Murine exposure to gold nanoparticles during early pregnancy promotes abortion by inhibiting ectodermal differentiation

Abstract

BackgroundGold nanoparticles (AuNPs) have been widely studied for biomedical applications, although their safety and potential toxicity in pregnancy remains unknown. The aim of this study is to explore the effect of AuNPs maternal exposure at different gestational ages on fetal survival and development, as well as the potential mechanism of AuNPs affecting embryos and fetuses.MethodsThirty nm polyethylene glycol (PEG)-coated AuNPs (A30) were administered to pregnant mice via intravenous injection (5 μg Au/g body weight) over three days at either early or late pregnancy. Fetal abortion rate and morphological development in E16.5 were then detected in detail. The pregnant mice physiological states with A30 exposure were examined by biochemical, histological or imaging methods; and materno-fetal distribution of gold elements was assayed by electron microscopy and mass spectrometry. Murine embryonic stem cells derived embryoid-bodies or neuroectodermal cells were treated with A30 (0.0025 to 0.25 μg Au/mL) to examine A30 effects on expression levels of the germ differentiation marker genes. Tukey’s method was used for statistical analysis.ResultsExposure to A30 during early (A30E) but not late (A30L) pregnancy caused a high abortion rate (53.5%), lower fetal survival rate and abnormal decidualization compared with non-exposed counterparts. The developmental damage caused by A30 followed an “all-or-nothing” pattern, as the non-aborted fetuses developed normally and pregnancies maintained normal endocrine values. A30 caused minor impairment of liver and kidney function of A30E but not A30L mice. TEM imaging of fetal tissue sections confirmed the transfer of A30 into fetal brain and live as aggregates. qPCR assays showed A30 suppressed the expression of ectodermal, but not mesodermal and endodermal differentiation markers.ConclusionsThese results illustrate that maternal A30 exposure in early pregnant results in A30 transfer into embryonic tissues, inhibiting ectodermal differentiation of embryonic stem cells, leading to abnormal embryonic development and abortion. While exposure to A30 during late pregnancy had little or no impact on dams and fetuses. These findings suggest the safety of biomedical applications employing AuNPs during pregnancy is strongly influenced by fetal maturity and gestational age at exposure and provide the clues for AuNPs safe application period in pregnancy.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0061-2) contains supplementary material, which is available to authorized users.

Translocation of (ultra)fine particles and nanoparticles across the placenta; a systematic review on the evidence of in vitro, ex vivo, and in vivo studies

“…, poly(glycidyl methacrylate) (PGMA), and PS) (Table 3 ). Fetal/embryonic NP accumulation was observed in 32 of the included animal studies, more specifically NPs were detected in the fetal brain [ 27 , 44 , 48 , 52 , 60 , 73 , 78 , 80 , 81 , 91 ], fetal liver [ 27 , 48 , 50 , 52 , 60 , 69 , 73 , 83 , 84 , 86 ], fetal lung [ 27 , 48 , 52 , 75 ], fetal kidney [ 48 , 52 , 84 ], fetal gastrointestinal tract (GIT) [ 88 ], and fetal blood [ 92 ]. The preferred method for NP administration was intravenous (i.v.)…”

“…Other studies reported a time-dependent accumulation of Ag NPs, CeO 2 NPs, and fullerenes as they found that the fetal NP concentration increased over time, reached a peak, and then declined [ 54 , 67 , 87 ]. Moreover, critical exposure windows during gestation were evaluated by defining changes in particle transfer after varying the day of NP exposure [ 60 , 61 , 70 , 71 , 87 ]. Pregnant rats were divided into five groups and differently exposed with radioactively-labeled fullerenes ( 14 C(C60)) via single i.v.…”

“…Higher Au NP levels in maternal tissues (e.g., spleen) compared to fetal tissues. [ 60 ] CD-1 mice 25 Au NPs/ PEG 30 b i.v./ 0 or 5 mg/kg/ GD5.5–7.5 and 11.5–13.5 e ICP-MS TEM Quantitative detection of Au NPs in fetal tissue after exposure during early and late pregnancy. Qualitative visualization of Au NPs in fetal brain and liver.…”

“…Alignment of rodent and lagomorph reproductive timelines with that of humans is based on Theiler (mouse) [ 138 ], Witschi (rat) [ 139 ], Edwards (rabbit) [ 140 ], and Carnegie (human) [ 141 ] stages of development. The included studies employed various gestational windows of NP exposure ranging from exposure during early or late gestation [ 60 , 67 , 70 , 71 , 74 , 85 , 89 ] to continuous exposure during the whole pregnancy [ 1 , 52 , 68 , 72 , 76 , 81 , 92 , 93 ] to assess the time-dependence of transplacental particle transfer. In this regard, polymeric NPs accumulated in different compartments of the rat conceptus during early (GD10), but not late (GD20) gestation, consistent with the lack of a developed placenta during early gestation [ 89 ].…”

“…As summarized in Table 5 , a multitude of imaging approaches was used to visualize NPs in an in vitro , ex vivo , and in vivo context. Some included studies investigated maternal-fetal NP distribution at the whole-body level by using magnetic resonance imaging [ 71 , 89 ], in vivo/ex vivo fluorescence imaging [ 61 , 62 , 73 , 89 ], or radiolabeling techniques [ 53 , 57 , 70 , 87 ]; whereas other reports focused on the subcellular localization of NPs by exploiting transmission [ 23 , 24 , 27 , 29 – 32 , 41 , 43 , 45 , 47 , 49 , 52 , 54 , 57 , 58 , 60 , 61 , 73 , 75 , 91 , 92 ] or scanning electron microscopy [ 75 , 80 , 93 ]. Fluorescence microscopy is generally the method-of-choice to monitor the cellular and tissue-level distribution of fluorescent NPs [ 143 ].…”