Effects of depleted uranium after short-term exposure on vitamin D metabolism in rat

Uranium is a natural radioactive heavy metal. Its toxicity has been demonstrated for different organs, including bone, kidney, liver and brain. Effects of an acute contamination by depleted uranium (DU) were investigated in vivo on vitamin D3 biosynthetic pathway. Rats received an intragastric administration of DU (204 mg/kg) and various parameters were studied either on day 1 or day 3 after contamination. Cytochrome P450 (CYP27A1, CYP2R1, CYP27B1, CYP24A1) enzymes involved in vitamin D metabolism and two vitamin D3-target genes (ECaC1, CaBP-D9K) were assessed by real time RT-PCR in liver and kidneys. CYP27A1 activity was measured in liver and vitamin D and parathyroid hormone (PTH) level were measured in plasma. In acute treated-rats, vitamin D level was increased by 62% and decreased by 68% in plasma, respectively at day 1 and at day 3, which paralleled with a concomitant decrease of PTH level (90%) at day 3. In liver, cyp2r1 mRNA level was increased at day 3. Cyp27a1 activity decreased at day 1 and increased markedly at day 3. In kidney, cyp27b1 mRNA was increased at days 1 and 3 (11- and 4-fold respectively). Moreover, ecac1 and cabp-d9k mRNA levels were increased at day 1 and decreased at day 3. This work shows for the first time that DU acute contamination modulates both activity and expression of CYP enzymes involved in vitamin D metabolism in liver and kidney, and consequently affects vitamin D target genes levels. © Springer-Verlag 2006

Enriched uranium affects the expression of vitamin D receptor and retinoid X receptor in rat kidney

An increasing awareness of the radiological impact of the nuclear power industry and other nuclear technologies is observed nowadays on general population. This led to renew interest to assess the health impact of the use of enriched uranium (EU). The aim of this work was to investigate in vivo the effects of a chronic exposure to EU on vitamin D3 metabolism, a hormone essential in mineral and bone homeostasis. Rats were exposed to EU in their drinking water for 9 months at a concentration of 40 mg l-1 (1 mg/rat day). The contamination did not change vitamin D plasma level. Vitamin D receptor (vdr) and retinoid X receptor alpha (rxrα), encoding nuclear receptors involved in the biological activities of vitamin D, showed a lower expression in kidney, while their protein levels were paradoxically increased. Gene expression of vitamin D target genes, epithelial Ca2+ channel 1 (ecac1) and Calbindin-D28k (cabp-d28k), involved in renal calcium transport were decreased. Among the vitamin D target organs examined, these molecular modifications occurred exclusively in the kidney, which confirms that this organ is highly sensitive to uranium exposure. In conclusion, this study showed that a chronic exposure to EU affects both mRNA and protein expressions of renal nuclear receptors involved in vitamin D metabolism, without any modification of the circulating vitamin D. © 2008 Elsevier Ltd. All rights reserved

Chronic contamination with 137Cesium affects Vitamin D3 metabolism in rats

Twenty years after Chernobyl disaster, many people are still chronically exposed to low dose of 137Cs, mainly through the food consumption. A large variety of diseases have been described in highly exposed people with 137Cs, which include bone disorders. The aim of this work was to investigate the biological effects of a chronic exposure to 137Cs on Vitamin D3 metabolism, a hormone essential in bone homeostasis. Rats were exposed to 137Cs in their drinking water for 3 months at a dose of 6500 Bq/l (approximately 150 Bq/rat/day), a similar concentration ingested by the population living in contaminated territories in the former USSR countries. Cytochromes P450 enzymes involved in Vitamin D3 metabolism, related nuclear receptors and Vitamin D3 target genes were assessed by real time PCR in liver, kidney and brain. Vitamin D, PTH, calcium and phosphate levels were measured in plasma. An increase in the expression level of cyp2r1 (40%, p < 0.05) was observed in the liver of 137Cs-exposed rats. However a significant decrease of Vitamin D (1,25(OH)D3) plasma level (53%, p = 0.02) was observed. In brain, cyp2r1 mRNA level was decreased by 20% (p < 0.05), while the expression level of cyp27b1 is increased (35%, p < 0.05) after 137Cs contamination. In conclusion, this study showed for the first time that chronic exposure with post-accidental doses of 137Cs affects Vitamin D3 active form level and induces molecular modifications of CYPs enzymes involved its metabolism in liver and brain, without leading to mineral homeostasis disorders. Crown Copyright © 2006

Vitamin D metabolism impairment in the rat's offspring following maternal exposure to 137cesium

Previous works clearly showed that chronic contamination by 137cesium alters vitamin D metabolism. Since children are known to be a high-risk group for vitamin D metabolism disorders, effects of 137Cs on vitamin D biosynthetic pathway were investigated in newborn rats. The experiments were performed in 21-day-old male offspring of dams exposed to 137Cs in their drinking water at a dose of 6,500 Bq/l (150 Bq/rat/day) during the lactation period. Significant modifications of blood calcium (-7%, P < 0.05), phosphate (+80%, P < 0.01) and osteocalcin (-25%, P < 0.05) levels were observed in contaminated offspring, associated with an increase of blood vitamin D3 (+25%, P < 0.01). Besides, decreased expression levels of cyp2r1 and cyp27b1 (-26 and -39%, respectively, P < 0.01) were measured in liver and kidney suggesting a physiological adaptation in response to the rise in vitamin D level. Expressions of vdr, ecac1, cabp-d28k, ecac2 and cabp-9k involved in renal and intestinal calcium transport were unaffected. Altogether, these data show that early exposure to post-accidental doses of 137Cs induces the alteration of vitamin D metabolism, associated with a dysregulation of mineral homeostasis. © 2008 Springer-Verlag

In vivo effects of chronic contamination with depleted uranium on vitamin D3 metabolism in rat

The extensive use of depleted uranium (DU) in today's society results in the increase of the number of human population exposed to this radionuclide. The aim of this work was to investigate in vivo the effects of a chronic exposure to DU on vitamin D3 metabolism, a hormone essential in mineral and bone homeostasis. The experiments were carried out in rats after a chronic contamination for 9 months by DU through drinking water at 40 mg/L (1 mg/rat/day). This dose corresponds to the double of highest concentration found naturally in Finland. In DU-exposed rats, the active vitamin D (1,25(OH)2D3) plasma level was significantly decreased. In kidney, a decreased gene expression was observed for cyp24a1, as well as for vdr and rxrα, the principal regulators of CYP24A1. Similarly, mRNA levels of vitamin D target genes ecac1, cabp-d28k and ncx-1, involved in renal calcium transport were decreased in kidney. In the brain lower levels of messengers were observed for cyp27a1 as well as for lxrβ, involved in its regulation. In conclusion, this study showed for the first time that DU affects both the vitamin D active form (1,25(OH)2D3) level and the vitamin D receptor expression, and consequently could modulate the expression of cyp24a1 and vitamin D target genes involved in calcium homeostasis. © 2006 Elsevier B.V. All rights reserved

Chronic contamination with 137cesium in rat: Effect on liver cholesterol metabolism

After the Chernobyl nuclear accident, epidemiological studies on human populations living in 137Cs-contaminated areas revealed the increase frequencies of thyroid cancer and evoked the apparition of cardiovascular diseases, hormonal effect, liver alteration, and lipid disorder. Actually, it raises a problem of public safety for the populations living on these territories that are exposed to low levels of 137Cs during a long period through food. Then it is necessary to study potential effect of this chronic contamination. To mimic this situation, the authors investigate the potential biological effects of chronic exposure to 137Cs at a postaccidental dose (150 Bq/rat/day) on hepatic metabolism of cholesterol in rat. Plasma lipid level, gene expression and activity were analyzed. It was observed that in 137Cs-exposed rats, gene expression of low-density lipoprotein receptor (LDLr), apolipoprotein B (apoB), and liver X receptor α (LXRα) are increased (95%, p < .05; 34%, p < .05; 20%, p < 0.05, respectively), whereas transporter adenosine triphosphate-binding cassette transporter G5 (ABCG5) is decreased (42%, p < .05). In addition, cytochrome P450 27A1 (CYP27A1) activity is increased (34%, p < .05) in contaminated rat liver. In conclusion, the results suggest that 137Cs contamination at low-level induces molecular modifications of the liver cholesterol metabolism without leading to a dysregulation of its homeostasis. These results suggest that chronic long term exposure at low-level of 137Cs may evolve to lipid disorder. Copyright © American College of Toxicology

Uranium: Propriétés et effets biologiques après contamination interne

Uranium is a radionuclide present in the environment since the origin of the Earth. In addition to natural uranium, recent deposits from industrial or military activities are acknowledged. Uranium's toxicity is due to a combination of its chemical (heavy metal) and radiological properties (emission of ionizing radiations). Acute toxicity induces an important weight loss and signs of renal and cerebral impairment. Alterations of bone growth, modifications of the reproductive system and carcinogenic effects are also often seen. On the contrary, the biological effects of a chronic exposure to low doses are unwell known. However, results from different recent studies suggest that a chronic contamination with low levels of uranium induces subtle but significant levels. Indeed, an internal contamination of rats for several weeks leads to detection of uranium in many cerebral structures, in association with an alteration of short-term memory and an increase of anxiety level. Biological effects of uranium on the metabolisms of xenobiotics, steroid hormones and vitamin D were described in the liver, testis and kidneys. These recent scientific data suggest that uranium could participate to increase of health risks linked to environmental pollution.L’uranium est un radionucléide présent dans l’environnement depuis l’origine de la terre. A cet uranium d’origine naturelle viennent s’ajouter des apports plus récents résultant des activités industrielles et militaires de l’homme. La toxicité de l’uranium résulterait d’une combinaison de ses propriétés chimiques (métal lourd) et radiologiques (émission de rayonnements ionisants). La toxicité aiguë se manifeste chez l’animal par une importante perte de poids et des signes d’atteinte rénale et cérébrale. Une altération de la formation osseuse, une modification du système reproducteur et des effets carcinogènes sont également couramment observés. A contrario, les effets biologiques d’une exposition chronique à de faibles doses sont peu connus. Cependant, les résultats de différentes études récentes suggèrent que la contamination chronique à faible niveau par l’uranium induirait des effets biologiques subtils mais significatifs dans des organes qui ne sont pas connus pour être des organes sensibles à la contamination par l’uranium. C’est le cas du système nerveux central par exemple puisque, récemment, ont été montrées une altération de la mémoire à court terme et une augmentation du niveau d’anxiété, associées à la présence d’uranium dans différentes structures cérébrales chez l’animal (essentiellement rongeur). La grande nouveauté dans la connaissance des effets d’une contamination chronique par l’uranium est la mise en évidence d’effets biologiques de l’uranium sur plusieurs métabolismes majeurs de l’organisme, incluant le métabolisme des médicaments, des hormones stéroïdiennes, de la vitamine D et du fer. Ces données scientifiques récentes suggèrent que l’uranium pourrait participer à l’augmentation des risques sanitaires liés à la pollution de l’environnement

Les cytochromes P450: Métabolisme des xénobiotiques, régulation et rôle en clinique

Cytochromes P450 (CYPs) are a superfamily of 57 genes coding for drug metabolizing enzymes and endobiotic metabolizing enzymes (steroids, eicosanoids, vitamins...). This is the main metabolizing enzyme system for foreign compounds, including drugs, which has a primary role in organism protection against potential harmful insults from the environment (pollutants, pesticides...). The CYPs regulation is essentially transcriptional: nuclear receptors are recognized as key mediators for the control of drug metabolizing enzymes. Their ligands are exogenous and also endogenous molecules that can up-regulate or down-regulate these transcription factors. Treatment with drugs or xenobiotics, which are nuclear receptor agonists or antagonists, can lead to severe toxicities, loss of therapeutic effect or endobiotic metabolism disorders. Genetic polymorphisms of these enzymes have an important role in their activity and must be taken into account during drug administration. Then, CYP activity depends on genotype and environment; this is recently used as biomarker to determine human exposure to environmental molecules or to predict the susceptibility to certain pathologies

Effect of acetaminophen administration to rats chronically exposed to depleted uranium

The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40 mg/l) were treated by acetaminophen (APAP, 400 mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p < 0.01) and AST (p < 0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p < 0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination. © 2006 Elsevier Ireland Ltd. All rights reserved