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Published on: March 10, 2023
The lipid-mediated hypothesis of fumonisin B1 toxicodynamics tested in model membranes
Martín G Theumer1, Eduardo M Clop, Héctor R Rubinstein
1Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, Argentina.
Abstract:
The disruption of lipidic metabolism was considered a good candidate to explain FB1 toxicity mechanism. In the present work we investigated molecular organizational changes induced by FB1-biomembrane interaction possibly involved in mycotoxic effects. FB1 was self-aggregated with a critical micellar concentration of 1.97 mM. FB1 (0-81.4 microM), decreased in a dose-dependent manner, the fluorescence anisotropy of TMA-DPH (from 0.349+/-0.003 to 0.1720+/-0.0035) in dpPC bilayers, whilst no differences were registered with DPH. At 5.6 microM in the subphase, FB1 increased the lateral surface pressure (pi) of a Langmuir film to an extent that depended on the monolayer composition (Deltapi dpPC:DOTAP 3:1>Deltapi dpPC:dpPA3:1>Deltapi dpPC), the molecular packing (Deltapi decreased linearly as a function of the initial pi) and the subphase pH (Deltapi pH 2.6>Deltapi pH 7.4 and maximal pi allowing the drug penetration pi cut-off was 34.3 and 27.7 mN/m at pH 2.63 and 7.4, respectively). FB1 increased the surface potential of dpPC and dpPC:DOTAP monolayers and decreased that of dpPC:dpPA. This suggested that FB1 acquired different orientations and/or foldings depending on the surface electrostatics and the toxin charge state. Moreover, FB1-lipid interactions were transduced into long-range effects at the mesoscopic level affecting the lipidic self-separated lateral domains shape and density.
Insights
Fumonisin B1 (FB1) disrupts biomembrane organization by altering lipid packing and surface properties. These molecular changes in lipid metabolism are key to understanding FB1 mycotoxicity.
Area of Science:
- Biochemistry
- Biophysics
- Toxicology
Background:
- Fumonisin B1 (FB1) is a mycotoxin whose toxic mechanisms are not fully understood.
- Disruption of lipid metabolism is a potential pathway for FB1 toxicity.
- Investigating FB1's interaction with biomembranes can elucidate its toxic effects.
Purpose of the Study:
- To investigate the molecular organizational changes induced by FB1-biomembrane interactions.
- To understand the role of these changes in FB1-induced mycotoxic effects.
Main Methods:
- FB1 self-aggregation and critical micellar concentration determination.
- Fluorescence anisotropy measurements using TMA-DPH and DPH probes in lipid bilayers.
- Langmuir film analysis to assess changes in lateral surface pressure and surface potential.
- Monolayer composition, molecular packing, and pH-dependent effects were evaluated.
Main Results:
- FB1 self-aggregates with a critical micellar concentration of 1.97 mM.
- FB1 dose-dependently decreased fluorescence anisotropy in dpPC bilayers, indicating altered lipid dynamics.
- FB1 increased lateral surface pressure and altered surface potential of lipid monolayers, with effects dependent on monolayer composition, packing, and pH.
- FB1-lipid interactions induced long-range effects on lipid domain organization.
Conclusions:
- FB1 interacts with biomembranes, inducing significant molecular organizational changes.
- These changes in lipid metabolism and membrane structure are likely involved in FB1's mycotoxic mechanisms.
- FB1's interaction and orientation are influenced by membrane electrostatics and its own charge state.
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