Size dependent translocation and fetal accumulation of gold nanoparticles from maternal blood in the rat.
BACKGROUND
There is evidence that nanoparticles (NP) cross epithelial and endothelial body barriers. We hypothesized that gold (Au) NP, once in the blood circulation of pregnant rats, will cross the placental barrier during pregnancy size-dependently and accumulate in the fetal organism by 1. transcellular transport across the hemochorial placenta, 2. transcellular transport across amniotic membranes 3. transport through ~20 nm wide transtrophoblastic channels in a size dependent manner. The three AuNP sizes used to test this hypothesis are either well below, or of similar size or well above the diameters of the transtrophoblastic channels.


METHODS
We intravenously injected monodisperse, negatively charged, radio-labelled 1.4 nm, 18 nm and 80 nm ¹⁹⁸AuNP at a mass dose of 5, 3 and 27 μg/rat, respectively, into pregnant rats on day 18 of gestation and in non-pregnant control rats and studied the biodistribution in a quantitative manner based on the radio-analysis of the stably labelled ¹⁹⁸AuNP after 24 hours.


RESULTS
We observed significant biokinetic differences between pregnant and non-pregnant rats. AuNP fractions in the uterus of pregnant rats were at least one order of magnitude higher for each particle size roughly proportional to the enlarged size and weight of the pregnant uterus. All three sizes of ¹⁹⁸AuNP were found in the placentas and amniotic fluids with 1.4 nm AuNP fractions being two orders of magnitude higher than those of the larger AuNP on a mass base. In the fetuses, only fractions of 0.0006 (30 ng) and 0.00004 (0.1 ng) of 1.4 nm and 18 nm AuNP, respectively, were detected, but no 80 nm AuNP (<0.000004 (<0.1 ng)). These data show that no AuNP entered the fetuses from amniotic fluids within 24 hours but indicate that AuNP translocation occurs across the placental tissues either through transtrophoblastic channels and/or via transcellular processes.


CONCLUSIONS
Our data suggest that the translocation of AuNP from maternal blood into the fetus is NP-size dependent which is due to mechanisms involving (1) transport through transtrophoblastic channels - also present in the human placenta - and/or (2) endocytotic and diffusive processes across the placental barrier.
Institute of Lung Biology and Disease, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg/Munich, Germany. Manuela.Behnke@lgl.bayern.de.|Current address: Bavarian Health and Food Safety Authority, 85764, Oberschleissheim, Germany. Manuela.Behnke@lgl.bayern.de.
Manuela
M
Semmler-Behnke
Institute of Lung Biology and Disease, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg/Munich, Germany. j_lipka@gmx.de.
Jens
J
Lipka
Institute of Lung Biology and Disease, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg/Munich, Germany. alexander.wenk@helmholtz-muenchen.de.
Alexander
A
Wenk
Institute of Lung Biology and Disease, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg/Munich, Germany. stephanie.hirn@med.uni-muenchen.de.|Current address: Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany. stephanie.hirn@med.uni-muenchen.de.
Stephanie
S
Hirn
Institute of Lung Biology and Disease, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg/Munich, Germany. martin.schaeffler@helmholtz-muenchen.de.
Martin
M
Schäffler
Institute of Lung Biology and Disease, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg/Munich, Germany. furong.tian@googlemail.com.|Current address: Focus Research Institute, Dublin Institute of Technology, Dublin, Ireland. furong.tian@googlemail.com.
Furong
F
Tian
Institute of Inorganic Chemistry University Duisburg-Essen, 45117, Essen, Germany. guenter.schmid@uni-due.de.
Günter
G
Schmid
Department of Environmental Medicine, University of Rochester, Rochester, New York, USA. Gunter_Oberdorster@urmc.rochester.edu.
Günter
G
Oberdörster
Institute of Lung Biology and Disease, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg/Munich, Germany. kreyling@helmholtz-muenchen.de.|Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg/Munich, Germany. kreyling@helmholtz-muenchen.de.
Wolfgang G
WG
Kreyling
D000653:Amniotic Fluid / Q000737:chemistry; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005321:Extraembryonic Membranes / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000737:chemistry* / Q000378:metabolism; D006046:Gold / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D006050:Gold Radioisotopes; D007275:Injections, Intravenous; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D008954:Models, Biological; D010316:Particle Size; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011897:Random Allocation; D011921:Rats, Inbred WKY; D014018:Tissue Distribution; D066007:Toxicokinetics; D014599:Uterus / Q000737:chemistry / Q000378:metabolism
D006050:Gold Radioisotopes; D006046:Gold