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Table 3 Studies with evidences for indirect fetotoxicity pathways with unknown placental transfer of NMs

From: Recent insights on indirect mechanisms in developmental toxicity of nanomaterials

NP type/coating NP size Exposure/model application route/dose/exposure period developmental toxicity (gestational and litter parameters) developmental toxicity (other parameters) hypothesis by authors on indirect toxicity pathways publication
TiO2 21 nm rat inhalation/ cummulative lung burden of 525 μg/ GD 11–16 not evaluated increased placental vascular resistance and impaired umbilical vascular reactivity impaired fetoplacental vascular reactivity/ altered placental reactivity and anatomy [96]
Si 70 nm mouse i.v. injection/ 0.025 or 0.04 mg/g/ GD 13–14 increased fetal resorption and reduced fetal weight at 0.04 mg/ml particle uptake in placenta/ 0.04 mg/ml: abnormalities in placental structure and reduced placental weight/ nanosilica upregulated the inflammasome component NLRP3 and induced placental inflammation and ROS, resulting in pregnancy complications/ pregnancy complications were dependent on the balance between an inflammatory cytokine (IL-1a) and an anti-inflammatory cytokine (IL-10)/ complications were completely prevented by either inhibition of ROS generation or forced expression of IL-10 placental inflammation [16]
CdTe quantum dots 2 nm rat i.p./ 5, 10 or 20 mg/kg/ GD 13 dose dependent embryotoxicity/ reduced survival rate of fetuses/ reduction of fetal body length and mass/ disturbed ossification of limbs placental tissue damage (decreased placental weight, abnormal morphological features) impeded embryogenesis due to the placental damage rather than QD penetration and accumulation in the fetuses/ distinct developmental toxicity effects than upon Cd2+ exposure [97]
CdTe quantum dots/ CuO 3 nm/ 10–20 nm BeWo/HVMF placental microtissues 0–25 μg/mL/ 24 h not applicable reduction of β-hCG secretion at sub-lethal concentrations interference with hormone release [98]
Dendritic polyglycerol/sulfate, amine or neutral 5–7 nm first trimester placental explants 10 nM and 1 μM/ 24 h not applicable charge-dependent accumulation of particles/ no major acute toxicity but reduced secretion of β-hCG for charged particles at the lower concentration potentially hazardous influences of charged dendritic polygylcerol particles on early placental physiology by reduction of β-hCG hormone levels [99]
MWCNT 13 μm length mouse i.p or intratracheally/ 2,3,4 or 5 mg/kg/ GD 9 fetal malformations/ increased leucocyte and related hemocyte number and increased weight of spleen in dams none inflammatory mechanism [100]
CB 14 nm mouse inhalation: 42 mg/m3/ 1 h/day/ GD 8–18 instillation: 2.75, 13.5 or 67 μg/mouse/ GD 7, 10, 15 and 18 neither inhalation nor instillation affected gestation and lactation DNA strand breaks in maternal and offspring liver after inhalation but not instillation exposure/ persistent lung inflammation in exposed mothers translocation across lung, GI tract and placenta expected to be very low for highly insoluble CB; changes in signalling cascades proposed e.g. inflammatory molecules [17]
CB 14 nm mouse intratracheal instillation/ 2.75, 13.5 or 67 μg/mouse/ GD 7, 10, 15 and 18 see (Jackson 2011) changes in the expression of several genes and proteins associated with inflammation in maternal lungs/ hepatic response in offspring at highest dose responses in newborns secondary to inflammation in dams [101]
CB/ TiO2/ DEP not determined mouse intratracheal instillation/ 50 μg/mouse/ GD 14 not evaluated increased allergic susceptibility in offspring components of DEP (especially PAHs) could mediate pro-allergic effects by increased production of Th2 cytokines (e.g., IL- 4), known to be important mediators of allergy and asthma [102]
graphene oxide 4 different sizes (1–40 μm; 20 nm-1.4 μm; 0.2–1 μm; 10–30 μm) 2D BeWo or BeWo Transwell cultures 0–40 μg/mL/ 6 h, 24 h or 48 h not applicable particle uptake in BeWo cells/ no major acute toxicity but reduced secretion of β-hCG and transient reduction in barrier integrity interference with hormone release and barrier integrity [103]
PM2.5 < 2.5 μm human ambient PM2.5 exposures over the entire pregnancy from 5.54 to 29 μg/m3 not evaluated positive relationship between PM2.5 exposure during preconception and pregnancy and intrauterine inflammation intrauterine inflammation upon PM2.5 exposure in pregnancy may influence subsequent fetal growth, development,and health outcomes [49]
PM10 < 10 μm human mean exposure levels during pregnancy were 30.3 μg/m3 for PM10 and 39.9 μg/m3 for NO2 not evaluated short-term maternal PM10 exposure was modestly associated with elevated maternal CRP levels in early pregnancy and that long-term maternal PM10 and NO2 exposure during pregnancy was associated with elevated fetal CRP levels at delivery exposure to air pollution during pregnancy may lead to maternal and fetal inflammatory responses [104]
PM10 < 10 μm human mean exposure levels during pregnancy were 30.3 μg/m3 for PM10 and 39.9 μg/m3 for NO2 not evaluated associations of PM10 and NO2 exposure with changes in fetal sFlt-1 and PlGF levels at delivery/ higher PM10 and NO2 exposures were associated with lower placenta weight/ air pollution exposure was not consistently associated with other markers of placental growth and function maternal air pollution exposure may influence markers of placental growth and function [104]
  1. BC black carbon, CB carbon black, DEP diesel exhaust particles, GD gestation day, ICP-OES inductively coupled plasma optical emission spectrometry, hCG human chorionic gonadotropin, HVMF human villous mesencyhmal fibroblasts, IGF insulin growth factor, i.p. intraperitoneally, i.v: intravenous, NP nanoparticles, PAHs polycyclic aromatic hydrocarbons, PM particulate matter, ROS reactive oxygen species, TEM transmission electron microscopy