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Intravenous Exposure of Pregnant Mice to Silver Nanoparticles: Silver Tissue Distribution and Effects in Maternal and Extra-Embryonic Tissues and Embryos Open Access

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Engineered nanomaterials (ENMs), generally considered to measure less than 100 nm in at least one dimension, have become the subject of intense research and development over the past decade. They are unique because their incredibly small size and high surface area-to-volume ratio often translate into novel properties and enhanced reactivities. For this reason, ENMs of various types, shapes, and sizes are being increasingly used in a wide variety of industries and technologies. Silver nanoparticles (AgNPs) in particular are generating considerable interest. Because of their efficient antimicrobial activity, AgNPs are being added to products such as wound bandages, catheters, clothing, and kitchen utensils. Additionally, AgNPs are photosensitive, making them potentially useful in biomedical imaging tools. Despite their increasing use, there exist major knowledge gaps in the toxicological profile for AgNPs. One such gap concerns the potential effects of prenatal AgNP exposure on the developing fetus, as well as effects on reproductive organs and fertility in both males and females. This subject deserves close attention because the potential for human exposure to AgNPs is increasing, and because the sensitive processes of reproduction and development can be especially susceptible to chemical insult.This research explores the tissue distribution of silver, as well as adverse effects in pregnant mice and embryos, following prenatal AgNP exposure. Chapter one of this dissertation is a survey of the published literature on the reproductive and/or developmental toxicity of AgNPs. The available data indicate that AgNPs adversely affect sperm count, viability, and/or motility both in vivo and in vitro, and cause apoptosis and necrosis in spermatogonial stem cells and testicular cells. Additionally, AgNP exposure results in mortality and morphological deformities in fish embryos, but produces no adverse effects in chicken embryos. The current published research on in vivo AgNP exposure to mammals during gestation consists of only three studies, one of which is described in chapter two of this dissertation. These studies report results that may suggest a potential for adverse effects on fetal development (e.g., decreased viability and fetal and placental weights, increased incidence of developmentally young embryos), but additional research is needed.Chapter two of this dissertation investigates the distribution of silver in tissues of pregnant mice and gestation day (GD) 10 embryos following intravenous maternal exposure to 50 nm AgNPs during early organogenesis (GDs 7-9). Examinations of embryo morphology and histology were also performed. Results demonstrated the presence of silver in all organs and tissues examined. Silver concentrations were highest in liver, spleen, and visceral yolk sac, and lowest in embryos. Groups of mice were also treated with soluble silver nitrate, and the pattern of silver tissue distribution following silver nitrate exposure was similar to that which followed AgNP treatment. Transmission electron microscopy-energy dispersive x-ray spectroscopy (TEM-EDS) confirmed the presence of vesicle-bound nanoparticulate silver in visceral yolk sac endoderm, but not mesoderm. This finding, along with the high silver concentration in visceral yolk sac and low silver concentration in embryos, suggests that visceral yolk sac tissue mitigates AgNP transfer to embryos. No significant treatment-related effects on embryo morphology or tissue histology were detected.Chapter three constitutes an expanded study of silver distribution in pregnant mice and developing embryos, with the addition of 10 nm AgNP treatment groups and examination of fetuses at GD16. Very low concentrations of silver were measured in GD10 embryos and GD16 fetuses following 10 nm AgNP treatment or in GD16 fetuses following 50 nm AgNP treatment. Highest silver concentrations were measured in maternal liver, spleen, and visceral yolk sac. AgNP particle size (10 or 50 nm) did not consistently affect silver tissue distribution. At GD10, 50 nm AgNP treatment resulted in significantly higher silver concentrations than 10 nm AgNP treatment for liver, spleen, and visceral yolk sac only; at GD16, in visceral yolk sac only, 10 nm AgNP treatment resulted in a significantly higher silver concentration than 50 nm AgNP treatment. In liver, spleen, visceral yolk sac, and uterus, absolute silver concentrations following 10 nm AgNP treatment were significantly lower at GD16 compared to GD10; the patterns of silver tissue distribution were similar at both time points. Silver nitrate and 10 nm AgNP treatments resulted in similar tissue concentrations in GD10 tissues with the exception of visceral yolk sac, for which the silver concentration was significantly higher after silver nitrate treatment. Silver distribution patterns were generally similar between 10 nm AgNP and silver nitrate treatments. No histological abnormalities were noted in maternal tissues, extra-embryonic tissues, or embryos. A significantly increased incidence of developmentally young (for gestational age) GD10 embryos was seen following 10 nm AgNP treatment; no significant morphological effects were observed in embryos or maternal tissues. Further research will be needed to fully evaluate potential effects of prenatal AgNP exposure on embryos.

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