Nanoparticles and neurotoxicity: new insights but still too many gray areas

Three publications in particular caught our attention this summer. Their common point? The study of the possible effects of certain nanoparticles on the brain, on the barrier that protects it and on the functioning of certain neurons. Their results, which are relatively worrying, plead for the intensification of research efforts on the neurotoxicity of nanos, insufficiently studied until now.

Some nanos manage to cross the barrier supposed to protect our brain

Un ticket posted on the website of the European Nanomaterials Observatory (EUON) in mid-September relays the results of a survey published last summer showing that certain nanoscale substances can cross – and even damage – the blood-brain barrier (BHE) which usually protects the brain from pathogens and toxins circulating in the blood. The study was carried out on an artificial model imitating the human BBB. If the nanos are considered in nanomedicine as an interesting avenue for developing vectors capable of crossing the BBB and transporting medicinal substances to the brain in order to treat certain neurological pathologies, it is on the other hand much less desirable that our brain be exposed, the rest of the time , to manufactured nanoparticles present in the air, water or products around us (and which would have managed to pass into the bloodstream after having crossed other barriers: pulmonary, intestinal or dermal). 

However, all nanoparticles do not necessarily seem capable of crossing this barrier; the size, shape or solubility of nano substances are decisive, even more so than their concentration.

According to researcher Eugenia Valsami-Jones from the University of Birmingham who co-authored the aforementioned post and scientific paper, smaller particles and spherical particles are more likely to pass through the BBB than larger particles or fibrous form.

Other key information: the silver and zinc oxide nanoparticles studied can cross the BBB, unlike the cerium or iron oxide nanoparticles – the latter having a very low solubility in the liquid medium used for the culture of human cells used in this artificial BBB model.

Although only a small part of the nanoparticles ultimately reaches the brain (the rest of the nanoparticles being redirected to the bloodstream side), these results raise the crucial question of the short, medium and long-term effects of exposure to our nervous system to nanoparticles.

The publication of this study comes ten years after that of the CEA, widely relayed at the time, attesting to a possible passage of titanium dioxide nanoparticles through an artificial model of BBB based on rodent cells).
What happened in the meantime? Is this fundamental subject the subject of other research projects today?
AVICENN is interested in any element on this subject, especially since the nanomaterials that can cross the blood-brain barrier are also likely to damage it in passing – at the risk of making it more permeable to other potentially neurotoxic products (this is the so-called “Horse effect”). of Troy"). 

What adverse effects of nanos on (and via) neurons?

Damage to brain functions had already been reported in animals as a result of exposure to various nanomaterials, with the effects – direct or indirect – of cognitive problems, memory and learning disorders, degeneration nerve cells or even neuronal death and brain damage, a decline in locomotor skills¹See our sheet on the effects of nanos on health, paragraph “Effects on the brain and nervous system”).

Last year, work by Eugenia Valsami-Jones cited above showed that nanoparticles of silver and zinc oxide that have passed through the BBB can then harm astrocytes  (central nervous system cells that control and modulate neuronal activity).

And this summer, two studies conducted by French teams and published in the journal Particle and Fiber Toxicology came to enrich the table (still fragmented) of the potential attacks of nanos on the neuronal activity.

A pro-Alzheimer effect of nanoparticles of titanium dioxide and carbon black?

A survey published in July by researchers from theINSERM, CNRS and ANSES shows for the first time that nanoparticles of titanium dioxide and carbon black, once in contact with mouse neurons in culture, can trigger the expression of molecular signals specific to those expressed in Alzheimer's disease, this neurodegenerative disease that causes progressive loss of memory and certain intellectual functions.

As a reminder, these nanoparticles are at the top of the ranking in the tonnages of nanos declared in the French r-nano registry (between 10 and 100 tons each year for each of these nano substances). 

However, these nanoparticles trigger a cascade of intra-cellular molecular events leading to…:

• to the overexpression of a receptor on the surface of these neurons which increases their sensitivity to an inflammatory state, an observation confirmed in vivo in mice;
• and an accumulation of Aβ peptides, neurotoxic known and observed in Alzheimer's disease.

While more research is needed to definitively establish a causal link between exposure to nanoparticles and Alzheimer's disease, this study provides novel insight into how certain nanoparticles might contribute to the development of neurodegenerative diseases. 

An alteration of neurons involved in respiratory function associated with exposure to TiO2 nanoparticles during fetal life 

The other survey conducted by researchers from Bordeaux (INCIA, ICMCB) and published in August 2022 in the same journal Particle and Fiber Toxicology shows that daily exposure of mice to titanium dioxide nanoparticles during gestation leads to respiratory hyperventilation in newborn mice. Pregnant mice ingested chocolate spread throughout the gestation period (approximately 19 days) – with or without the addition of TiO nanoparticles₂. After birth, during the first week of life of newborns, the researchers observed a significantly higher respiratory rate in previously exposed mice. in utero with TiO nanoparticles₂ compared to that of pups whose mothers had not been exposed. In addition, their respiratory ability to adapt to exciting environmental stimuli (such as an increase in ambient temperature, for example) is less than that of the control group. However, respiratory regulation can prove to be decisive, particularly in young individuals, who are inherently more vulnerable. 

By combining approaches in vivo et ex vivo on preparations isolated from the brainstem containing the nerve centers controlling respiratory function, this study shows that exposure to nanoparticles of TiO₂ during fetal life can lead to impaired respiratory function through damage to the associated nerve centers during the first days of life²As a reminder, in 2020, INRAE ​​researchers had shown than TiO nanoparticles₂ such as those present in E171 can pass through the placenta (another important physiological barrier), and that the human fetus is, in fact, exposed to it in utero.
Note: TiO nanoparticles₂ (P25) used in these two studies are close to those used in particular in certain sunscreens, but are significantly different from those present in the additive E171 (now prohibited in food but still present in medicines) for which the evaluation of potential neurotoxicity requires additional studies. 

Essential challenges to be met in nano-neurotoxicology   

These studies raise questions about the neurotoxicity of certain nanomaterials³See Nano- and neurotoxicology: An emerging discipline, Bencsik A et al., Prog Neurobiol., 160:45-63, January 2018 and other publications listed in our sheet on the effects of nanos on health, paragraph “Effects on the brain and nervous system”). In any case, they testify to the many shortcomings in this area, which can partly be explained by the many obstacles that remain to be overcome in order to study the neurotoxicity of nanomaterials more specifically. A important article published in 2021 in the journal Frontiers in Toxicology list in this respect the challenges to be met in the field of nano-neurotoxicology. They are firstly of a scientific and methodological nature: the heterogeneity of nanomaterials (whose toxicity is likely to vary according to their physico-chemical characteristics), combined with the very great diversity of possible interactions between these nano-objects and the different biological environments, make these studies complex. But the challenges are also political, regulatory and pedagogical with training in the requirements of this discipline. Close attention should be given to the recommendations made by the authors of the article, Anna Bencsik (ANSES) and Philippe Lestaevel (IRSN), in order to advance understanding and precaution with regard to nanomaterials and their effects on the nervous system. More cooperation and political and financial support are, among other things, absolutely necessary – both nationally and internationally. What are the research projects on these questions today? Who are the actors mobilized on this subject (researchers or research teams, industrialists, health authorities, others)? Is specific funding dedicated to it?
In our “knowledge society”, there is an urgent need to intensify research on what constitutes, according to the researchers themselves, one of the major challenges of neurotoxicology in the 21st century.