Table 2 Studies with evidences for indirect fetotoxicity pathways with 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 | placental transfer | developmental toxicity (gestational and litter parameters) | developmental toxicity (other parameters) | hypothesis by authors on indirect toxicity pathways | publication |
|---|---|---|---|---|---|---|---|---|
CdSe/CdS/ZnS quantum dots/PEG-phospholipid micelle | 60 nm | mouse | i.v./ 100 mg/kg/ GD 17 | increased Cd levels in umbilical cord and fetuses by ICP-MS | no gestational or fetal abnormalities or complications | no significant abnormalities in maternal blood biomarkers, histopathology or behavior | acute hepatocellular injury and possible stress caused by the injection did eventually contribute to the high miscarriage rate in macaques | [89] |
macaques | i.v./ 25 mg/kg/ GD 100 | slightly increased Cd levels in fetal organs by ICP-MS | increased rate of miscarriage | no pathological changes in the placenta or major organs of the miscarried fetuses/ no inflammatory response or injury in maternal liver and lung tissues/ acute maternal hepatocellular injury | ||||
Si and TiO2 | 70 nm and 35 nm | mouse | i.v./ 0.8 mg/mouse /GD 16 and 17 | Si and TiO2 NP in placenta, fetal liver and brain by TEM | decrease of maternal body weight at GD 17/18/ lower uterine weights/ higher fetal resorption rates/ smaller fetuses | Si NP induced structural and functional abnormalities in placenta (decreased sFlt-1)/ heparin improved fetal weight and sFlt-1 levels in Si NP exposed mice | adverse effects are linked to structural and functional abnormalities in the placenta/ activation of coagulation, complement and oxidative stress in the placenta | [90] |
Ag | 12.3/ 22.4 / 10.4 nm | mouse | instillation/ total 300 μg/mouse/ 100 μg at GD 2.5, GD 9.5 and GD 16.5 | Ag in placenta and fetal lung by ICP-MS | not evaluated | long-lasting impairment of lung development in offspring/ decreased placental efficiency together with the presence of NPs in the placenta/ no increase of inflammatory mediators in amniotic fluid, placenta or offspring lungs/ decreased pulmonary expression of VEGF-α and MMP-9 at the fetal stage (GD 17.5) and FGF-18 at the alveolarization stage (postnatal day 14.5) | probably involves placental insufficiency secondary to the presence of NPs in this organ with ensuing down regulation of critical mediators of lung development without any amniotic fluid or fetal lung inflammation/ not mediated via fetal or maternal lung inflammation/ combination of direct and indirect pathways possible due to low placental transfer of Ag | [76] |
Ag | 18–20 nm | mouse | inhalation/ 1 or 4 h/day to 640 μg/m3/ GD 0.5–14.5 | Ag in maternal tissues, placenta and fetus by TEM/ no particles or ions detected by spICP-MS | increased number of resorbed foetuses | reduced oestrogen plasma levels (in 4 h/day exposures)/ increased expression of pregnancy-relevant inflammatory cytokines in the placentas/ no major pathological changes in the lung of the mothers and only minor lesions in maternal liver and kidney | adverse effects at least in part related to the release of inflammatory mediators by the placenta/ reduction of circulating oestrogen levels could indicate an endocrine disrupting action of Ag NPs | [91] |
Ag/ PEGylate or carboxylate | 2–15 or 5–15 nm | ex vivo human placenta perfusion | 40 or 75 μg/ml / 6 h perfusion | low levels of Ag NPs > 25 nm in fetal circulation by spICP-MS | not applicable | low translocation of Ag ions and Ag NPs (below 0.02% of initial dose)/ considerable uptake of Ag NPs in placental tissue (4.2% of initial dose for AgCOONa; 0.75% for AgPEG) | low translocation but comparably high accumulation of ionic Ag and Ag NPs in placental tissue may result in indirect placenta-mediated developmental toxicity | [92] |
Diesel exhaust | 69 nm | rabbit | inhalation/ 1 mg/m3 for 2 h/day, 5 days/week/ GD 3–27 | non-aggregated and “fingerprint” NP observed in maternal blood, trophoblasts and fetal blood by TEM | growth retardation | reduced placental efficiency/ reduced placental vascularization/ reduced plasma insulin and IGF1 concentrations/ in second generation, fetal metabolism was modified | adverse effects on placental structure and function and reduced plasma IGF-1 may contribute to the observed growth retardation/ effects could be due to either NP or contaminants (e.g. PAHs) | [93] |
MWCNT/ oxidized and 99mTc | 1–2 μm length, diameter 20–30 nm | mouse | i.v./ 20 mg/kg/ GD17 | NPs in placental tissue and foetal liver, lung and heart by radioactivity measurements | poor embryo development/ fetal growth restriction/ embryonic death/ abortion/ reduced fetal weight/ fetal heart and brain damage | decreased progesterone levels and increased oestradiol levels in serum/ decreased VEGF levels and increased ROS amounts in placental tissue/ number of placental blood vessels decreased | fetal growth restriction due to vascular reduction in the placenta/ toxicity higher in first time pregnancies as adaptations in the placenta may occur/ oMWCNT affect secretion of progestational hormones | [94] |
SWCNT and MWCNT/amine-functionalized (PL-PEG-NH2)/ 64Cu for translocation | SWCNT:1–2 nm diameterMWCNT: < 8 nm, 20–30 nm or 50 nm diameter, 500–2000 nm length | mouse (p53+/+; p53 +/−; p53 −/−) | i.v./ 2 mg/kg or 5 mg/kg/ GD 10.5, 12.5 or 15.5/ single or repeated doses | all CNTs in placental tissue and fetal liver by positron emission tomography | larger sized MWCNT restricted the development of fetuses and induced brain deformity (only at GD 10.5 and only in p53−/− fetuses)/ SWCNTs and smaller sized MWCNTs showed no or less fetotoxicity | MWCNTs directly triggered p53-dependent apoptosis and cell cycle arrest in response to DNA damage/ N-acetylcysteine (antioxidant) pevented CNT-induced nuclear DNA damage andreduce brain development abnormalities | placenta mediated toxicity thorugh interference with placental function | [95] |