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] |