Cell proliferation and cell death are disturbed during prenatal and postnatal brain development after uranium exposure.

The developing brain is more susceptible to neurotoxic compounds than adult brain. It is also well known that disturbances during brain development cause neurological disorders in adulthood. The brain is known to be a target organ of uranium (U) exposure and previous studies have noted that internal U contamination of adult rats induces behavioral disorders as well as affects neurochemistry and neurophysiological properties. In this study, we investigated whether depleted uranium (DU) exposure affects neurogenesis during prenatal and postnatal brain development. We examined the structural morphology of the brain, cell death and finally cell proliferation in animals exposed to DU during gestation and lactation compared to control animals. Our results showed that DU decreases cell death in the cortical neuroepithelium of gestational day (GD) 13 embryos exposed at 40mg/L and 120mg/L and of GD18 fetuses exposed at 120mg/L without modification of the number of apoptotic cells. Cell proliferation analysis showed an increase of BrdU labeling in the dentate neuroepithelium of fetuses from GD18 at 120mg/L. Postnatally, cell death is increased in the dentate gyrus of postnatal day (PND) 0 and PND5 exposed pups at 120mg/L and is associated with an increase of apoptotic cell number only at PND5. Finally, a decrease in dividing cells is observed in the dentate gyrus of PND21 rats developmentally exposed to 120mg/L DU, but not at PND0 and PND5. These results show that DU exposure during brain development causes opposite effects on cell proliferation and cell death processes between prenatal and postnatal development mainly at the highest dose. Although these modifications do not have a major impact in brain morphology, they could affect the next steps of neurogenesis and thus might disrupt the fine organization of the neuronal network.

Chronic Gamma-Irradiation Induces a Dose-Rate-Dependent Pro-inflammatory Response and Associated Loss of Function in Human Umbilical Vein Endothelial Cells.

A central question in radiation protection research is dose and dose-rate relationship for radiation-induced cardiovascular diseases. The response of endothelial cells to different low dose rates may contribute to help estimate risks for cardiovascular diseases by providing mechanistic understanding. In this study we investigated whether chronic low-dose-rate radiation exposure had an effect on the inflammatory response of endothelial cells and their function. Human umbilical vein endothelial cells (HUVECs) were chronically exposed to radiation at a dose of 1.4 mGy/h or 4.1 mGy/h for 1, 3, 6 or 10 weeks. We determined the pro-inflammatory profile of HUVECs before and during radiation exposure, and investigated the functional consequences of this radiation exposure by measuring their capacity to form vascular networks in matrigel. Expression levels of adhesion molecules such as E-selectin, ICAM-1 and VCAM-1, and the release of pro-inflammatory cytokines such as MCP-1, IL-6 and TNF-α were analyzed. When a total dose of 2 Gy was given at a rate of 4.1 mGy/h, we observed an increase in IL-6 and MCP-1 release into the cell culture media, but this was not observed at 1.4 mGy/h. The increase in the inflammatory profile induced at the dose rate of 4.1 mGy/h was also correlated with a decrease in the capacity of the HUVECs to form a vascular network in matrigel. Our results suggest that dose rate is an important parameter in the alteration of HUVEC inflammatory profile and function.

Chronic uranium exposure dose-dependently induces glutathione in rats without any nephrotoxicity.

Uranium is a heavy metal naturally found in the earth's crust that can contaminate the general public population when ingested. The acute effect and notably the uranium nephrotoxicity are well known but knowledge about the effect of chronic uranium exposure is less clear. In a dose-response study we sought to determine if a chronic exposure to uranium is toxic to the kidneys and the liver, and what the anti-oxidative system plays in these effects. Rats were contaminated for 3 or 9 months by uranium in drinking water at different concentrations (0, 1, 40, 120, 400, or 600 mg/L). Uranium tissue content in the liver, kidneys, and bones was linear and proportional to uranium intake after 3 and 9 months of contamination; it reached 6 µg per gram of kidney tissues for the highest uranium level in drinking water. Nevertheless, no histological lesions of the kidney were observed, nor any modification of kidney biomarkers such as creatinine or KIM-1. After 9 months of contamination at and above the 120-mg/L concentration of uranium, lipid peroxidation levels decreased in plasma, liver, and kidneys. Glutathione concentration increased in the liver for the 600-mg/L group, in the kidney it increased dose dependently, up to 10-fold, after 9 months of contamination. Conversely, chronic uranium exposure irregularly modified gene expression of antioxidant enzymes and activities in the liver and kidneys. In conclusion, chronic uranium exposure did not induce nephrotoxic effects under our experimental conditions, but instead reinforced the antioxidant system, especially by increasing glutathione levels in the kidneys.

Influence of depleted uranium on hepatic cholesterol metabolism in apolipoprotein E-deficient mice.

Depleted uranium (DU) is uranium with a lower content of the fissile isotope U-235 than natural uranium. It is a radioelement and a waste product from the enrichment process of natural uranium. Because of its very high density, it is used in the civil industry and for military purposes. DU exposure can affect many vital systems in the human body, because in addition to being weakly radioactive, uranium is a toxic metal. It should be emphasized that, to be exposed to radiation from DU, you have to eat, drink, or breathe it, or get it on your skin. This particular study is focusing on the health effects of DU for the cholesterol metabolism. Previous studies on the same issue have shown that the cholesterol metabolism was modulated at molecular level in the liver of laboratory rodents contaminated for nine months with DU. However, this modulation was not correlated with some effects at organs or body levels. It was therefore decided to use a "pathological model" such as hypercholesterolemic apolipoprotein E-deficient laboratory mice in order to try to clarify the situation. The purpose of the present study is to assess the effects of a chronic ingestion (during 3 months) of a low level DU-supplemented water (20 mg L(-1)) on the above mentioned mice in order to determine a possible contamination effect. Afterwards the cholesterol metabolism was studied in the liver especially focused on the gene expressions of cholesterol-catabolising enzymes (CYP7A1, CYP27A1 and CYP7B1), as well as those of associated nuclear receptors (LXRα, FXR, PPARα, and SREBP 2). In addition, mRNA levels of other enzymes of interest were measured (ACAT 2, as well as HMGCoA Reductase and HMGCoA Synthase). The gene expression study was completed with SRB1 and LDLr, apolipoproteins A1 and B and membrane transporters ABC A1, ABC G5. The major effect induced by a low level of DU contamination in apo-E deficient mice was a decrease in hepatic gene expression of the enzyme CYP7B1 (-23%) and nuclear receptors LXRα (-24%), RXR (-32%), HNF4α (-21%) when compared to unexposed ones. These modifications on cholesterol metabolism did not lead to increased disturbances that are specific for apolipoprotein E-deficient mice, suggesting that chronic DU exposure did not worsen the pathology in this experimental model. In conclusion, the results of this study indicate that even for a sensitive pathologic model the exposure to a low dose of DU has no relevant impact. The results confirm the results of our first study carried out on healthy laboratory rodents where a sub-chronic contamination with low dose DU did not affect in vivo the metabolism of cholesterol.

Cholesterol 7alpha-hydroxylase (CYP7A1) activity is modified after chronic ingestion of depleted uranium in the rat.

Depleted uranium (DU) is a radioactive heavy metal derived from the nuclear energy production. Its wide use in civilian and military items increases the risk of its environmental dissemination, and thus the risk of internal contamination of populations living in such contaminated territories. Previous studies have shown that vitamin D and cerebral cholesterol metabolisms were affected following chronic ingestion of DU. Even more than the brain, the liver is a crucial organ in cholesterol homeostasis since it regulates cholesterol distribution and elimination at body level. The aim of this work was to assess the impact of a low-level chronic ingestion of DU on hepatic cholesterol metabolism. Rats were contaminated with DU in their drinking water at a concentration of 40mg/l for 9 months. The major effect induced by DU was a decrease of CYP7A1 specific activity (-60%) correlated with a matching decrease of its product 7alpha-hydroxycholesterol in the plasma. Hepatic gene expression of transporters ABC A1, ABC G5, ABC G8 and of nuclear receptor RXR was increased, whereas that of catabolism enzyme CYP7B1 was decreased. Thus, after a chronic ingestion of DU, rats experience a modulation of cholesterol catabolism but overcome it, since their cholesterolemia is preserved and no pathology is declared.

The effect of knee joint angle on torque control.

The purpose of the author's investigation was to examine the effect of knee joint angle on torque control of the quadriceps muscle group. In all, 12 healthy adults produced maximal voluntary contractions and submaximal torque (15, 30, and 45% MVC [maximal voluntary contraction]) at leg flexion angles of 15 degrees , 30 degrees , 60 degrees , and 90 degrees below the horizontal plane. As expected, MVC values changed with respect to joint angle with maximum torque output being greatest at 60 degrees and least at 15 degrees . During the submaximal tasks, participants appropriately scaled their torque output to the required targets. Absolute variability (i.e., standard deviation) of torque output was greatest at 60 degrees and 90 degrees knee flexion. However, relative variability as indexed by coefficient of variation (CV) decreased as joint angle increased, with the greatest CV occurring at 15 degrees . These results are congruent with the hypothesis that joint angle influences the control of torque.

Practice and age-related loss of adaptability in sensorimotor performance.

The purpose of the present investigation was to examine whether the ability to adapt to task constraints is influenced by short-term practice in older adults. Young (18-29 years old) and old (65-75 years old) adults produced force output to a constant force target and a 1-Hz sinusoidal force target by way of the index finger flexion. Participants completed each task 5 times per session for 5 concurrent sessions. The amount and structure of force variability was calculated using linear and nonlinear analyses. As expected, there was a decrease in the magnitude of variability (coefficient of variation) in both tasks and task-related change in the structure of force variability (approximate entropy) with training across groups. The authors found older adults to have a greater amount of variability than their younger counterparts in both tasks. Older adults also demonstrated an increase in the structure of force output in the constant task but a decrease in structure in the sinusoidal task. Age differences in the adaptability to task constraints persisted throughout practice. The authors propose that older adults' ability to adapt sensorimotor output to task demands is not a result of lack of familiarity with the task but that it is, instead, characteristic of the aging process.

A method for assessing balance control in rodents.

Recent research has shown that after spinal cord injury, the nervous system reorganizes. Nevertheless, little is known of the effects of neural reorganization, or plasticity, on motor skills. In this work, we present a method that utilizes kinetic and kinematic analysis, for investigating balance control in a rodent model of incomplete spinal cord injury. In this setup, the animals sit unconstrained on their hindlimbs on a platform while they eat a Fruitloop. In this posture, the animal is supporting all the body weight on its hindquarters removing the need for the animal to support itself on its hindlimb or maintain appropriate forelimb-hindlimb coordination for functional gait. The platform is bolted to a force transducer to provide measurements of shear forces in orthogonal directions in the horizontal plane. Reflective markers on the hip and tail of the animal indicate sway of the animals body. Using this method the effect of extensive 12 week long treadmill locomotor training on balance control in rodents with incomplete thoracic spinal cord contusion injury (iSCI) was assessed. One iSCI rat did not undergo training, while a sham injured and 3 other iSCI rats underwent training. The shear forces and sway produced by the injured untrained rat were much larger than for the sham or the injured but trained rats. Stance width assessed from overground walking in a separate study was also larger in the injured untrained rat. These data suggest that balance control may be improved by a locomotor training paradigm. This simple method for assessing balance control could thus be utilized in longitudinal studies to evaluate the effectiveness of pharmacological and locomotor therapies for repair and recovery after spinal cord injury.

Splitting of porcine embryos at the four-cell or morula stage.

Porcine embryos obtained from estrus-induced prepuberal gilts were split at the 4-cell and morula stage. The in vitro development of the demi-embryos was compared with that of intact control embryos. The intact control embryos developed according to expectation. The in vitro survival of the demi-embryos was inferior to that of the respective controls. The splitting of 4-cell embryos was easier to accomplish and more efficient than the splitting of morulae. The in vitro development of the 4-cell embryos was also slightly better, although this difference was not significant. In vitro development of demi-embryos originating from morulae split at room temperature was slightly although nonsignificantly inferior to that of demi-embryos from morulae split on a warming stage at 37 degrees C. Between 14 and 18 demi-embryos were transferred to synchronous recipient gilts after 24 to 48 h of culture. Of 3 gilts receiving split 4-cell embryos, 1 gilt aborted 2 normal fetuses on Day 90 of pregnancy and 1 carried a single piglet to term. Of the 4 gilts receiving split morulae, 1 gilt had 4 normal and 3 degenerated fetuses upon slaughter on Day 35 of pregnancy.