New insights into mechanism of bisphenol analogue neurotoxicity: implications of inhibition of O-GlcNAcase activity in PC12 cells.

Bisphenol analogues including bisphenol A and its derivatives are ubiquitous environmental contaminants and have been linked to adverse neurodevelopment effects on animals and humans. Most toxicological research focused on estrogen receptor mediated pathways and did not comprehensively clarify the observed toxicity. O-GlcNAcase (OGA), the highest level in brain, plays a critical role in controlling neuronal functions at multi-levels from molecule to animal behaviors. In this work, we intend to investigate the underlying molecular mechanisms for the neurotoxicity of bisphenol analogues by identifying their cellular targets and the resultant effects. The inhibitory actions of seven bisphenol analogues on the OGA activity at molecular level were investigated by our developed electrochemical biosensor. We found that their potency varied with substituent groups, in which tetrabromo bisphenol A (TBBPA) was the strongest. The seven bisphenol analogues (0-100 µM exposure) significantly inhibited OGA activity and up-regulated protein O-GlcNAcylation level in PC12 cells. Inhibition of OGA by bisphenol analogues further induced intracellular calcium, ROS, inflammation, repressed proliferation, interfered with cell cycle, induced apoptosis. And especially, 10 µM tetrabromo bisphenol A (TBBPA) exposure could impair the growth and development of neurite in human neural stem cells (hNSCs). Molecular docking for OGA/bisphenol analogue complexes revealed the hydrophobicity-dominated inhibition potency. OGA, as a new cellular target of bisphenol analogues, would illuminate the molecular mechanism of bisphenol analogues neurotoxicity.

Bisphenol F Disrupts Thyroid Hormone Signaling and Postembryonic Development in Xenopus laevis.

The safety of bisphenol A (BPA) alternatives has attracted much attention due to their wide use. In this study, we investigated the effects of bisphenol F (BPF), an alternative to BPA, on thyroid hormone (TH) signaling and postembryonic development in vertebrates using T3-induced and spontaneous Xenopus metamorphosis as models. We found that in the T3-induced metamorphosis assay, higher concentrations of BPF (100-10000 nM) antagonized T3-induced TH-response gene transcription and morphological changes including intestinal remodeling in a concentration-dependent manner, whereas 10 nM BPF exerted stimulatory effects on T3-induced integral metamorphosis when inhibited T3-induced TH-response gene transcription, demonstrating TH signaling disrupting effects of BPF. In the spontaneous metamorphosis assay, correspondingly, BPF inhibited development at metamorphic climax (with high endogenous TH levels), but promoted pre- and pro-metamorphic development (with low endogenous TH levels), displaying a developmental stage-dependent manner. Importantly, we observed agonistic actions of BPF on Notch signaling in intestines, showing that BPF disrupts vertebrate development possibly via multi pathways besides TH signaling. Thus, we infer the biphasic concentration-response relationship between BPF exposure and T3-induced metamorphosis could result from the interactions of TH signaling with other signaling pathways such as Notch signaling. Our study highlights the adverse influences of BPF on vertebrate development.

Characterization of Three Tetrabromobisphenol-S Derivatives in Mollusks from Chinese Bohai Sea: A Strategy for Novel Brominated Contaminants Identification.

Identification of novel brominated contaminants in the environment, especially the derivatives and byproducts of brominated flame retardants (BFRs), has become a wide concern because of their adverse effects on human health. Herein, we qualitatively and quantitatively identified three byproducts of tetrabromobisphenol-S bis(2,3-dibromopropyl ether) (TBBPS-BDBPE), including TBBPS mono(allyl ether) (TBBPS-MAE), TBBPS mono(2-bromoallyl ether) (TBBPS-MBAE) and TBBPS mono(2,3-dibromopropyl ether) (TBBPS-MDBPE) as novel brominated contaminants. Meanwhile, the mass spectra and analytical method for determination of TBBPS-BDBPE byproducts were presented for the first time. The detectable concentrations (dry weight) of TBBPS-MAE, TBBPS-MBAE and TBBPS-MDBPE were in the ranges 28-394 µg/g in technical TBBPS-BDBPE and 0.1-4.1 ng/g in mollusks collected from the Chinese Bohai Sea. The detection frequencies in mollusk samples were 5%, 39%, 95% for TBBPS-MAE, TBBPS-MBAE and TBBPS-MDBPE, respectively, indicating their prevailing in the environment. The results showed that they could be co-produced and leaked into the environment with production process, and might be more bioaccumulative and toxic than TBBPS-BDBPE. Therefore, the production and use of TBBPS derivatives lead to unexpected contamination to the surrounding environment. This study also provided an effective approach for identification of novel contaminants in the environment with synthesized standards and Orbitrap high resolution mass spectrometry.