A exposição prolongada ao fluoreto durante a adolescência à fase adulta modula o proteoma hipocampal e gera danos cognitivos associados a um padrão neurodegenerativo no hipocampo de camundongos

Abstract

Fluoride (F) is used in artificial water fluoridation due to its anticariogenic activity, but it is also present in soils and natural reservoirs due natural high levels or anthropogenic actions, featuring it as a potential environment toxicant. In addition to skeletal and dental fluorosis in people living in regions with high F levels, some studies have explored the association between F exposure and cognitive damages, and although the evidences have indicated that only high levels pose a deleterious effect on cognition, a heated debated has grown regarding the safety of water supply artificial fluoridation. In this way, this study investigated whether long-term F exposure, from adolescence to adulthood, under the paradigms of water fluoridation and environmental issue, would be associated with memory and learning impairments in mice, and unravel molecular and morphological aspects involved. For this, 21-days-old mice received for 60 days, 10mg/L or 50mg/L of F in drinking water; the control group received only water without addition of F. Then, the cognitive functions were assessed by the Morris Water Maze and Inhibitory Step-down Avoidance test, followed blood and hippocampus collection for plasma F level determination, and hippocampal global proteomic profile analysis by Mass Spectrometry. Some animals were perfused for immunohistochemical analyses of mature neurons density in CA1, CA3, hilus and dentate gyrus (DG) regions. The results indicated that prolonged exposure to F from adolescence to adulthood increased plasma F bioavailability, and the higher F concentration triggered short- and long-term memory impairments, being associated with the modulation of the global proteomic profile, and a neurodegenerative pattern in the CA3 and DG regions. Our data, in a translational perspective, gives evidences of potential molecular targets of F neurotoxicity in the hippocampus and reinforces the safety of low fluoride concentration exposure, besides the need for attention of people living in endemic regions.