Abstract
Local accumulation of xenobiotics in human and animal tissues may cause adverse effects. Large differences in their concentrations may exist between individual cell types, often due to the expression of specific uptake and export carriers. Here we established a two-photon microscopy-based technique for spatio-temporal detection of the distribution of mycotoxins in intact kidneys and livers of anesthetized mice with subcellular resolution. The mycotoxins ochratoxin A (OTA, 10 mg/kg b.w.) and aflatoxin B1 (AFB1, 1.5 mg/kg b.w.), which both show blue auto-fluorescence, were analyzed after intravenous bolus injections. Within seconds after administration, OTA was filtered by glomeruli, and enriched in distal tubular epithelial cells (dTEC). A striking feature of AFB1 toxicokinetics was its very rapid uptake from sinusoidal blood into hepatocytes (t1/2 ~ 4 min) and excretion into bile canaliculi. Interestingly, AFB1 was enriched in the nuclei of hepatocytes with zonal differences in clearance. In the cytoplasm of pericentral hepatocytes, the half-life (t1/2~ 63 min) was much longer compared to periportal hepatocytes of the same lobules (t1/2 ~ 9 min). In addition, nuclear AFB1 from periportal hepatocytes cleared faster compared to the pericentral region. These local differences in AFB1 clearance may be due to the pericentral expression of cytochrome P450 enzymes that activate AFB1 to protein- and DNA-binding metabolites. In conclusion, the present study shows that large spatio-temporal concentration differences exist within the same tissues and its analysis may provide valuable additional information to conventional toxicokinetic studies.
Highlights
Concentrations of toxic substances may vary considerably within a tissue
We evaluated the possibilities and limitations of two-photon-based intravital imaging to study the spatio-temporal kinetics of two mycotoxins in intact livers and kidneys of mice
Intravital two-photon imaging was performed to study the spatio-temporal kinetics of ochratoxin A (OTA) in the kidney tissue of mice
Summary
Concentrations of toxic substances may vary considerably within a tissue. These spatial differences can be caused by active transport mechanisms or physicochemical properties. Tissues usually consist of different cell types with distinct abilities to enrich specific substances. Particles of > 100 nm or LPS are preferentially taken up by tissue macrophages of the liver and much less by hepatocytes (Koppert et al 2018; Reif et al 2017). Differences may exist between individual cells of the same type, such as hepatocytes in the central and periportal regions of liver lobules. High local concentrations of substances may be generated by active transport processes into space-restricted tissue compartments, for example when hepatocytes secrete bile acids or xenobiotics into narrow bile canaliculi (Ghallab et al 2019a). Increased concentrations may lead to toxicity, additional parameters, such as the celltype-specific toxifying or detoxifying metabolic capacity, play a critical role (Albrecht et al 2019; Leist et al 2017)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.