The Downside of Nano: Pregnancy Complications

“The increasing use of nanomaterials has raised concerns about their potential risks to human health.” – Yamashita et al, Nature Nanotech. 2011

A recent article in Nature Nanotechnology investigates the potential risks of nanomaterials, specifically various sized silica and titanium dioxide nanoparticles, for causing pregnancy complications in mice. With up to 15% of human pregnancies in the United States being affected by poor fetal growth due to defects in or damages to placental tissue , researchers argue that nanomaterials found in many drug formulations as well as several food and women’s cosmetic products deserve a careful investigation. Bulk silica, or silicon dioxide SiO2, akin to common sand, is an FDA approved food additive as an anti-caking agent. However, the increased use of nanosized particles of silica, in diameter smaller than 1/1000th the width of a human hair, has raised health safety concerns, especially for pregnant woman. Nanosized particles of silica are purported found in several food products including Slim Shake Chocolate, in specialized brands of cooking pans and sprays, in pesticides and fertilizers _, and in several cosmetic products. Lancome®’s Rénergie® Microlift facial product for woman was advertised with the following product label: “Microlifters are made of nano-particles of silica and proteins form a network to immediately lift and tighten skin.” This exact product and label, interestingly, no longer appear on the Lancome website. Understandably so… there may be some cause for concern here.
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NPR: Safety of Nano-Cosmetics Questioned by NELL GREENFIELDBOYCE : Listen.mp3

Poor fetal growth, also called intrauterine growth restriction (IUGR), and low birth weight are the most importance causes of mortality and morbidity in unborn and newborn infants . The past decade and the advent of nanotechnology, the synthesis and manipulation of materials on the scale of 10-9 meters, have brought on concerns over air pollutant and nanoparticle health-damaging effects for the developing fetus. It is known that the fetus is more sensitive to environmental toxins than adults (Wigle 2008). This is especially true for toxins that can cross the placental barrier from mother to fetus. Recent studies have shown that many nanomaterials can cross this barrier, and cause toxic effects on the brain of the fetus or newborn infant (Takeda 2009, Shimizu 2009). This toxicity is dependent not only on the type of nanomaterial, but also on the material’s size, surface chemistry, and surface charge. While many studies related to nanomaterial toxicity to animal offspring have been conducted, until the recent article in Nature Nanotechnology by Yamashita and coworkers, the effects of nanomaterials on pregnant animals and their fetuses had not yet been studied.

Yamashita and coworkers have revealed that silica nanoparticles less than 100nanometers in diameter accumulate in the fetal liver and fetal brain of pregnant mice. Particles in this size range also have detrimental effects on tissues and cells in the placenta of mice, the placenta being an organ that links the developing fetus to the uterine wall and allows maternal-fetal nutrient and waste exchange. In the study, nano-silica treatment caused placental dysfunction and reduced blood flow to fetuses in pregnant mice. While the nano-silica had no visible effects on maternal liver and kidney, mice that received these particles via injection had up to 30% lower uterine weights, and significantly higher rates of a ‘miscarriage’ equivalent.

The suggested mechanisms of detrimental effects by nano-silica as observed in mice include processes of coagulation, immune system activation producing system inflammation, and/or through oxidative stress. Nanoparticles of silica are already known to cause inflammation responses in human cells. Oxidative stress is a direct result of the presence of reactive oxygen species, such as oxygen ions and peroxides. Importantly, several types of nanomaterials have been reported to cause oxidative stress, and thus DNA damage, cell ‘suicidal’ death, and inflammation in human tissues. Nanosized particles of silica smaller than 100nm in diameter were shown by Yamashita and coworkers to fall into this category, inducing oxidative stress and thus cell death in the fetal tissues of pregnant mice. Oxidative damage to fetal tissues is theorized to affect mother-fetus nutrient exchange, resulting in undernutrition and low fetal weight.

Size and surface modification are a possible ways of creating safer nanomaterials. -(Yamashita et al)

The detrimental effects of silica nanoparticles on pregnant mice were shown to be dependent on nanoparticle size. This result has implications for commercial products containing nano-silica materials smaller than 100 nanometers. Possible means of reducing potential health effects caused by such products include increasing nanoparticle size above 200nm, or modifying the surface of the silica nanoparticles. Silica nanoparticles modified with chemical compounds that change the charge of the particle surface and prevent association with natural proteins in the body did not affect uterine weight of pregnant mice, or cause oxidative stress to placenta tissues.

As a side note: Titanium dioxide nanoparticles with diameters less than 35nm were also shown to have detrimental effects on pregnant mice. However, titanium dioxide nanoparticles are mainly used in topical products (such as sunscreens), and exposure through the skin only may not be adequate to raise health concerns for humans.

In summary, Nanosilica particles with diameters less than 100nm were shown to induce ‘miscarriage’ and fetal growth restriction in mice. While these results raise concerns for humans, the authors of the study are careful to point out that due to differences between mice and humans, we must be careful in extrapolating this data to potential effects in humans. Also, doses of nanoparticles used in the mouse studies were typical of ‘preclinical doses for drug delivery applications of silica particles’. These dose amounts might not be representative of the typically small doses absorbed through the skin from cosmetic products. However, further investigations of nano-silica in human health are warranted. Such investigations are especially necessary in the cases of nano-silica use in food additives and consumption by pregnant women.

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1. Cetin I., Alvino G. Intrauterine growth restriction: implications for placental metabolism and transport. A Review. Placenta 30(Suppl. A), S77-S82 (2009)
2. Wigle, D. T. et al. Epidemiologic evidence of relationships between reproductive and child health outcomes and environmental chemical contaminants. J. Toxicol. Environ. Health. B. Crit. Rev. 11, 373-517 (2008).
3. Takeda, K. et al. Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J. Health Sci. 55, 95-102 (2009).
4. Shimizu, M. et al.Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse. Part. Fibre Toxicol. 6, 20 (2009).
5. Chaudhry, Castle, Watkins. Nanotechnologies in Food. RSC Nanoscience & Nanotechnology, 2010.
6. Safety of Nano-Cosmetics Questioned. NPR Podcast
Yamashita K, Yoshioka Y, Higashisaka K, Mimura K, Morishita Y, Nozaki M, Yoshida T, Ogura T, Nabeshi H, Nagano K, Abe Y, Kamada H, Monobe Y, Imazawa T, Aoshima H, Shishido K, Kawai Y, Mayumi T, Tsunoda S, Itoh N, Yoshikawa T, Yanagihara I, Saito S, & Tsutsumi Y (2011). Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nature nanotechnology, 6 (5), 321-8 PMID: 21460826