Distribution of soluble uranium in the nuclear cell compartment at subtoxic concentrations.

Uranium is naturally found in the environment, and its extensive use results in an increased risk of human exposure. Kidney cells have mainly been used as in vitro models to study effects of uranium exposure, and very little about the effects on other cell types is known. The aim of this study was to assess the impact of depleted uranium exposure at the cellular level in human kidney (HEK-293), liver (HepG2), and neuronal (IMR-32) cell lines. Cytotoxicity studies showed that these cell lines reacted in a roughly similar manner to depleted uranium exposure, responding at a cytotoxicity threshold of 300-500 µM. Uranium was localized in cells with secondary ion mass spectrometry technology. Results showed that uranium precipitates at subtoxic concentrations (>100 µM). With this approach, we were able for the first time to observe the soluble form of uranium in the cell at low concentrations (10-100 µM). Moreover, this technique allows us to localize it mainly in the nucleus. These innovative results raise the question of how uranium penetrates into cells and open new perspectives for studying the mechanisms of uranium chemical toxicity.

Telomerase Regulation from Beginning to the End.

The vast body of literature regarding human telomere maintenance is a true testament to the importance of understanding telomere regulation in both normal and diseased states. In this review, our goal was simple: tell the telomerase story from the biogenesis of its parts to its maturity as a complex and function at its site of action, emphasizing new developments and how they contribute to the foundational knowledge of telomerase and telomere biology.

Cerebral cortex and hippocampus respond differently after post-natal exposure to uranium.

The central nervous system (CNS) is known to be sensitive to pollutants during its development. Uranium (U) is a heavy metal that occurs naturally in the environment as a component of the earth's crust, and populations may therefore be chronically exposed to U through drinking water and food. Previous studies have shown that the CNS is a target of U in rats exposed in adulthood. We assessed the effects of U on behavior and cholinergic system of rats exposed from birth for 10 weeks at 10 mg.L⁻¹ or 40 mg.L⁻¹. For behavioral analysis, the sleep/wake cycle (recorded by telemetry), the object recognition memory and the spatial working memory (Y-maze) were evaluated. Acetylcholine (ACh) and acetylcholinesterase (AChE) levels were evaluated in the entorhinal cortex and hippocampus. At 40 mg.L⁻¹, U exposure impaired object recognition memory (-20%), but neither spatial working memory nor the sleep/wake cycle was impaired. A significant decrease was observed in both the ACh concentration (-14%) and AChE activity (-14%) in the entorhinal cortex, but not in the hippocampus. Any significant effect on behaviour and cholinergic system was observed at 10 mg U.L⁻¹. These results demonstrate that early exposure to U during postnatal life induces a structure cerebral-dependant cholinergic response and modifies such memory process in rats. This exposure to U early in life could have potential delayed effects in adulthood.

Transcriptomic effects of depleted uranium on acetylcholine and cholesterol metabolisms in Alzheimer's disease model.

Some heavy metals, or aluminium, could participate in the development of Alzheimer disease (AD). Depleted uranium (DU), another heavy metal, modulates the cholinergic system and the cholesterol metabolism in the brain of rats, but without neurological disorders. The aim of this study was to determine what happens in organisms exposed to DU that will/are developing the AD. This study was thus performed on a transgenic mouse model for human amyloid precursor protein (APP), the Tg2576 strain. The possible effects of DU through drinking water (20 mg/L) over an 8-month period were analyzed on acetylcholine and cholesterol metabolisms at gene level in the cerebral cortex. The mRNA levels of choline acetyl transferase (ChAT) vesicular acetylcholine transporter (VAChT) and ATP-binding cassette transporter A1 (ABC A1) decreased in control Tg2576 mice in comparison with wild-type mice (respectively -89%, -86% and -44%, p < 0.05). Chronic exposure of Tg2576 mice to DU increased mRNA levels of ChAT (+189%, p < 0.05), VAChT (+120%, p < 0.05) and ABC A1 (+52%, p < 0.05) compared to control Tg2576 mice. Overall, these modifications of acetylcholine and cholesterol metabolisms did not lead to increased disturbances that are specific of AD, suggesting that chronic DU exposure did not worsen the pathology in this experimental model.

Heavy metal uranium affects the brain cholinergic system in rat following sub-chronic and chronic exposure.

Uranium is a heavy metal naturally present in the environment that may be chronically ingested by the population. Previous studies have shown that uranium is present in the brain and alters behaviour, notably locomotor activity, sensorimotor ability, sleep/wake cycle and the memory process, but also metabolism of neurotransmitters. The cholinergic system mediates many cognitive systems, including those disturbed after chronic exposure to uranium i.e., spatial memory, sleep/wake cycle and locomotor activity. The objective of this study was to assess whether these disorders follow uranium-induced alteration of the cholinergic system. In comparison with 40 control rats, 40 rats drank 40 mg/L uranyl nitrate for 1.5 or 9 months. Cortex and hippocampus were removed and gene expression and protein level were analysed to determine potential changes in cholinergic receptors and acetylcholine levels. The expression of genes showed various alterations in the two brain areas after short- and long-term exposure. Nevertheless, protein levels of the choline acetyltransferase enzyme (ChAT), the vesicular transporter of acetylcholine (VAChT) and the nicotinic receptor beta2 sub-unit (nAChRbeta2) were unmodified in all cases of the experiment and muscarinic receptor type 1 (m1AChR) protein level was disturbed only after 9 months of exposure in the cortex (-30%). Acetylcholine levels were unchanged in the hippocampus after 1.5 and 9 months, but were decreased in the cortex after 1.5 months only (-22%). Acetylcholinesterase (AChE) activity was also unchanged in the hippocampus but decreased in the cortex after 1.5 and 9 months (-16% and -18%, respectively). Taken together, these data indicate that the cholinergic system is a target of uranium exposure in a structure-dependent and time-dependent manner. These cholinergic alterations could participate in behavioural impairments.