Skip to main content

Table 3 Basic characteristics of the 50 animal studies investigating maternal-fetal transfer of ambient (ultra)fine particles and engineered NPs

From: Translocation of (ultra)fine particles and nanoparticles across the placenta; a systematic review on the evidence of in vitro, ex vivo, and in vivo studies

Ref Strain/ Species Sample size Exposure Detection technique Main findings
Particle type/Coating or label Size (nm) Administration route/ dose/ exposure period (Semi-) Quantitative Qualitative
Metallic NPs
 [44] CD-1 mice 18 Al2O3 NPs 20.9 ± 9.5 or 112.4 ± 24.5b nasal drip/ 0 or 50 mg/kg/ 14 days before mating-PND0g AAS / Higher Al levels in hippocampi of pups from mice exposed to Al2O3 NPs before and during pregnancy compared to control pups.
 [45] CD-1 mice 29 Ag NPs/ citrate 50b i.v./ 0, 1.2, or 2.2 mg/kg/ GD7–9d ICP-MS TEM and EDX Distribution of Ag NPs to most maternal organs and extra-embryonic tissues without significant fetal accumulation.
 [46] CD-1 mice 40 Ag NPs/ citrate 10a i.v./ 0 or 2.2 mg/kg/ GD7–9d ICP-MS Hyperspectral microscopy imaging No transfer of Ag NPs across the placenta in large amounts but accumulation in the visceral yolk sac and maternal tissue.
 [47] C57Bl/6 mice 12–15 Ag NPs 19.3 ± 2.3b nose-only inhalation/ 0 or 0.64 mg/m3 for 1 or 4 h/day/ GD0.5–14.5e spICP-MS and ICP-MS TEM/EDX Ag NPs identified and quantified in placenta, yet very low fetal levels.
 [48] Sprague Dawley rats 40 Ag NPs/ citrate 55b oral/ 0, 0.2, 2, or 20 mg/kg/ GD7–20d AAS / Higher Ag tissue contents in all treated groups compared to control dams and pups, indicating transplacental Ag NP transfer.
 [49] Wistar rats 12 Ag NPs/ chitosan 19.5 ± 6.72b i.p./ 0 or 100 mg/kg/ GD 6, 8, and 10d AAS TEM Coated and plain Ag NPs detected in significantly higher levels in maternal tissues, placenta, and fetuses compared to control rats. Chitosan coating decreased the silver content significantly.
 [50] Wistar Rats 60 Ag NPs/ citrate 20 ± 4a oral/ 0 or 25 mg/kg/ GD1–19d ICP-MS / Silver content in the rat offspring’s liver of exposed group differs significantly from control group, suggesting a transplacental transfer of Ag NPs.
 [51] Sprague Dawley rats 36 Ag NPs/ PVP 20 or 110a i.v./ 0 or 1 mg/kg/ GD18d and oral/ 0 or 10 mg/kg/ GD18d ICP-MS / Ag NPs measured in the rat placenta and fetuses for both NP sizes. Concentration of Ag NPs in the placenta higher than measured in blood or fetuses for both administration routes.
 [52] Sprague Dawley rats 8 Ag NPs/ citrate 7.9 ± 0.95b oral/ 0 or 250 mg/kg/ 14 days before mating-PND4d ICP-MS TEM Accumulation of Ag NPs observed in pups of exposed dams with decreasing concentrations from kidney, lung, liver to brain.
 [53] Wistar rats 7 Ag NPs/ PVP and [110mAg] 34.9 ± 14.8b oral/ 1.69 or 2.21 mg/kg/ GD20g Gamma spectroscopy / Ag NPs identified in fetuses of pregnant rats in amounts significantly exceeding the detection limit.
 [54] Wistar rats 30 Ag NPs 4.32 to 16.9b i.v./ 0 or 2 mg/kg/ GD19d ICP-OES TEM Time-dependent increase in fetal Ag NP levels, reaching a peak 6 h after injection and showing a decline afterward.
 [55] CD-1 mice 16 Au NPs 19.6 or 49.3a i.v./ 0 or 100 mg/kg/ GD16–17g ICP-MS AMG Higher amount of Au NPs in maternal livers and placentae from mice injected with 20 nm compared to 50 nm NPs without detectable levels in fetal organs for both sizes.
 [56] C57Bl/6 mice 13 Au NPs 2 or 40a i.v./ 0, 12.13, or 58.21 mg/mouse/ GD17g / AMG No accumulation of both Au NP sizes in fetuses nor placentae.
 [57] Wistar-Kyoto rats 12 Au NPs/S-TPP and [198Ag] 1.4, 18, or 80a i.v./ 0.005 or 0.025 mg/rat/ GD18g Gamma spectroscopy / All three Au NP sizes found in placenta of pregnant rats. Fractions of 1.4 and 18 nm Au NPs but not 80 nm Au NPs found in the fetuses.
 [58] C57Bl/6 mice 18 Au NPs/ PEG 3, 13, or 30a i.v./ 0.9 mg/kg/ GD17g ICP-MS TEM All three Au NP sizes reached the placenta of pregnant mice, but fetal Au NP concentrations were negligible.
 [59] Albino rats 15 Au NPs/ PEG 5.1 ± 0.6 or 32.0 ± 3.6b i.v./ 0 or 0.8 mg/kg/ GD10g AAS AMG Both Au NP sizes penetrate the rat placenta. Higher Au NP levels in maternal tissues (e.g., spleen) compared to fetal tissues.
 [60] CD-1 mice 25 Au NPs/ PEG 30b i.v./ 0 or 5 mg/kg/ GD5.5–7.5 and 11.5–13.5e ICP-MS TEM Quantitative detection of Au NPs in fetal tissue after exposure during early and late pregnancy. Qualitative visualization of Au NPs in fetal brain and liver.
 [61] CD-1 mice 156 Au NPs/ PEG, citrate, or ferritin 13b i.v./ 0, 0.9, or 7.2 mg/kg/ GD5.5–15.5e ICP-MS TEM, in vivo fluorescence imaging, fluorescence microscopy, and X-ray microscopy Accumulation of the three Au NP types in extra-embryonic tissue and fetus according to surface composition. Higher Au NP levels during early gestation compared to late gestation.
 [62] Kunming mice 48 CdTe/CdS core/shell QDs/ MPA, SiO2, or PEG 1.67 ± 0.29, 2.59 ± 0.43, 3.21 ± 0.32, 4.09 ± 1.02, or 4.20 ± 0.86b i.v./ 0, 0.02, 0.05, 0.086, or 0.125 mg/mouse/ GD21g ICP-OES In vivo fluorescence imaging Quantitative Cd detection in mice pups after maternal injection with QDs. Cd accumulation increased with decreasing size and increasing dosage of injected QDs. Qualitative assessment unable to demonstrate intact QDs in fetuses.
 [63] Kunming mice 10 CdSe/CdS/ZnS core/shell/shell QDs/ phospho-lipid micelle n.d. i.v./ 0 or 0.81 mg/kg/ 14 days before matingd / Bright-field light microscopy and fluorescence microscopy No QD accumulation in the placenta following prenatal IV injection of QDs in mice.
 [64] Kunming mice 10 CdSe/ZnS core/shell QDs 13b i.v./ 0 or 12.5 nmol/mouse/ GD13-GD18d ICP-MS / Significant elevations in placental Cd levels for pregnant mice exposed to QDs.
 [65] Kunming mice 20 CdSe and CdSe/ZnS QDs n.d. i.v./ 0 or 0.1 nmol/mouse/ GD16–17d ICP-MS / Cd detected in the placenta after exposure to different types of QDs. But no significant difference in fetal Cd levels for the exposed group compared to the control group.
 [66] CD-1 mice 15 to 63 CdO NPs 11.0 ± 0.1 or 15.3 ± 0.1c nose-only inhalation/ 0, 0.1 mg/m3 for 1.25 h every other day or 0.23 mg/m3 for 2.5 h/day/ GD4.5–16.5e AAS, ICP-MS / Cd accumulation in mouse uterus and placenta, as well as other maternal organs, in an associated way with inhaled CdO NPs. CdO NPs were undetectable in fetuses.
 [67] BALB/c mice 56 CeO2 NPs 3–5b i.v./ 0 or 5 mg/kg/ GD5–7f ICP-MS / CeO2 NPs detected in decidual tissue and placentas of IV treated mice during early gestation.
 [68] C57Bl/6 mice 19 Cu NPs 35.6 ± 1.7c whole-body inhalation/ 0 or 3.5 mg/m3 for 4 h/day/ GD3–19f ICP-MS / No quantitative detection of Cu in the placental nor fetal tissue of exposed mice.
 [69] CD-1 mice 80 Fe2O3 NPs/PEI or PAA n.d. i.p./0 or 10 mg/kg/ GD9 or 9–16d UV-vis spectrophoto-meter Bright-field light microscopy Both Fe2O3 NP types crossed the placenta. Only mice treated with PEI-NPs for eight consecutive doses showed a significant increase in Fe levels in fetal livers and placentae.
 [70] Wistar rats 8 MMSNPs/ [99mTc] 58.9 ± 8.1b i.v./ 0 or 18.5 MBq/mL/ GD11 or 20g Gamma spectroscopy / SiO2 NPs crossed the placenta of pregnant rats, both during early and late stages of gestation. SiO2 NPs reach the fetal bloodstream and bioaccumulate in both embryos and fetuses.
 [71] C57Bl/6 mice 11 MMSNPs/ gadolinium oxide-core and TFP 100–200b i.v./ 0 or 1 mg/mouse/ GD7–9 or 14–15d MRI and ultrasound imaging / SiO2 NPs observed in embryos of mice following early gestation injections while being excluded from the embryo by the placenta following late gestation injection.
 [72] CD-1 mice 44 Pt NPs 20.9 ± 11.4a oral/ 0, 0.25, 0.5, or 1 mg/kg/ 14 days before mating-PND4g ICP-MS / No detection of Pt NPs in pups of mice orally exposed before, during, and after gestation.
 [73] BALB/c mice n.d. SiO2 and TiO2 NPs/ fluorophore 35, 70, 300, or 1000a i.v./ 0 or 0.8 mg/mouse/ GD16 or 16–17g / In vivo fluorescence imaging, fluorescence microscopy, and TEM Only smaller SiO2 and TiO2 NPs found in the placenta, fetal liver, and fetal brain.
 [74] CD-1 mice 70 SiO2 NPs/ amine or carboxyl 25, 60, or 115a i.v./ 0 or 0.2 mg/mouse/ GD5.5, 12,5, or 16.5e ICP-OES / SiO2 NPs administered at different gestational stages reached placenta and fetus. Biodistribution influenced by NP size, surface charge, and gestational stage.
 [75] Wistar rats 30 TiO2 NPs 21b oral/ 0 or 200 mg/kg/ GD6–12d / TEM and SEM/EDX TiO2 NPs bypass the placenta and reached late-term neonatal rat lung tissue.
 [76] CD-1 mice 20 TiO2 NPs 6.5a oral/ 0, 25, 50, or 100 mg/kg/ GD0–17d ICP-MS / Significantly increased Ti content in placenta and fetus with received TiO2 NP dose compared to controls.
 [77] C57Bl/6 mice 45 TiO2 NPs 97c Whole-body inhalation/ 0 or 42 mg/m3 for 1 h/day/ GD8–18g ICP-MS / No quantitative detection of Ti in mice pups following maternal inhalation of nanosized TiO2.
 [78] Wistar rats 12 TiO2 NPs 10a oral/ 0 or 100 mg/kg/ GD2–21g ICP-MS / Ti accumulated in hippocampus of rat offspring after gestational TiO2 NP exposure.
 [79] C57Bl/6 mice 15 TiO2 NPs 5–6b i.v./ 0, 0.1, or 1 mg/mouse/ GD9d SF-ICP-MS / No significant accumulation of Ti in maternal plasma, placenta, fetal liver, and fetal brain for the 3 groups exposed to different concentrations of TiO2 NPs.
 [80] CD-1 mice 12 TiO2 NPs 25–70a s.c./ 0 or 0.1 mg/mouse/ GD3, 7, 10, and 14g / FE-SEM/EDX TiO2 NP transfer from pregnant mice into the brain and testis of their offspring.
 [81] SPF mice 20 TiO2 NPs 5.5a oral/ 0, 1.25, 2.5, or 5 mg/kg/ prenatal day 7-PND21g ICP-MS / Maternal gestational exposure to TiO2 NPs enhanced Ti content in offspring’s’ hippocampi.
 [82] Sprague Dawley rats 4 ZnO NPs/ citrate 20a oral/ 0 or 400 mg/kg/ GD5–19d ICP-OES / No significant difference in fetal Zn content between control and ZnO NP exposed group.
 [83] Sprague Dawley rats 10 ZnO NPs/ APTES > 35a i.v./ 0 or 20 mg/kg/ GD6–20d ICP-MS / Significantly elevated Zn levels in fetal liver after IV injection of pregnant rats with ZnO NPs.
 [84] Sprague Dawley rats 24 ZnO NPs < 100a oral/ 0 or 500 mg/kg/ 14 days before mating-day 4 of lactationg ICP-MS / Significantly higher levels of Zn in liver and kidneys, but not in blood and brain of rat offspring exposed to ZnO NPs before, during, and after gestation.
 [85] CD-1 mice 40 ZnO NPs 13.2 ± 3.7, 57.1 ± 4.1, or 1900 ± 504b oral/ 0 or 7.2 mg/mouse/ GD1–10 or 7–16f ICP-MS / Zn detected in the placentae of mothers exposed to ZnO NPs during early gestation in contrast to mothers exposed to bulk ZnO. Only the smallest ZnO NPs crossed the placenta to reach the fetus.
 [86] CD-1 mice 60 ZrO2 NPs 16 ± 4b oral/0, 2.5, 25, or 50 mg/kg/ GD9–11, GD13–15, or GD16–18f ICP-MS TEM/EDX Fetal accumulation of ZrO2 NPs following oral exposure of pregnant mice during different stages of pregnancy.
Carbonaceous NPs
 [87] Sprague Dawley rats 30 Fullerene/ [14C(U)] 26 ± 7b i.v./ 0 or 0.2 mg/kg/ GD11, 15, or 18g Gamma spectroscopy / Radioactive signals from C60 NPs detected in placenta and fetuses of exposed pregnant dams. Stronger signal 24 h compared to 8 days post-injection.
 [88] Sprague Dawley rats 8 Fullerene/ [14C(U)] < 10a i.v./ 0 or 0.3 mg/kg/ GD 15g Gamma spectroscopy / Radioactive signals detected in the placenta and fetuses of pregnant dams, indicative of transplacental C60 NP transfer.
Polymeric NPs
 [89] Wistar rats 24 PGMA NPs/PEI, fluorophore, and magnetite core n.d. i.v./ 0 or 0.5 mg/rat/ GD10 or 20f MRI and fluorescence microscopy Ex vivo fluorescence imaging and confocal microscopy Both PGMA NP types detected in the rat conceptus during early gestation. Greater accumulation of cationic NPs within the chorionic plate than anionic NPs.
 [27] FVB/N mice 40 PS NPs/ carboxyl and fluorophore 20, 40, 100, 200, and 500a i.v./ 0.3 mg/mouse/ GD17g HPLC and fluorescence microscopy / Placental uptake and transfer of fluorescent PS NPs with diameters up to 500 nm. NPs observed in various organs of fetuses after 4 h of administration to pregnant mice.
 [90] Mice 15 PS NPs/ fluorophore and PEG or carboxyl 50–70a i.v./ 0 or 0.00231 mg/kg/ GD10–15g / Confocal microscopy Both PS NP types found in placenta but not in embryonic tissues.
Ambient (ultra)fine particles
 [91] New-Zealand white rabbits 8 DEP 69c nose-only inhalation/ 0 or 1 mg/m3 for 2 h/day, 5 days/week/ GD3–27g / TEM NP-like structures observed in olfactory tissues of fetuses from DEP exposed mothers.
 [92] New-Zealand white rabbits n.d. DEP 69c nose-only inhalation/ 0 or 1 mg/m3 for 2 h/day, 5 days/week / GD3–27g / TEM NP-like structures observed in placenta, maternal blood space, trophoblasts and fetal blood of exposed rabbits.
  1. Data are shown as mean ± standard deviation, aprimary particle size stated by the manufacturer, bprimary particle size determined by TEM, cGeometric size determined by SMPS, dGD0 = sperm positive/vaginal plug positive, eGD 0.5 = sperm positive/vaginal plug positive, fGD1 = sperm positive/vaginal plug positive, gGD0 not defined
  2. Abbreviations - AAS atomic absorption spectrometry, Ag silver, Al2O3 aluminum oxide or alumina, AMG autometallography, APTES 3-aminopropyl triethoxydsilane, Au gold, CdO cadmium oxide, CdS cadmium sulfide, CdTe cadmium telluride, CdSe cadmium selenide, d diameter, DEP diesel exhaust particles, DLS dynamic light scattering, DMSA dimercaptosuccinic acid, EDX energy-dispersive X-ray spectroscopy, Fe2O3 iron oxide, FE-SEM/EDX field emission-type scanning electron microscopy/energy-dispersive X-ray spectroscopy, GD gestation day, HPLC high-performance liquid chromatography, ICP-MS inductively coupled plasma-mass spectrometry, ICP-OES inductively coupled plasma-optical emission spectrometry, i.p. intraperitoneal, i.v. intravenous, MBq megabecquerel, MMSNPs magnetic mesoporous silica nanoparticles, MPA 3-mercaptopropionic acid, MRI magnetic resonance imaging, n.d. not defined, NP nanoparticle, NTA nanoparticle tracking analysis, PAA poly(acrylic acid), PEG poly(ethylene glycol), PEI poly(ethyleneimine), PGMA poly(glycidyl methacrylate), PND postnatal day, PS polystyrene, PVP polyvinylpyrrolidone, QD quantum dot, s.c. subcutaneous, SF-ICP-MS sector field inductively coupled plasma-mass spectrometry, SiO2 silicon dioxide or silica, SMPS scanning mobility particle sizer, S-TPP sulfonated triphenylphosphine, TEM transmission electron microscopy, TFP trifluoropropyl, TiO2 titanium dioxide, ZnO zinc oxide, ZnS zinc sulfide, ZrO2 zirconium dioxide