Direct Olfactory Transport of Inhaled Manganese (⁵⁴MnCl₂) to the Rat Brain: Toxicokinetic Investigations in a Unilateral Nasal Occlusion Model

Abstract

Inhalation exposure of humans to high concentrations of manganese (Mn) is associated with elevated Mn levels in the basal ganglia and an extrapyramidal movement disorder. In the rat, direct olfactory transport of Mn from the nose to the brain has been demonstrated following intranasal instillation of ⁵⁴MnCl₂. However, the contribution this route makes to brain Mn delivery following inhalation is unknown and was the subject of our study. Male 8-week old CD rats underwent a single 90-min nose-only exposure to a ⁵⁴MnCl₂ aerosol (0.54 mg Mn/m³; MMAD 2.51 μm). The left and right sides of the nose and brain, including the olfactory pathway and striatum, were sampled at 0, 1, 2, 4, and 8 days postexposure. Control rats were exposed to ⁵⁴MnCl₂ with both nostrils patent to evaluate the symmetry of Mn delivery. Another group of rats had the right nostril plugged to prevent nasal deposition of ⁵⁴MnCl₂ on the occluded side. Gamma spectrometry (n = 6 rats/group/time point) and autoradiography (n = 1 rat/group/time point) were used to compare the levels of ⁵⁴Mn found on the left and right sides of the nose and brain to determine the contribution of olfactory uptake to brain ⁵⁴Mn levels. Brain and nose samples from the side with the occluded nostril had negligible levels of ⁵⁴Mn activity, validating the nasal occlusion procedure. High levels of ⁵⁴Mn were observed in the olfactory bulb and tract/tubercle on the side or sides with an open nostril within 1–2 days following inhalation exposure. These results demonstrated, for the first time, that the olfactory route contributes the majority (up to >90%) of the ⁵⁴Mn found in the olfactory pathway, but not in the striatum, of the rat brain up to 8 days following a single inhalation exposure. These findings suggest that the olfactory route may make a significant contribution to brain Mn levels following inhalation exposure in the rat.