Maternal-fetal distribution of manganese in the rat following inhalation exposure to manganese sulfate.

Studies examining the pharmacokinetics of manganese during pregnancy have largely focused on the oral route of exposure and have shown that the amount of manganese that crosses the rodent placenta is low. However, limited information exists regarding the distribution of manganese in fetal tissues following inhalation. The objective of this study was to determine manganese body burden in CD rats and fetuses following inhalation of a MnSO4 aerosol during pregnancy. Animals were evaluated following pre-breeding (2 weeks), mating (up to 14 days) and gestational (from gestation day (GD) 0 though 20) exposure to air or MnSO4 (0.05, 0.5, or 1 mg Mn/m(3)) for 6h/day, 7 days/week. The following maternal samples were collected for manganese analysis: whole blood, lung, pancreas, liver, brain, femur, and placenta. Fetal tissues were examined on GD 20 and included whole blood, lung, liver, brain, and skull cap. Maternal lung manganese concentrations were increased following exposure to MnSO4 at >or=0.05 mg Mn/m(3). Maternal brain and placenta manganese concentrations were increased following exposure of pregnant rats to MnSO4 at >or=0.5 mg Mn/m(3). Increased fetal liver manganese concentrations were observed following in utero exposure to MnSO4 at >or=0.5 mg Mn/m(3). Manganese concentrations within all other fetal tissues were not different from air-exposed controls. The results of this study demonstrate that the placenta partially sequesters inhaled manganese, thereby limiting exposure to the fetus.

Tissue manganese concentrations in lactating rats and their offspring following combined in utero and lactation exposure to inhaled manganese sulfate.

There is little information regarding the tissue distribution of manganese in neonates following inhalation. This study determined tissue manganese concentrations in lactating CD rats and their offspring following manganese sulfate (MnSO4) aerosol inhalation. Except for the period of parturition, dams and their offspring were exposed to air or MnSO4 (0.05, 0.5, or 1 mg Mn/m3) for 6 h/day, 7 days/week starting 28 days prior to breeding through postnatal day (PND) 18. Despite increased manganese concentrations in several maternal tissues, MnSO4 inhalation exposure did not affect body weight gain, terminal (PND 18) body weight, or organ weights in the dams. Exposure to MnSO4 at 1 mg Mn/m3 resulted in decreased pup body weights on PND 19 and decreased brain weights in some PND 14 to PND 45 pups. Exposure to MnSO4 at > or =0.05 mg Mn/m3 was associated with increased stomach content, blood, liver, and skull cap manganese concentrations in PND 1 pups, increased brain, lung, and femur manganese concentrations in PND 14 pups, and elevated olfactory bulb, cerebellum, and striatum manganese concentrations in PND 19 pups. When compared to controls, MnSO4 exposure to > or =0.5 mg Mn/m3 increased liver and blood manganese concentrations in PND 14 pups and increased liver, pancreas, and femur manganese concentrations in PND 19 pups. Manganese concentrations returned to control values in all offspring tissues by PND 45 +/- 1. Our data demonstrate that neonatal tissue manganese concentrations observed following MnSO4 inhalation are dependent on the MnSO4 exposure concentration and the age of the animal.

Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following subchronic (13-week) inhalation exposure.

Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to further characterize the nasal toxicity of manganese sulfate (MnSO(4)) and manganese phosphate (as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnSO(4) (0.01, 0.1, and 0.5 mg Mn/m(3)), or hureaulite (0.1 mg Mn/m(3)). Nasal pathology, brain GFAP levels, and brain manganese concentrations were assessed immediately following the end of the 90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO(4) exposure to > or = 0.01, > or = 0.1, and 0.5 mg Mn/m(3), respectively. Exposure to MnSO(4) or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure to MnSO(4) (0.5 mg Mn/m(3)) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, we could not confirm that manganese inhalation would result in altered brain GFAP concentrations.

Inhaled iron, unlike manganese, is not transported to the rat brain via the olfactory pathway.

Iron and manganese share structural, biochemical, and physiological similarities. The objective of this study was to determine whether iron, like manganese, is transported to the rat brain via the olfactory tract following inhalation exposure. Eight-week-old male CD rats were exposed to approximately 0.31 mg Fe per m(3) (mass median aerodynamic diameter = 2.99 microm; geometric standard deviation = 1.15) via inhalation for a target duration of 90 min. Following exposure, rats were euthanized immediately (0) or at 1, 2, 4, 8, or 21 days postexposure. In addition to nasal and regional brain tissues, blood, and viscera were also collected. 59Fe concentrations were determined by gamma spectrometry. Further, heads were collected and frozen, and autoradiograms were prepared to visualize the location of 59Fe from the nose to the brain. Finally, olfactory mucosa samples collected at 0, 2, 4, and 21 days postexposure were further analyzed using high-performance liquid chromatography (HPLC) plus gamma spectroscopy to determine the association between 59Fe and transferrin. Data obtained from gamma spectrometry revealed that most of the iron remained in the nasal regions of the olfactory system and that less than 4% of iron deposited on the olfactory mucosa was observed in the olfactory bulb. Autoradiograms confirmed the data obtained from gamma spectrometry. 59Fe activity was absent in the olfactory regions of the brain even 4 days postexposure. Further, HPLC-gamma spectroscopy analyses indicated that 59Fe in the olfactory mucosa was coeluted with transferrin. Hence iron, unlike manganese, is not readily transported to the brain via the olfactory tract.

Olfactory transport: a direct route of delivery of inhaled manganese phosphate to the rat brain.

Experiments examining the dosimetry of inhaled manganese generally focus on pulmonary deposition and subsequent delivery of manganese in arterial blood to the brain. Growing evidence suggests that nasal deposition and transport along olfactory neurons represents another route by which inhaled manganese is delivered to certain regions of the rat brain. The purpose of this study was to evaluate the olfactory uptake and direct brain delivery of inhaled manganese phosphate ((54)MnHPO(4)). Male, 8-wk-old, CD rats with either both nostrils patent or the right nostril occluded underwent a single, 90-min, nose-only exposure to a (54)MnHPO(4) aerosol (0.39 mg (54)Mn/m(3); MMAD 1.68 microm, sigma(g) 1.42). The left and right sides of the nose, olfactory pathway, striatum, cerebellum, and rest of the brain were evaluated immediately after the end of the (54)MnHPO(4) exposure and at 1, 2, 4, 8, and 21 d postexposure with gamma spectrometry and autoradiography. Rats with two patent nostrils had equivalent (54)Mn concentrations on both sides of the nose, olfactory bulb, and striatum, while asymmetrical (54)Mn delivery occurred in rats with one occluded nostril. High levels of (54)Mn activity were observed in the olfactory bulb and tubercle on the same side (i.e., ipsilateral) to the open nostril within 1-2 d following (54)MnHPO(4) exposure, while brain and nose samples on the side ipsilateral to the nostril occlusion had negligible levels of (54)Mn activity. Our results demonstrate that the olfactory route contributes to (54)Mn delivery to the rat olfactory bulb and tubercle. However, this pathway does not significantly contribute to striatal (54)Mn concentrations following a single, short-term inhalation exposure to (54)MnHPO(4).