Prenatal developmental toxicity of silver nanoparticles and the potential risks

Abstract

Silver nanoparticles (AgNP) are one of the most commonly used nanomaterials in commercial products, such as food packaging materials. Humans are prone to oral exposure to AgNP through direct consumption and leachate from AgNPcontaining products to the environment. In vivo studies demonstrated that AgNP would lead to malformation in zebra-fish embryos in a dose-dependent manner. Maternal oral exposure to AgNP would lead to a detectable amount of silver in developing rat fetuses. Distribution and toxicity of AgNP are closely related to its physicochemical properties, such as size, surface chemistry and shape, and degree of dissolution, highlighted the importance of using AgNP of the same physicochemical properties to ensure fair comparison across different studies. The hypothesis of the present study is that maternal exposure to AgNP would lead to transplacental transfer of silver, AgNP and/or silver-containing molecules, and such transfer would result in prenatal developmental toxicity in fetuses. In order to address this hypothesis, the present study investigated the transplacental transfer of AgNP and the potential risks by using in vivo model, human placental perfusion model and human placental villous explant cultures. Polyvinylpyrrolidone-coated AgNP (PVP-AgNP) was chosen for the present study.

In the prenatal developmental toxicity study, upon oral exposure of 150-600 mg/kg/day of PVP-AgNP to pregnant rats during gestation day 6-19, silver and silver-containing NPs were detected in kidneys, livers, brains, placentas and blood of pregnant animals. Though relatively high levels of silver and silver-containing NP were detected in placentas, fetuses were not perfectly protected from silver and silver-containing NP exposure. However, such exposure level would not lead to developmental toxicity to fetuses, as demonstrated by skeletal and visceral examination of fetuses.

Human placental perfusion was conducted to investigate whether transplacental transfer of silver would also occur in human placenta. With 25μg/ml of PVPAgNP (100 times higher than average concentration of silver in pregnant dams) in the maternal reservoir, no silver was detected in the fetal reservoir after 4 hour of perfusion. Further study would be required to increase the number of successful perfusion.

The effect of PVP-AgNP exposure to human placenta was examined with the use of human placental villous explants. Upon exposure of villous explants to 0.025-25μg/ml of PVP-AgNP, no significant changes in expression of p38MAPK (p38), extracellular kinases (ERK1/2) and stress-activated protein kinase/c-Jun amino terminal kinases (SAPK/JNK), their phosphorylated forms occurred when compared to control, though a dose-dependent increase was observed in phosphorylated-mitogen-activated protein kinases (MAPKs) expression.

In conclusion, 150-600 mg/kg/day of PVP-AgNP would lead to transplacental transfer of silver, silver ion, and/or silver-containing NP to developing fetuses in rats, but not in term human placenta using ex vivo models. Exposure of human placental tissue to 0.025-25μg/ml of PVP-AgNP for 24 hours did not seem to associate with oxidative stress. Further investigation is required for safety assurance of PVP-AgNP to the vulnerable populations.