Table 1 Studies with evidences for indirect fetotoxicity pathways without 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 |
|---|---|---|---|---|---|---|---|---|
TiO2 | 5–6 nm | mouse | i.v./ 100 or 1000 μg/mouse/ GD9 | not detected in fetus or placenta by ICP-MS | no overt fetal malformations or changes in pregnancy outcomes/ no impact on postnatal growth | behavioral deficits relevant to ASD and related neurodevelopmental disorders in neonates | maternal mediated unknown pathways due to absence of particles in placenta and fetal tissues | [75] |
TiO2/CeO2 | 12.3 ± 0.1/ 22.4 ± 0.2 nm | mouse | instillation/ total 300 μg/mouse/ 100 μg at GD 2.5, GD 9.5 and GD 16.5) | Ti and Ce detected in the placenta but not in fetal tissues 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 | [76] |
UV-Titan L181/polyalcohols | 20.6 ± 0.3 nm | mouse | inhalation/ 1 h/day to 42 mg/m3/ GD 8–18 | not detected in fetal liver by ICP-MS | no impact on gestational and litter parameters | moderate neurobehavioural deficits/ persistent lung inflammation in pregnant dams | dissolution and translocation of contaminating metal ions/ placental transfer of inflammatory cytokines released from NP-exposed maternal lung tissue | [77] |
CuO | 16 nm | mouse | inhalation/ 3.5 mg/m3 for 4 h/day/ GD 3–19 | not detected by ICP-MS (similar Cu levels in placenta and fetus as controls) | survival rate of 7 week old pups reduced/ no impact on litter size, male/female ratio, body weight and lenght at birth | maternal pulmonary inflammation/ no histopathological changes of placenta tissue/ immunomodulatory effects in offspring (differential expression of several Th1/Th2 or other immune response genes in spleen) | changes in maternal inflammatory and immune responses | [78] |
CdO | 11–15 nm | mouse | inhalation/ 100 μg/m3 every other day or 230 μg/m3 daily for 2.5 h/ GD 4.5–16.5 | Cd detected in placenta but not in fetus by gAAS and ICP-MS (Cd in placenta) | decreased incidence of pregnancy/ decreased fetal length/ delayed neonatal growth/ delayed maternal weight gain | altered placental weight | disruption in placental oxygen transfer by Cd [79]/ decrease in fetal length could be due to alterations in the fetal and/or maternal IGF system [80, 81]/ changes in the placental transport of zinc, vitamin B12, and other micronutrients due to placental Cd [82] | [83] |
SWCNT /OH-functionalized | 1–2 nm diameter and 5–30 μm length | mouse | oral/ 10 mg/kg or 100 mg/kg/ GD 9 | not detected in placenta, fetal liver and fetal kidney by TEM | increased fetal resorption and fetal morphological and skeletal abnormalities at 10 mg/kg but not at higher dose | none | oxidative stress and inflammatory response in placenta/maternal tissue | [84] |
SWCNT/non-oxidized, oxidized and ultra-oxidized | 2.37 nm diameter, 0.85 μm length/ 1.58 nm diameter, 0.76 μm length/1.8 nm diameter, 0.37 μm length | mouse | i.v./ 10 ng to 30 μg/mouse/ GD 5.5 | not detected by histological and micro-Raman analyses | high percentage of early miscarriages and fetal malformations; lowest effective dose 100 ng/mouse | vascular lesions and increased ROS in placenta/ increased ROS in malformed fetuses/ no increased ROS or evident morphological alterations in maternal tissues | oxidative stress in placental tissue | [85] |
CoCr | 29 nm | BeWo Transwell bilayer with underlying BJ fibroblasts | 40 μg/ml/ 24 h | not detected by ICP-MS (similar Co and Cr levels in whole fetus as controls) | not applicable | DNA damage to the fibroblasts without significant cell death/ mechanism involving transmission of purine nucleotides (e.g. ATP) and intercellular signalling within the placental barrier through connexin gap junctions or hemichannels and pannexin channels | fetal damage mediated by placental tissue via release of mediators (e.g. ATP) | [86] |
CoCr | 29 nm | Bewo Transwell mono- or bilayers with underlying BJ fibroblasts or Oct4-hES | 40 μg/ml / 24 h | not detected [86] | not applicable | DNA damage to fibroblasts or Oct4- hES cells only with BeWo double layer | indirect toxicity only across bilayered (human)/multilayered (mice) placental barrier | [87] |
mouse | i.v./ 0.12 mg or 0.012 mg/mouse/ GD 9.5 or 12.5 | not detected by ICP-MS (similar Co and Cr levels in whole fetus as controls) | no pathological changes in neonatal visceral organ | DNA damage in neonatal blood and liver at GD 12.5 (placenta with three layers established) but not at GD 9.5 (nutrient exchange via uterus and yolk sac)/ no pathological changes in placenta | ||||
CoCr | 29 nm | Bewo Transwell bilayers and conditioned media transfer to NPC or NPC-derived astrocytes and neurons | 40 μg/ml / 24 h | not detected [86] | not applicable | altered differentiation of human NPC and DNA damage in the derived neurons and astrocytes/ importance of autophagy and IL-6 release from placental tissue in NP-induced DNA-damaging singalling/ NPs can cause developmental neurotoxicity across placental barriers/ astrocytes are key mediators of this neurotoxicity/ fetal hippocampus is particularly affected in mice | exposure of the human placenta to CoCr NPs could initiate a singalling cascade that perturbs the relationship between astrocytes and neurons during neurodevelopment | [88] |
mouse | i.v./ 0.12 mg / dpc 9 | not detected [87] | see [87] |