could not be found from previous reports to the best of the authors’ knowledge. The chemical categories were assigned by ClassyFire, and the category comparison was based on the categories covered by the updated TSHR agonist dataset in the current study.…”

Thyroid Carcinoma: A Review for 25 Years of Environmental Risk Factors Studies

“…BPA blocks the activity of human recombinant thyroid peroxidase (TPO) [ 68 ]. At the receptor level, BPA binds to the thyroid hormone receptor (TR) as a weak ligand and functions as an antagonist to T3, thereby preventing TR-mediated transcriptional activity [ 29 , 69 ]. In a recent study, Marotta et al 2022 found that overweight/obese individuals subjects exposed to BPA showed high serum level of TSH [ 70 ].…”