Biomedical Engineering Reference
In-Depth Information
the concentration of some elements in the excreted feces with respect to the control group.
This response to silica was divided into a short-term and a long-term response. The short-term
response was observed by the increase of excreted potassium (K) (up to 60%) from acute admin-
istration. No significant changes in K were found in subacute administration, but it was observed
that fecal calcium (Ca), phosphorous (P), and magnesium (Mg) excretion was time-dependent
and increased (up to 29%, 18%, and 39% at day 28 for Ca, P, and Mg, respectively), probably
due to a decreased absorption of these elements as a result of silica administration. These incre-
ments present an increasing statistical significance, especially at day 28 (end of the subacute
study) with respect to other days (Omar et al. 2012). A decrease in the absorption of Ca and P is
of special importance because both Ca
2+
and
PO
3−
ions control many essential cellular processes
(Clapham 2007). Such a decrease in Ca and P, although not inducing an immediate short-term
toxicity effect or perceptible damage on either the GI tract or liver and kidneys, may have some
long-term repercussions such as changes in mitochondrial function, apoptotic cell death, or bone
metabolism (Clapham 2007).
Isabelle et al. studied the cytotoxicity of different sizes of nano-SiO
2
, investigated on two renal
proximal tubular cell lines, human HK-2 and porcine LLC-PK1. The molecular pathways involved
were studied with a focus on the involvement of oxidative stress. Specific inhibitors of endocytic
pathways showed an internalization process by macropinocytosis and clathrin-mediated endocy-
tosis for 100 nm nano-SiO
2
nanoparticles. Silica particles are known to induce nephropathy in
workers by direct and indirect toxic effects via the deposition of particles in the renal parenchyma
(Steenland et al. 2002; Isabelle et al. 2012).
In this study, proximal tubular (human HK-2, porcine LLC-PK1) cell lines were used to assess
the potential toxicity of nano-SiO
2
on kidney cells. The analysis of the mechanism involved was
based on the study of oxidative stress. A study demonstrated that nano-SiO
2
are internalized into the
cell and especially localized in the cytoplasm. Studies also indicate that nano-SiO
2
is toxic on kid-
ney cells and that their toxicity depends mainly on their size. Cell mortality increased significantly
in LLC-PK1 as their size decreased, with a CI
50
value sevenfold lower than that at 100 nm (Isabelle
et al. 2012). Wang et al. reported that cytotoxicity was size- and time-dependent, with 20 nm silica
nanoparticles being more cytotoxic than larger ones (50 nm). It appears that below 30 nm, changes
in the structure increase the toxic potential due to variations in surface reactivities (Auffan et al.
2009a; Wang et al. 2009a).
For a mechanistic point of view, the production of ROS in kidney cells was significantly increased
after exposure to nano-SiO
2
, notably at 20 nm. As previously described on other cell types, the gen-
eration of ROS is size-dependent (Wang et al. 2009b; Napierska et al. 2010; Ye et al. 2010; Nabeshi
et al. 2011; Gong et al. 2012). This effect is also dependent on the surface area of nano-SiO
2
. Indeed,
20 nm nano-SiO
2
has a surface area which is found to be about fivefold more important as compared
to 100 nm and produced significant oxidative stress in tubular cells compared to 100 nm particles,
suggesting great surface reactivity at 20 nm. A high reactivity could lead to toxicity due to impor-
tant nanoparticles interactions with biological systems and the cellular environment. Moreover,
some authors suggest that the size-dependent toxic effect is caused by a different mechanism of
ROS generation. In fact, the amount of hydroxyl radical generated in cellular models is highly
dependent on the size, with high ROS production in 14 nm particles as compared to 100 and 500 nm
silica nanoparticles (Shang et al. 2009).
Therefore, the toxic effects seem to be triggered by oxidative stress, as evidenced by great
anion superoxide productions with 20 nm nano-SiO
2
. This generation of primary ROS seems to
occur through a mechanism that involves NADPH oxidase (Ushio-Fukai 2006; Nabeshi et al.
2011). After the ingestion of the xenobiotic into endosomes, NADPH oxidase is activated and
generates ROS (Nabeshi et al. 2011). The anion superoxide formed could lead to the formation of
radical hydroxyl, which is more reactive and destructive for cells. This radical hydroxyl induces
the destruction of the membrane structure via the peroxidation of unsaturated lipids. This leads
to a loss of physiological cellular integrity, resulting in cell death. The increase in ROS levels
