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

  • Organ Toxicity and Mechanisms
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Abstract

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.

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Acknowledgements

The work was supported by the National Natural Science Foundation of China (No. 21377142, 21577163, 21477146, 21621064, 91543203) and Chinese Academy of Sciences (XDB14040100, QYZDJ-SSW-DQC020).

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Author notes

  1. Yu-Xin Gu and Xiao-Xing Liang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China

    Yu-Xin Gu, Xiao-Xing Liang, Nuo-Ya Yin, Yu Yang, Bin Wan, Liang-Hong Guo & Francesco Faiola

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yu-Xin Gu, Xiao-Xing Liang, Nuo-Ya Yin, Bin Wan, Liang-Hong Guo & Francesco Faiola

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  1. Yu-Xin Gu
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Gu, YX., Liang, XX., Yin, NY. et al. New insights into mechanism of bisphenol analogue neurotoxicity: implications of inhibition of O-GlcNAcase activity in PC12 cells. Arch Toxicol 93, 2661–2671 (2019). https://doi.org/10.1007/s00204-019-02525-3

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