Via what mechanisms does uranium affect the brain?

Uranium can act either directly or indirectly to trigger the effects observed on the central nervous system (CNS). However, the indirect effect seems unlikely. In fact, the rats used in our studies, exposed to 2 mg/kg/day of uranium, were healthy. The general parameters (food intake, water intake and body weight) did not change significantly (Lestaevel et al., 2009). More specifically, no change in the plasma levels of renal dysfunction markers was observed. The absence of any harmful effect of uranium on the kidneys can be explained by the quantity measured in these organs (0.12 µg of uranium per gram of kidney (Lestaevel et al., 2005), i.e. much lower than the concentration considered to be nephrotoxic (3.0 µg of uranium per gram of kidney).

Consequently, under our experimental conditions, uranium does not trigger renal toxicity or a cascade effect, which could lead indirectly to the effects observed on the CNS.
Conversely, a direct central effect of uranium seems to be the most likely hypothesis to explain the neurological effects observed. Possible candidates include neurotransmitters and oxidative stress.

- Neurotransmitters

Acetylcholine, dopamine and serotonin are neurotransmitters involved in numerous physiological processes such as memory, sleep and anxiety, all of which are altered following chronic uranium contamination. Uranium could thus act on the synthesis and degradation pathways of these neurotransmitters, culminating in the neurological disorders described in the previous paragraph.

Acetylcholine is involved in learning and memory processes. We highlighted a significant reduction in acetylcholine levels in the entorhinal cortex of rats contaminated with depleted uranium (DU) or enriched uranium (EU) for 1.5 months at the daily dose of 2 mg/kg (-22% and –26%, respectively) (Bensoussan et al., 2009). Under the same experimental conditions, this decrease is associated with an increase (+20%) in acetylcholinesterase activity – the enzyme that breaks down acetylcholine – in the hippocampus of rats contaminated with EU (Bensoussan et al., 2009). These results suggest that acetylcholine which the concentration decreases in cerebral structures involved in cognitive processes, is no longer functioning correctly. This disorder could explain, at least in part, the memory disturbances observed.

Dopamine is an essential neurotransmitter for locomotor activity. We have shown that 1.5 months’ contamination with DU alters the synthesis/degradation process of dopamine (Bussy et al., 2006) whereas locomotor activity is not modified by uranium (Lestaevel et al., 2005). However, dopamine is involved in other types of behaviour, e.g. pleasurable sensations, which have not yet to be examined after uranium exposure.

Finally, the serotoninergic pathway,, which is involved in the wake-sleep cycle, anxiety or depression, is also sensitive to uranium exposure. In fact, the synthesis/degradation pathway of serotonin was modified during 9 months’ exposure to DU (2 mg/kg/day) (Bussy et al., 2006). This disorder could cause sleeping disorders and increase anxiety.

To conclude, all these studies show that uranium affects several neurotransmitter pathways and these changes could be partly responsible for the effects observed on the various neurophysiological functions described earlier.

- Oxidative stress

Oxidative stress is defined as the result of an imbalance between pro-oxidant substances and the defence system (anti-oxidant agents) resulting in the onset of harmful, often irreversible effects on the cell. The brain is particularly sensitive to oxidative stress because it possesses weak anti-oxidant defence mechanisms and is rich in polyunsaturated fatty acids – the principal target of lipid peroxidation. Cerebral lipid oxidation was increased in rats during chronic exposure via the drinking water of 2 weeks’ or 6 months’ duration (DU, 8 mg/kg/day) (Briner and Muray, 2005) or 9 months’ duration (4% EU, 2 mg/kg/day) (Lestaevel et al., 2009). However, this oxidation was less significant in the case of contamination with DU compared to EU, which is consistent with the more marked effects observed with EU compared to DU on the cognitive processes.

The induction of oxidative stress markers has also been observed in various structures of the brain. After ingestion of DU for 3 months at dose levels of 10, 20 and 40 mg/kg via the drinking water, the induction of thiobarbituric acid reactive substances (TBARS) correlates positively with the concentration of U measured in the cortex and cerebellum. The cerebellum also showed positive oxidated glutathione induction and a reduction in reduced glutathione depending on the dose of DU ingested. Finally, in the hippocampus, catalase (CAT) and superoxide dismutase (SOD) are increased linearly with the dose of U ingested (Albina et al., 2005). Our studies have highlighted the opposite effects observed following chronic contamination with DU and EU (2 mg/kg/day, via the drinking water). DU increased the induction of oxidative stress markers (increase in CAT) whereas EU seemed to reduce these parameters (reduction in SOD and glutathione peroxidase) (Lestaevel et al., 2009) in the cerebral cortex. These data could explain the effects observed on lipid peroxidation.

These results therefore show that, following chronic contamination, uranium triggers a defence mechanism to counteract oxidative stress characterised by a change in certain anti-oxidant enzymes. The increase in anti-oxidant defences may well be a cerebral response triggering a detoxification process and thus allowing the CNS to protect itself against uranium-induced toxicity. In conclusion, these studies show the involvement of oxidative stress in the mechanism of action of uranium in the brain.

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references

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 Bensoussan H, Grandcolas L, Dhieux B, Delissen O, Vacher CM, Dublineau I, Voisin P, Gourmelon P, Taouis M, Lestaevel P, 2009. Heavy metal uranium affects the brain cholinergic system in rat following sub-chronic and chronic exposure. Toxicology. 261, 59-69.

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