Uranium crosses the blood-brain barrier, new evidence.

[Kathy]

I thought some of you might find these studies of interest. Both are examples of chronic exposure to uranium via ingestion.

The first study determined that the uranium was only absorbed into the body via the small intestine. Not the mouth (buccal cavity) and not the large intestine (proximal colon). No, only via the small intestine. Interestingly, the distal ileum is part of the small intestine. The distal ileum is classified a specified risk material (SRM).

(1) Int. J. Radiat. Biol. 2005 Jun;81(6):473-82

Absorption of uranium through the entire gastrointestinal tract of the rat.

Dublineau I, Grison S, Baudelin C, Dudoignon N, Souidi M, Marquette C, Paquet F, Aigueperse J, Gourmelon P.

Institut de Radioprotection et de Surete Nucleaire, Direction de la RadioProtection de l'Homme, Service de Radiobiologie et d'Epidemiologie, Laboratoire de Radiotoxicologie experimentale, Fontenay-aux-Roses Cedex, France. [email protected].

The aim was to determine the gastrointestinal segments preferentially implicated in the absorption of uranium. The apparent permeability to uranium (233U) was measured ex vivo in Ussing chambers to assess uranium passage in the various parts of the small and large intestines. The transepithelial electrical parameters (potential difference, short-circuit current, transepithelial resistance and tissue conductance) were also recorded for each segment. Determination of in vivo uranium absorption after in-situ deposition of 233U in digestive segments (buccal cavity, ileum and proximal colon) and measurements of uranium in peripheral blood were then made to validate the ex vivo results. In addition, autoradiography was performed to localize the presence of uranium in the digestive segments. The in vivo experiments indicated that uranium absorption from the digestive tract was restricted to the small intestine (with no absorption from the buccal cavity, stomach or large intestine). The apparent permeability to uranium measured with ex vivo techniques was similar in the various parts of small intestine. In addition, the experiments demonstrated the existence of a transcellular pathway for uranium in the small intestine. The study indicates that uranium absorption from the gastrointestinal tract takes place exclusively in the small intestine, probably via a transcellular pathway.

PMID: 16249162 [PubMed - indexed for MEDLINE]

In this second study, they analysed whether using acute exposure results held true during chronic exposure to uranium. The results did not hold true. Chronic exposure to rats in their drinking water resulted in accummulation of uranium in their teeth and in their BRAINS. It is recommended that chronic exposure modelling be further looked into.

(2) Health Phys. 2006 Feb;90(2):139-147. LWWonline – Lippincott Williams & Wilkins

ACCUMULATION AND DISTRIBUTION OF URANIUM IN RATS AFTER CHRONIC EXPOSURE BY INGESTION.

Paquet F, Houpert P, Blanchardon E, Delissen O, Maubert C, Dhieux B, Moreels AM, Frelon S, Gourmelon P.

* IRSN/DRPH/SRBE Laboratoire de Radiotoxicologie Experimentale, BP 166, 26702 Pierrelatte, Cedex, France; dagger IRSN/DRPH/SDI/Laboratoire d'Evaluation de la Dose Interne, BP17, 92262 Fontenay aux Roses, Cedex, France; double dagger IRSN/DRPH, BP17, 92262 Fontenay aux Roses, Cedex, France.

Data describing the biokinetics of radionuclides after contamination come mainly from experimental acute exposures of laboratory animals and follow-up of incidental exposures of humans. These data were compiled to form reference models that could be used for dose calculation in humans. In case of protracted exposure, the same models are applied, assuming that they are not modified by the duration of exposure. This work aims at testing this hypothesis. It presents new experimental data on retention of uranium after chronic intake, which are compared to values calculated from a biokinetic model that is based on experiments of acute exposure of rats to uranium. Experiments were performed with 56 male Sprague Dawley rats, from which 35 were exposed during their whole adult life to 40 mg L of uranyl nitrate dissolved in mineral water and 21 were kept as controls. Animals were euthanatized at 32, 95, 186, 312, 368, and 570 d after the beginning of contamination. Urine and all tissues were removed, weighted, mineralized, and then analyzed for uranium content by Kinetics Phosphorescence Analysis (KPA) or by ICP-MS. Experimental data showed that uranium accumulated in most organs, following a nonmonotonous pattern. Peaks of activities were observed at 1-3, 10, and 19 mo after the beginning of exposure. Additionally, accumulation was shown to occur in tissues such as teeth and brain that are not usually described as target organs. Comparison with model prediction showed that the accumulation of uranium in target organs after chronic exposure is overestimated by the use of a model designed for acute exposure. These differences indicate that protracted exposure to uranium may induce changes in biokinetic parameters when compared to acute contamination and that calculation of dose resulting from chronic intake of radionuclides may need specific models that are not currently available.

In this third study, acute exposure to depleted uranium (injected intraperitoneally) caused neurotoxic effects. It definitely crossed through the blood-brain barrier.

Toxicology 2005 Sep 1;212(2-3):219-26
The brain is a target organ after acute exposure to depleted uranium.

Lestaevel P, Houpert P, Bussy C, Dhieux B, Gourmelon P, Paquet F.

Institut de Radioprotection et de Surete Nucleaire, Departement de Radio-Protection de l'Homme, Laboratoire de Radio-Toxicologie Experimentale, BP 166, 26702 Pierrelatte, France. [email protected].

The health effects of depleted uranium (DU) are mainly caused by its chemical toxicity. Although the kidneys are the main target organs for uranium toxicity, uranium can also reach the brain. In this paper, the central effects of acute exposure to DU were studied in relation to health parameters and the sleep-wake cycle of adult rats. Animals were injected intraperitoneally with 144+/-10 microg DU kg-1 as nitrate. Three days after injection, the amounts of uranium in the kidneys represented 2.6 microg of DU g-1 of tissue, considered as a sub-nephrotoxic dosage. The central effect of uranium could be seen through a decrease in food intake as early as the first day after exposure and shorter paradoxical sleep 3 days after acute DU exposure (-18% of controls). With a lower dosage of DU (70+/-8 microg DU kg-1), no significant effect was observed on the sleep-wake cycle. The present study intends to illustrate the fact that the brain is a target organ, as are the kidneys, after acute exposure to a moderate dosage of DU. The mechanisms by which uranium causes these early neurophysiological perturbations shall be discussed.

What is the toxic agent, when prions are ashed? (no protein remains)

This information is important, if you know anybody returning from Iraq or even Afganastan, they should be aware of these "new" findings. Supposedly, some of the states are going to test their soldiers for DU upon their return.

 

[Kathy]

The implications of these studies is that uranium (specific to this test) in drinking water entered the body via the small intestine. The SRM (distal ileum) is part of the small intestine.

In naturally occurring cases of BSE no prions have been found on/in/at the distal ileum. Only in artificial transmission experiments have prions been found in a few of the animals after experimental transmission of prions or brain homogenate.

The basic rule of metal ions is that the will disperse throughout the body to form some sort of concentration balance. Body functions take place, however, that concentrate these metals in various organs and parts of the body. These are usually defense mechanisms that are trying to expell the metals, or excess metals, from the body. This is why they measure uranium contamination in living mammals via the urine.

I hope that some of you reading these postings are understanding the consequences of these results. The brain is a target for the accummulation of uranium. What other metals are concentrating in the brain?

Brown and Wong showed that patients with sporadic CJD had low levels of copper and high levels of manganese in their brain tissue.

J Neurochem. 2001 Sep;78(6):1400-8. Related Articles, Links

Aberrant metal binding by prion protein in human prion disease.

Wong BS, Chen SG, Colucci M, Xie Z, Pan T, Liu T, Li R, Gambetti P, Sy MS, Brown DR.

National Prion Disease Pathology Surveillance Center, Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

Human prion diseases are characterized by the conversion of the normal prion protein (PrP(C)) into a pathogenic isomer (PrP(Sc)). Distinct PrP(Sc) conformers are associated with different subtypes of prion diseases. PrP(C) binds copper and has antioxidation activity. Changes in metal-ion occupancy can lead to significant decline of the antioxidation activity and changes in conformation of the protein. We studied the trace element status of brains from patients with sporadic Creutzfeldt-Jakob disease (sCJD). We found a decrease of up to 50% of copper and an increase in manganese of approximately 10-fold in the brain tissues from sCJD subjects. We have also studied the metal occupancy of PrP in sCJD patients. We observed striking elevation of manganese and, to a lesser extent, of zinc accompanied by significant reduction of copper bound to purified PrP in all sCJD variants, determined by the PrP genotype and PrP(Sc) type, combined. Both zinc and manganese were undetectable in PrP(C) preparations from controls. Copper and manganese changes were pronounced in sCJD subjects homozygous for methionine at codon 129 and carrying PrP(Sc) type-1. Anti-oxidation activity of purified PrP was dramatically reduced by up to 85% in the sCJD variants, and correlated with increased in oxidative stress markers in sCJD brains. These results suggest that altered metal-ion occupancy of PrP plays a pivotal role in the pathogenesis of prion diseases. Since the metal changes differed in each sCJD variants, they may contribute to the diversity of PrP(Sc) and disease phenotype in sCJD. Finally, this study also presented two potential approaches in the diagnosis of CJD; the significant increase in brain manganese makes it potentially detectable by MRI, and the binding of manganese by PrP in sCJD might represent a novel diagnostic marker.

PMID: 11579148 [PubMed - indexed for MEDLINE]

Absorption into the body, and subsequently the brain, occurs either by ingestion, inhalation, absorbtion through the skin or direct injection. Clearly metal imbalance/contamination is associated with prion disease.
In these uranium studies ingestion of uranium in water occurred ONLY in the small intestine. Not the mouth and not the large intestine.

 

[Kathy]

If you don't believe that uranium might be involved with neurodegenerative diseases, here is another report which I found last night. For the first time, they say, they have identified uranium in 20 selected proteins, in the human brain. Read for yourself.

Note the last sentence: "This technique allows the study of posttranslational modifications in human brain proteins." Post translational modifications of proteins is prion talk.

Anal Chem 2005 Sep 15;77(18):5851-60. ACS Publications.

Determination of phosphorus-, copper-, and zinc-containing human brain proteins by LA-ICPMS and MALDI-FTICR-MS.
Becker JS, Zoriy M, Becker JS, Pickhardt C, Damoc E, Juhacz G, Palkovits M, Przybylski M.

Central Division of Analytical Chemistry, Research Centre Julich, 52425 Julich, Germany.

Human brain proteins containing phosphorus, copper, and zinc were detected directly in protein spots in gels of a human brain sample after separation by two-dimensional gel electrophoresis using laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS). A powerful laser ablation system with cooled laser ablation chamber was coupled to a double-focusing sector field ICPMS. The separated protein spots in 2D gels were fast screened using the optimized microanalytical LA-ICPMS technique measured at medium mass resolution with a focused laser beam (wavelength, 213 nm; diameter of laser crater, 50 mum; and laser power density, 3 x 10(9) W cm(-)(2)) with respect to selected three essential elements. Of 176 protein spots in 2D gel from a human brain sample, phosphorus, copper, and zinc were detected in 31, 43, and 49 protein spots, respectively. For the first time, uranium as a naturally occurring radioactive element was found in 20 selected protein spots. The detection limits for P, S, Cu, Zn and U were determined in singular protein spots with 0.0013, 1.29, 0.029, 0.063, and 0.000 01 mg g(-)(1), respectively. A combination of LA-ICPMS with matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR-MS) was applied for the identification of selected protein spots from human brain protein separated by 2D gel electrophoresis. Combining MALDI-FTICR-MS for the structure analysis of metal- and phosphorus-containing human brain proteins with LA-ICPMS, the direct analysis of heteroelements on separated proteins in 2D gels can be performed. For quantification of analytical LA-ICPMS data, the number of sulfur atoms per protein (and following the sulfur concentration) determined by MALDI-FTICR-MS was used for internal standardization. From the known sulfur concentration in protein, the concentration of other heteroelements was calculated. In addition, the number of phosphorylation and the phosphorylation sites of phosphorylated proteins in the human brain sample detected by LA-ICPMS were determined by MALDI-FTICR-MS. This technique allows the study of posttranslational modifications in human brain proteins.