PhD abstract
The emergence of nanopesticides (NPe), novel agrochemicals which include nanomaterials (NM) within pesticide formulations, raises questions regarding the health effects of these nano-enabled products that may be inhaled after being sprayed. No study has yet explored the inhalation effects of substances mixing pesticides and NM, although these compounds might be able to exert neurotoxic effects, especially when exposures occur during critical life stages, such as neurodevelopment. Therefore, as the chemicals used in the NPe formulation could potentially cause cocktail effects which are currently not addressed, the development of new study models is essential to assess the health risk associated with these new technologies. This interdisciplinary study encompassed a metrological phase describing the development of an aerosol exposure device dedicated to rodents. As part of an approach aiming to harmonize toxicological protocols, this device must fulfill the requirements of inhalation toxicology studies, in order to offer a reliable and reproducible exposure procedure. In a second part, this manuscript presents an in vivo study carried out with mice thanks to the ad hoc device, which were used to produce aerosols involving two substances, the paraquat herbicide (PQ), titanium dioxide nano-objects (nTiO2) and their mixture modelling a NPe. The objective of this phase was the evaluation of the neurotoxic effects resulting from repeated exposures to our aerosols of interest, in particular to study the occurrence of cocktail effects on the brain. A whole-body exposure chamber was set up and metrologically characterized. It is a versatile device, which can be operated in various studies using several rodent species or scenarios of exposure. The generated aerosols were characterized in terms of mass and number concentrations, size distribution and atmosphere homogeneity and the proper functioning of the facility was then evaluated on the field. The different parameters monitored during its characterization were found to be stable, thus validating the suitability of this new exposure chamber as a tool to explore aerosol inhalation effects. Gene expression was assessed in the striatum of pups using RNA-seq, to highlight dysregulations in response to the aerosol exposure during gestation. Despite the use of low doses considered theoretically safe, aerosol exposures induced alterations in gene expression, which supports the idea that PQ and nTiO2 may both have adverse effects on neurodevelopment. The exposures of adult mice for several weeks also showed that nTiO2 inhalation could induce neurotoxic effects on the dopaminergic neurons. Although no synergistic effect was observed, the data suggested that interactions between these two substances occurred by modulating their toxicological effects. Finally, the findings underlined that the prenatal phase is essential in the assessment of the health risk associated with exposure to atmospheric pollutants such as NPe, which confirms the need to use in vivo methods depicting realistic exposure scenarios.
Key words
Aerosol exposure chamber, Inhalation toxicology study, Nanopesticide, nanomaterial, Pesticide, Neurodevelopment, TiO2, Paraquat