TY - JOUR
T1 - A Murine Oral-Exposure Model for Nano- and Micro-Particulates
T2 - Demonstrating Human Relevance with Food-Grade Titanium Dioxide
AU - Riedle, Sebastian
AU - Wills, John W.
AU - Miniter, Michelle
AU - Otter, Don E.
AU - Singh, Harjinder
AU - Brown, Andy P.
AU - Micklethwaite, Stuart
AU - Rees, Paul
AU - Jugdaohsingh, Ravin
AU - Roy, Nicole C.
AU - Hewitt, Rachel E.
AU - Powell, Jonathan J.
N1 - Funding Information:
S.R. and J.W.W. contributed equally to this work as first authors, N.C.R., R.E.H. and J.J.P. equally contributed as senior authors. The authors would like to thank Doug Hopcroft and Dr. Jianyu Chen (both Manawatu Microscopy and Imaging Centre, Massey University, Palmerston North) for help with electron microscopy of titanium containing diets; Ric Broadhurst and Genevieve Baildon (Campus Services, AgResearch, Hamilton) for providing the mice; Leigh Ryan and Jason Peters (both Food Nutrition & Health Team, AgResearch, Palmerston North) for help with animal study and tissue sampling; and Dr. John Koolaard and Catherine Lloyd-West (Campus Services, AgResearch, Palmerston North) for help with statistical analyses. The research was mainly supported by the Riddet Institute through its Centre of Research Excellence funding which has been awarded to the Riddet Institute by the New Zealand government. Additional funding was provided by AgResearch, MRC Elsie Widdowson Laboratory (formerly MRC Human Nutrition Research, Grant No. U105960399) and Nutrigenomics New Zealand, a collaboration between AgResearch, Plant and Food Research, and The University of Auckland (primarily supported by funding from the Ministry for Science and Innovation contract C11 ? 1009). S.R. was supported by doctoral scholarships from Massey University and AgResearch. All of the work in this study that was carried out at the University of Cambridge was supported by the UK Medical Research Council (R.J., R.E.H., and J.J.P.; Grant No. MR/R005699/1). J.W. would like to acknowledge Girton College and the University of Cambridge Herchel-Smith fund for providing him with Fellowships.
Funding Information:
S.R. and J.W.W. contributed equally to this work as first authors, N.C.R., R.E.H. and J.J.P. equally contributed as senior authors. The authors would like to thank Doug Hopcroft and Dr. Jianyu Chen (both Manawatu Microscopy and Imaging Centre, Massey University, Palmerston North) for help with electron microscopy of titanium containing diets; Ric Broadhurst and Genevieve Baildon (Campus Services, AgResearch, Hamilton) for providing the mice; Leigh Ryan and Jason Peters (both Food Nutrition & Health Team, AgResearch, Palmerston North) for help with animal study and tissue sampling; and Dr. John Koolaard and Catherine Lloyd‐West (Campus Services, AgResearch, Palmerston North) for help with statistical analyses. The research was mainly supported by the Riddet Institute through its Centre of Research Excellence funding which has been awarded to the Riddet Institute by the New Zealand government. Additional funding was provided by AgResearch, MRC Elsie Widdowson Laboratory (formerly MRC Human Nutrition Research, Grant No. U105960399) and Nutrigenomics New Zealand, a collaboration between AgResearch, Plant and Food Research, and The University of Auckland (primarily supported by funding from the Ministry for Science and Innovation contract C11 × 1009). S.R. was supported by doctoral scholarships from Massey University and AgResearch. All of the work in this study that was carried out at the University of Cambridge was supported by the UK Medical Research Council (R.J., R.E.H., and J.J.P.; Grant No. MR/R005699/1). J.W. would like to acknowledge Girton College and the University of Cambridge Herchel‐Smith fund for providing him with Fellowships.
Publisher Copyright:
© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Human exposure to persistent, nonbiological nanoparticles and microparticles via the oral route is continuous and large scale (1012–1013 particles per day per adult in Europe). Whether this matters or not is unknown but confirmed health risks with airborne particle exposure warns against complacency. Murine models of oral exposure will help to identify risk but, to date, lack validation or relevance to humans. This work addresses that gap. It reports i) on a murine diet, modified with differing concentrations of the common dietary particle, food grade titanium dioxide (fgTiO2), an additive of polydisperse form that contains micro- and nano-particles, ii) that these diets deliver particles to basal cells of intestinal lymphoid follicles, exactly as is reported as a “normal occurrence” in humans, iii) that confocal reflectance microscopy is the method of analytical choice to determine this, and iv) that food intake, weight gain, and Peyer's patch immune cell profiles, up to 18 weeks of feeding, do not differ between fgTiO2-fed groups or controls. These findings afford a human-relevant and validated oral dosing protocol for fgTiO2 risk assessment as well as provide a generalized platform for application to oral exposure studies with nano- and micro-particles.
AB - Human exposure to persistent, nonbiological nanoparticles and microparticles via the oral route is continuous and large scale (1012–1013 particles per day per adult in Europe). Whether this matters or not is unknown but confirmed health risks with airborne particle exposure warns against complacency. Murine models of oral exposure will help to identify risk but, to date, lack validation or relevance to humans. This work addresses that gap. It reports i) on a murine diet, modified with differing concentrations of the common dietary particle, food grade titanium dioxide (fgTiO2), an additive of polydisperse form that contains micro- and nano-particles, ii) that these diets deliver particles to basal cells of intestinal lymphoid follicles, exactly as is reported as a “normal occurrence” in humans, iii) that confocal reflectance microscopy is the method of analytical choice to determine this, and iv) that food intake, weight gain, and Peyer's patch immune cell profiles, up to 18 weeks of feeding, do not differ between fgTiO2-fed groups or controls. These findings afford a human-relevant and validated oral dosing protocol for fgTiO2 risk assessment as well as provide a generalized platform for application to oral exposure studies with nano- and micro-particles.
KW - Peyer's patches
KW - diet
KW - nanoparticles
KW - titanium dioxide
KW - validated exposure
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U2 - 10.1002/smll.202000486
DO - 10.1002/smll.202000486
M3 - Article
C2 - 32363770
AN - SCOPUS:85084205650
VL - 16
JO - Small
JF - Small
SN - 1613-6810
IS - 21
M1 - 2000486
ER -