Hans Tjälve

Uptake of nickel into the brain via olfactory neurons in rats

Intranasal instillation of nickel ([63]Ni2+) in rats resulted in an uptake of the metal in the olfactory epithelium and a migration along primary olfactory neurons to the glomeruli of the olfactory bulb. The metal was then seen to pass to the interior of the bulb and further to the olfactory peduncle, the olfactory tubercle and the rostral parts of the prepiriform, frontal and cingulate corticis. These results indicate that (63)Ni2+ slowly passes to secondary and tertiary olfactory neurons. Intraperitoneal injection of (63)Ni2+ resulted in a low uptake in the brain, without preferential labelling of the olfactory pathways. Inhalation of nickel compounds can impair the olfactory system. An uptake of nickel in the olfactory neurons may underly these lesions.

Uptake of cobalt from the nasal mucosa into the brain via olfactory pathways in rats

In the olfactory epithelium the primary olfactory neurons are in contact with the environment in the nasal cavity and they are also connected to the olfactory bulbs of the brain. These neurons may therefore provide a pathway by which foreign materials may reach the brain. Inhalation of cobalt-containing dust or fumes occurs in several workplaces, which may result in high exposure of the nasal tissues. In the present study, we used autoradiography and gamma-spectrometry to examine the transport of cobalt in the olfactory system after intranasal administration of 57Co2+ in rats. The results showed an uptake of the metal in the olfactory mucosa and a transport to the olfactory bulbs of the brain. The metal accumulated in the olfactory nerve layer and the terminals of the primary olfactory neurons in the glomerular layer of the bulb. In addition, low levels of cobalt were seen to migrate into the interior of the bulbs and the anterior parts of the olfactory cortex, indicating that the metal is able to leave the terminals of the primary olfactory neurons. Occupational exposure to cobalt, which is a neurotoxic metal, occurs in several workplaces, e.g. the hard metal industry. Memory deficits have been observed among workers exposed to hard metal via inhalation, and it was considered that cobalt may be the neurotoxic component of the hard metal. We propose that inhaled hard metal (as a dust powder or in a mist form) is deposited in the nasal passages and that released cobalt, after uptake into the brain via the olfactory pathway, may cause neurotoxicity. We consider that the olfactory route of entry of cobalt into the brain may be important and should be taken into account when risk assessments are performed concerning occupational inhalation of this metal.

Tissue disposition of 109cd2+ in the brown trout (Salmo trutta) studied by autoradiography and impulse counting †

Brown trouts, Salmo trutta, were exposed to 109Cd2+ in concentrations of 0.1, 0.5, 1.0 and 10.0 μg/1 in aquarial water during 1 or 2 weeks. The disposition of the 109Cd2+ in the tissues was then examined by whole‐body autoradiography and gamma spec‐trometry. The tissues accumulating the highest levels of 109Cd2+ were the olfactory apparatus, the gills and the trunk kidney. The autoradiography showed that in the olfactory apparatus there was a labelling of the epithelium of the olfactory rosette, the olfactory nerve and the anterior part of the olfactory bulb of the brain. The cadmium is probably taken up in the nerve cells in the olfactory epithelium and transported via axonal transport to the axonal terminations in the olfactory bulb of the brain. The 109Cd2+ in the gills comprised from about 75% to about 40% of the total body burden of the metal, the highest proportions being present at the lowest cadmium concentrations in the water and at the 1 week exposure interval. The 109Cd2+ in the kidney, which w...

Transport and subcellular distribution of intranasally administered zinc in the olfactory system of rats and pikes

Zinc is an essential element, which can act as a neuromodulator and also is bound in zinc proteins in the brain. The olfactory bulb contains high concentrations of zinc. In the present study, 65Zn(2+) was applied on the olfactory epithelium of rats and pikes and the transport of the metal in the olfactory system was then examined. Administration of 65Zn(2+) in the nasal cavity of rats or the olfactory chambers in pikes resulted in an uptake of the metal in the olfactory epithelium and a transport of the metal along the primary olfactory neurons to their terminations in the olfactory bulbs. Low levels of 65Zn(2+) passed these terminals and continued into the interior of the bulbs. In the rats 65Zn(2+) was also detected in the anterior parts of the olfactory cortex. Subcellular fractionations of the olfactory mucosa and olfactory bulb of rats given 65Zn(2+) intranasally showed that the metal is bound both to particulate cellular constituents and to cytosolic components in these tissues. Gel chromatography indicated that some of the zinc in the cytosol is bound to metallothionein in the olfactory mucosa and bulb. Inhalation of zinc-containing dusts or fumes occurs in some work-places and may imply high exposure of the nasal tissues. It is not known whether neurotoxicity may be related to uptake of zinc in the olfactory system. However, this is an issue which deserves attention, since zinc dysregulation has been implied to play a role in Alzheimers disease. In addition, impairment of the sense of smell and degenerative changes of the olfactory tissues have been seen in early stages of some neurodegenerative disorders.

Uptake of 203Hg2+ in the olfactory system in pike

Inorganic mercury (203Hg2+) was applied to the olfactory chambers or was given i.v. to pike (Esox lucius) and the uptake of the metal in the olfactory system and the brain was examined by autoradiography and gamma spectrometry. Application of 203Hg2+ in the olfactory chambers resulted in an accumulation of the metal in the olfactory nerves and the anterior parts of the olfactory bulbs of the brain. The levels of 203Hg2+ in other brain areas, such as the telencephalon, the optic tecti and the cerebellum, remained low. Application of 203Hg2+ in only one olfactory chamber resulted in an uptake of the metal only in the ipsilateral olfactory nerve and olfactory bulb. Intravenous injection of the 203Hg2+ resulted in a labelling of the olfactory system and the brain, which was much lower than of the blood. These results indicate that the 203Hg2+ is taken up in the olfactory neurones from the olfactory receptor cells in the olfactory rosettes and is transported to the terminal parts of the olfactory neurones in the olfactory bulbs. The uptake of mercury as well as some other metals in the olfactory system may result in noxious effects and this may be an important component in the toxicology of metals in fish.

Extrahepatic bioactivation of aflatoxin B1 in fetal, infant and adult rats

Whole-body autoradiography of 3H-labelled aflatoxin B1 (3H-AFB1) in female non-pregnant adult and infant Sprague-Dawley rats showed retention of tissue-bound radioactivity, in addition to the liver, in the mucosa and some glands in the nose, and in the mucosa of the nasopharynx, trachea, bronchioles, colon and caecum. The extrahepatic binding was most pronounced in the infant rats. In a rat pretreated with the glutathione (GSH)-depleting agent phorone, bound labelling was also seen in the superficial part of the mucosa of the glandular stomach. Autoradiography of 3H-AFB1 in pregnant rats showed a marked localization of bound AFB1-metabolites in the fetal nasal olfactory and tracheal mucosa. In vitro experiments demonstrated that the nasal olfactory mucosa had a much higher capacity than the liver to form AFB1-metabolites which bound to DNA and protein. The bioactivation was observed both pre- and post-natally and increased with age. Bioactivation was found also in the caecum, the colon and the lateral nasal gland (Stenos gland), but not in the small intestine, oesophagus or Harderian gland. Our results indicated that glutathione-S transferase activity catalysing the AFB1-8,9-epoxide GSH-conjugation was present in the nasal olfactory mucosa and liver at all pre- and post-natal ages examined. Several of the extrahepatic tissues able to bioactivate AFB1 have been reported to be targets for the carcinogenicity of the substance. Our results indicate that the extrahepatic carcinogenicity of AFB1 is correlated to a local bioactivation in the sensitive tissues.

Effect of thiuram sulphides on the uptake and distribution of nickel in pregnant and non-pregnant mice.

Oral administration of 63Ni2+ together with thiuram sulphides (tetramethylthiuram disulphide, tetraethylthiuram disulphide, tetrabutylthiuram disulphide, dipentamethylenethiuram monosulphide or dipentamethylenethiuram tetrasulphide) or sodium diethyldithiocarbamate resulted in highly increased levels of 63Ni2+ in several tissues of mice in comparison with animals given 63Ni2+ alone. Administration of these substances to pregnant animals induced increased levels of 63Ni2+ in the fetuses. The uptake of 63Ni2+ in the brains of both adults and fetuses was usually very markedly enhanced by these compounds--dipentamethylenethiuram monosulphide and tetraethylthiuram disulphide being the most efficient compounds in this respect. Determination of the chloroform/water partition coefficients for nickel in the presence of thiuram sulphides or sodium diethyldithiocarbamate showed that these compounds are able to form lipophilic complexes with the metal. A facilitated penetration through the cellular membranes of the lipophilic complexes between nickel and these substances can explain the effects on the fate of the nickel. However, the partition coefficient for nickel in presence of sodium diethyldithiocarbamate was much higher than for the thiuram sulphides, but in spite of that, the effect of sodium diethyldithiocarbamate on the disposition of 63Ni2+ in the mice was not more marked than for most of the thiuram sulphides. It has been shown that tetraethylthiuram disulphide undergoes a reductive fission in the gut to diethyldithiocarbamate, which is considered to be the active form of tetraethylthiuram disulphide. The marked effects on the disposition of the 63Ni2+ induced by the other thiuram sulphides examined in the present study suggest that a similar fission to chelating thiocarbamates will take place. However, the formation of lipophilic complexes with the original thiuram sulphides may contribute to the effects on the disposition of the 63Ni2+.

Effect of dietary iron-deficiency on the disposition of nickel in rats

Nickel was given orally to iron-deficient and iron-sufficient rats and the levels of the metal in various tissues were examined at several time intervals. The results showed higher levels of nickel in the tissues of the iron-deficient rats, as compared to the iron-sufficient ones, 3, 6, 24, 48 and 120 h following gastric intubation of the metal. The results also showed higher levels of the metal in some tissues of iron-deficient rats than in iron-sufficient ones 24 h after intra-peritoneal nickel administration. A lower urinary excretion of nickel was observed in the iron-deficient rats given the intraperitoneal injections, as compared to the iron-sufficient animals. Our results indicate that nickel, at least in part, is taken up by the absorptive mechanism for iron in the intestinal epithelium. In addition, the iron-status appears to affect the uptake of nickel from the blood into the tissues.

Cell-specific activation of aflatoxin B1 correlates with presence of some cytochrome P450 enzymes in olfactory and respiratory tissues in horse

Horses may be exposed to aflatoxin B(1) (AFB(1)) via inhalation of mouldy dust, leading to high exposure of olfactory and respiratory tissues. In the present study the metabolic activation of AFB(1) was examined in olfactory and respiratory tissues in horse. The results showed covalent binding of AFB(1)-metabolites in sustentacular cells and cells of Bowmans glands in the olfactory mucosa, in some cells of the surface epithelium of nasal respiratory, tracheal, bronchial and bronchiolar mucosa and in some glands in these areas. Immunohistochemistry revealed that cells expressing proteins reacting with CYP 3A4- and CYP 2A6/2B6-antibodies had a similar distribution as those having capacity to activate AFB(1). Our data indicate that the cell-specific activation of AFB(1) correlates with presence of some CYP-enzymes in olfactory and respiratory tissues in horse.

Cellular activation and neuronal transport of intranasally instilled benzo(a)pyrene in the olfactory system of rats

Nasal tissues can be exposed to benzo(a)pyrene (BaP), e.g. present in diesel exhaust particles and some workplace atmospheres. In this study rats were given 3H-BaP intranasally. Autoradiography and beta-spectrometry were then used to trace cells in the nasal olfactory mucosa having capacity to activate the compound to tissue-bound metabolites. We also examined if deposition of 3H-BaP on the olfactory mucosa results in translocation of labelled material to the brain along olfactory neurons. The results showed that intranasal administration of 3H-BaP results in formation of tissue-bound metabolites in sustentacular cells and in the cells of Bowmans glands. Initially the bound material was localised to a higher extent to the sustentacular cells than to the cells of Bowmans glands, whereas at longer survival intervals the uptake in the cells of Bowmans glands dominated. In the latter the covalently bound material was accumulated to a higher extent in the nuclei than in the cytoplasms. We speculate that BaP may interact with the aryl hydrocarbon receptor (AhR) in these cells and that AhR may target activated BaP to the nucleus. Our results further indicated that application of 3H-BaP on the nasal mucosa results in transport of BaP and/or BaP-metabolites along the axons of the olfactory neurons to the olfactory bulb.