Chronic ingestion of uranyl nitrate perturbs acetylcholinesterase activity and monoamine metabolism in male rat brain C. Bussy a , P. Lestaevel a , B. Dhieux a , C. Amourette b , F. Paquet a , P. Gourmelon c , P. Houpert a, * a Institut de Radioprotection et de Su ˆrete ´ Nucle ´aire, Direction de la radioprotection de l’homme, Service de radiobiologie et d’e ´pide ´miologie, Laboratoire de radiotoxicologie expe ´rimentale, BP166, 26702 Pierrelatte Cedex, France b Centre de Recherche du Service de Sante ´ des Arme ´es, De ´partement de radiobiologie, Radiopathologie, unite ´ de physiopathologie des communications intrace ´re ´brales, BP87, 38702 La Tronche Cedex, France c Institut de Radioprotection et de Su ˆrete ´ Nucle ´aire, Direction de la radioprotection de l’Homme, BP6, 92265 Fontenay aux roses Cedex, France Received 8 September 2005; accepted 4 November 2005 Available online 2 December 2005 Abstract Recent animal studies have shown that uranium can reach the brain after chronic exposure. However, little information is available on the neurological effects of chronic long-term exposure to uranium. In the present study, the effects during 1.5, 6 and 9-month periods of chronic ingestion of uranyl nitrate (UN) in drinking water (40 mg of uranium per litre) on cholinergic acetylcholinesterase (AChE) activity and on dopaminergic and serotoninergic metabolisms were investigated in several areas of male Srague Dawley rat brains. Uranium brain accumulation and distribution was also investigated after 1.5 and 9 months. Both after 1.5, 6 and 9 months of exposure, AChE activity was unaffected in the striatum, hippocampus and frontal cortex. Nevertheless, AChE activity was transitionally perturbed in the cerebellum after 6 months of exposure. After 1.5 months of exposure, DA level increased in hypothalamus. After 6 months of exposure, a tiny but significant modification of the DAergic turnover ratio was detected in the frontal cortex. And after 9 months, UN produced a significant decrease in the 5HIAA level and the 5HTergic turn-over ratio in the frontal cortex and also a decrease in the DOPAC level and DAergic turn-over ratio in the striatum. Uranium brain accumulation was statistically significant in striatum after 1.5 months and in striatum, hippocampus and frontal cortex after 9 months of exposure. Although neurochemical changes did not always correlated with increased accumulation of uranium in specific areas, these results suggest that chronic ingestion of UN can cause chronic and progressive perturbations of physiological level of neurotransmitter systems. Considering previous reports on behavioural uranium-induced effects and the involvement of neurotransmitters in various behavioural processes, it would be crucial to determine whether these neurochemical disorders were accompanied by neurobehavioral deficits even at 40 mg of uranium per litre exposure. # 2005 Elsevier Inc. All rights reserved. Keywords: Uranium; Brain; Chronic exposure; Dopamine; Serotonin; Acetylcholinesterase 1. Introduction Uranium is an ubiquitous, metallic and weakly radioactive element which is found in small amounts in rocks (mineral deposits), soils, water, air, plants and animals and consequently in all human beings as a natural, non essential component (ATSDR, 1999). In many parts of the world, the main source of human uranium exposure is geological in origin and usually comes from the natural content of drinking water rather than from industrial sources. However, little information is available concerning the potential health hazard of chronic ingestion of low uranium quantities. Uranium is not only a radiotoxicant as regards its radio- nuclide properties but also a heavy metal with chemiotoxicant properties (Maynard et al., 1949; Priest, 2001). Thus, chronic ingestion of uranium through drinking water may result in the manifestation of toxicity in many parts of the body (ATSDR, 1999; US-EPA, 2000; WHO, 2001; Craft et al., 2004). Actually, NeuroToxicology 27 (2006) 245–252 * Corresponding author. Tel.: +33 4 75 50 43 87; fax: +33 4 75 50 43 26. E-mail address: pascale.houpert@irsn.fr (P. Houpert). 0161-813X/$ – see front matter # 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuro.2005.11.003