Ultrafine particles (UFP) with a diameter of ≤0.1 μm, are contributors to ambient air pollution and derived mainly from traffic emissions, yet their health effects remain poorly characterized. The olfactory mucosa (OM) is located at the rooftop of the nasal cavity and directly exposed to both the environment and the brain. Mounting evidence suggests that pollutant particles affect the brain through the olfactory tract, however, the exact cellular mechanisms of how the OM responds to air pollutants remain poorly known. Here we show that the responses of primary human OM cells are altered upon exposure to UFPs and that different fuels and engines elicit different adverse effects. We used UFPs collected from exhausts of a heavy-duty-engine run with renewable diesel (A0) and fossil diesel (A20), and from a modern diesel vehicle run with renewable diesel (Euro6) and compared their health effects on the OM cells by assessing cellular processes on the functional and transcriptomic levels. Quantification revealed all samples as UFPs with the majority of particles being ≤0.1 μm by an aerodynamic diameter. Exposure to A0 and A20 induced substantial alterations in processes associated with inflammatory response, xenobiotic metabolism, olfactory signaling, and epithelial integrity. Euro6 caused only negligible changes, demonstrating the efficacy of aftertreatment devices. Furthermore, when compared to A20, A0 elicited less pronounced effects on OM cells, suggesting renewable diesel induces less adverse effects in OM cells. Prior studies and these results suggest that PAHs may disturb the inflammatory process and xenobiotic metabolism in the OM and that UFPs might mediate harmful effects on the brain through the olfactory route. This study provides important information on the adverse effects of UFPs in a human-based in vitro model, therefore providing new insight to form the basis for mitigation and preventive actions against the possible toxicological impairments caused by UFP exposure.

A 1 Virtanen Institute for Molecular Sciences University of Eastern Finland 70210 Kuopio Finland

Aerosol Physics Laboratory Physics Unit Tampere University 33014 Tampere Finland

Department of Computer Science University of Verona 37134 Verona Italy

Department of Genetic Toxicology and Epigenetics Institute of Experimental Medicine of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Department of Neurology Neuro Centre Kuopio University Hospital 70210 Kuopio Finland

Department of Neurology Neuro Centre Kuopio University Hospital 70210 Kuopio Finland; Brain Research Unit Department of Neurology School of Medicine University of Eastern Finland 70210 Kuopio Finland; Department of Neurology and Geriatrics Helsinki University Hospital and Neurosciences Faculty of Medicine University of Helsinki 00014 Helsinki Finland

Department of Otorhinolaryngology University of Eastern Finland and Kuopio University Hospital 70210 Kuopio Finland

Inhalation Toxicology Laboratory Department of Environmental and Biological Sciences University of Eastern Finland 70211 Kuopio Finland

VTT Technical Research Centre of Finland VTT 02044 Espoo Finland

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