Bisphenol Analogues Differentially Affect Human Islet Polypeptide Amyloid Formation

Bisphenols(BPs) are a group of chemicals with two hydroxyphenyl functionalities, BPs analogues like bisphenol A(BPA), bisphenol B(BPB), bisphenol F(BPF), bisphenol S(BPS), bisphenol AF(BPAF), bisphenol AP(BPAP), tetrabromobisphenol A(TBBPA) and tetrachlorobisphenol A(TCBPA) are widely used in the production of varnishes, plastic containers, medical materials, etc. There has been a growing concern worldwide about the environmental BPs exposure due to their potential adverse effects on human health. Epidemiological studies suggest BPA exposure is positively associated with the incidence of type 2 diabetes mellitus(T2DM), we previously reported that BPA exposure associated T2 DM risk increase may involve exacerbated toxic aggregation of hIAPP by BPA. Here, we investigated the effects of BPs analogues on hIAPP aggregation using thioflavin-T based fluorescence, transmission electronic microscopy, circular dichroism spectroscopy, dynamic light scattering, dot-blot and fluorescence-dye leakage assay. We demonstrated that bisphenol analogues show different effects on h IAPP amyloid formation. Unlike the accelerating effects of BPA, four BPs analogues(BPAF, BPAP, TBBPA and TCBPA, three of which have halogenated substitutions) showed inhibitory effects on h IAPP aggregation and decreased the membrane disruption capacity of hIAPP. Our results explain the possible relationship between the spatial structure and the inhibitory capacities of BPs analogues, and suggest halogenation of aromatic rings substantially enhance inhibitory capacities of small molecules on hIAPP-associated membrane disruption via modulating hIAPP aggregation.