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Different studies have suggested that fluoride is related to neurological disorders in children and adolescents, but clinical evidences of which neurological parameters associated to fluoride exposure are, in fact, still controversial. In this way, this systematic review and meta-analysis aimed to show if there is an association between fluoride exposure from different sources, doses and neurological disorders. Terms related to “ Humans ”; “ Central nervous system ”; “ Fluorides ”; and “ Neurologic manifestations ” were searched in a systematic way on PubMed , Scopus , Web of Science , Lilacs , Cochrane and Google Scholar. All studies performed on humans exposed to fluoride were included on the final assessment. A meta-analysis was then performed and the quality level of evidence was performed using the GRADE approach. Our search retrieved 4,024 studies, among which 27 fulfilled the eligibility criteria. The main source of fluoride was naturally fluoridated water. Twenty-six studies showed alterations related to Intelligence Quotient (IQ) while only one has evaluated headache, insomnia, lethargy, polydipsia and polyuria. Ten studies were included on the meta-analysis, which showed IQ impairment only for individuals under high fluoride exposure considering the World Health Organization criteria, without evidences of association between low levels and any neurological disorder. However, the high heterogeneity observed compromise the final conclusions obtained by the quantitative analyses regarding such high levels. Furthermore, this association was classified as very low-level evidence. At this time, the current evidence does not allow us to state that fluoride is associated with neurological damage, indicating the need for new epidemiological studies that could provide further evidences regarding this possible association.

Fluoride (F) is a naturally exists in nature but several studies have indicated it as an environmental toxicant to all leaving beings. Human F exposure has increased over the years since this ion has been used by industry on foods, beverages, toothpastes and on water supply. Although F is safe at optimal concentrations in water supply, human exposure to high levels could trigger neurofunctional deficits. In this study, human glial-like (U87) and neuronal-like (IMR-32) cells lineages were used to access F toxicity and CNS cell sensibility on both cell facing the same protocol. Cells were exposed to F over 3, 5 and 10 days on two different F concentrations. Fluoride exposed cells were evaluated by standard toxicity assays to cell viability, apoptosis, necrosis and general cell metabolism. Oxidative stress parameters were evaluated by ATP and ROS levels, lipid peroxidation, GSH/GSSG ratio and comet assay. No changes were observed in IMR-32 at any given time while after 10 days of exposure to 0.22μg/mL, U87 glial-like cells showed signs of toxicity such as decreased cell viability by necrosis while general cell metabolism was increased. Oxidative stress parameters were next evaluated only on U87 glial-like cells after 10 days of exposure. F induced a decrease on ATP levels while no changes were observed on reactive oxygen species and lipid peroxidation. GSH/GSSG ratio was decreased followed by DNA damage both on 0.22μg/mL F. Our results suggest an important differential behavior of the distinct types of cells exposed to the different fluoride concentrations, pointing that the U87 glial-like cells as more susceptible to damage triggered by this ion.

The pathophysiological basis of Parkinson's disease (PD) remains incompletely understood. However, the influence of environmental factors, such as continuous cadmium exposure, requires further investigation. Notably, common comorbidities such as iron deficiency anemia (IDA), chronic obstructive pulmonary disease (COPD), and zinc deficiency are linked with increased cadmium bioavailability, and elevated blood cadmium levels have been reported in individuals with PD. Cd (II) deposits in the midbrain, causing the accumulation of inflammatory lipids, which promote neuronal destruction. Cd-treated animals develop Parkinson-like syndromes, and cadmium exposure is associated with neuronal loss and disruption of dopaminergic receptor expression. Neurofilament light chain (NfL), a biomarker of neurodegeneration, has been found to be elevated in patients with Parkinson's disease and correlates with Cd blood concentrations. Iron deficiency promotes the secretion of FGF-23, which depletes vitamin D levels, further increasing the risk of PD. Moreover, COPD and IDA are two well-known examples of systemic hypoxia, which attracts metals bound to transferrin, such as cadmium and iron, leading to increased metal accumulation in various tissues, including the brain. Lead levels are also elevated in individuals with IDA, contributing to the risk of PD. Additionally, Cd exposure is associated with a reduced abundance of Lachnospiraceae in stool and decreased levels of butyrate, both of which are characteristic features of patients with Parkinson's disease. Therefore, this review aims to explore how COPD, IDA, and zinc deficiency-known risk factors for Parkinson's disease-lead to an increased cadmium burden and contribute to the onset and progression of the disease.

Fluoride is added to water due to its anticariogenic activity. However, due to its natural presence in soils and reservoirs at high levels, it could be a potential environmental toxicant. This study investigated whether prolonged exposure to fluoride from adolescence to adulthood—at concentrations commonly found in artificially fluoridated water and in fluorosis endemic areas—is associated with memory and learning impairments in mice, and assessed the molecular and morphological aspects involved. For this endeavor, 21-days-old mice received 10 or 50 mg/L of fluoride in drinking water for 60 days and the results indicated that the increased plasma fluoride bioavailability was associated with the triggering of short- and long-term memory impairments after high F concentration levels. These changes were associated with modulation of the hippocampal proteomic profile, especially of proteins related to synaptic communication, and a neurodegenerative pattern in the CA3 and DG. From a translational perspective, our data provide evidence of potential molecular targets of fluoride neurotoxicity in the hippocampus at levels much higher than that in artificially fluoridated water and reinforce the safety of exposure to low concentrations of fluoride. In conclusion, prolonged exposure to the optimum fluoride level of artificially fluoridated water was not associated with cognitive impairments, while a higher concentration associated with fluorosis triggered memory and learning deficits, associated with a neuronal density reduction in the hippocampus.

A major hindrance for the development of psychiatric drugs is the prediction of how treatments can alter complex behaviors in assays which have good throughput and physiological complexity. Here we report the development of a medium-throughput screen for drugs which alter anxiety-like behavior in adult zebrafish. The observed phenotypes were clustered according to shared behavioral effects. This barcoding procedure revealed conserved functions of anxiolytic, anxiogenic and psychomotor stimulating drugs and predicted effects of poorly characterized compounds on anxiety. Moreover, anxiolytic drugs all decreased, while anxiogenic drugs increased, serotonin turnover. These results underscore the power of behavioral profiling in adult zebrafish as an approach which combines throughput and physiological complexity in the pharmacological dissection of complex behaviors.

Background Cerebral malaria is the most severe form of infection with Plasmodium falciparum characterized by a highly inflammatory response. This systematic review aimed to investigate the association between TNF-α levels and cerebral malaria. Methods This review followed the Preferred Reporting of Systematic Review and Meta-analyses (PRISMA) guidelines. The search was performed at PubMed, LILACS, Scopus, Web of Science, The Cochrane Library, OpenGrey and Google Scholar. We have included studies of P. falciparum -infected humans with or without cerebral malaria and TNF-α dosage level. All studies were evaluated using a risk of bias tool and the GRADE approach. Results Our results have identified 2338 studies, and 8 articles were eligible according to this systematic review inclusion criteria. Among the eight articles, five have evaluated TNF- α plasma dosage, while two have evaluated at the blood and one at the brain (post-Morten). Among them, only five studies showed higher TNF-α levels in the cerebral malaria group compared to the severe malaria group. Methodological problems were identified regarding sample size, randomization and blindness, but no risk of bias was detected. Conclusion Although the results suggested that that TNF-α level is associated with cerebral malaria, the evidence is inconsistent and imprecise. More observational studies evaluating the average TNF-alpha are needed.

Mercury is a severe environmental pollutant with neurotoxic effects, especially when exposed for long periods. Although there are several evidences regarding mercury toxicity, little is known about inorganic mercury (IHg) species and cerebellum, one of the main targets of mercury associated with the neurological symptomatology of mercurial poisoning. Besides that, the global proteomic profile assessment is a valuable tool to screen possible biomarkers and elucidate molecular targets of mercury neurotoxicity; however, the literature is still scarce. Thus, this study aimed to investigate the effects of long-term exposure to IHg in adult rats’ cerebellum and explore the modulation of the cerebellar proteome associated with biochemical and functional outcomes, providing evidence, in a translational perspective, of new mercury toxicity targets and possible biomarkers. Fifty-four adult rats were exposed to 0.375 mg/kg of HgCl2 or distilled water for 45 days using intragastric gavage. Then, the motor functions were evaluated by rotarod and inclined plane. The cerebellum was collected to quantify mercury levels, to assess the antioxidant activity against peroxyl radicals (ACAPs), the lipid peroxidation (LPO), the proteomic profile, the cell death nature by cytotoxicity and apoptosis, and the Purkinje cells density. The IHg exposure increased mercury levels in the cerebellum, reducing ACAP and increasing LPO. The proteomic approach revealed a total 419 proteins with different statuses of regulation, associated with different biological processes, such as synaptic signaling, energy metabolism and nervous system development, e.g., all these molecular changes are associated with increased cytotoxicity and apoptosis, with a neurodegenerative pattern on Purkinje cells layer and poor motor coordination and balance. In conclusion, all these findings feature a neurodegenerative process triggered by IHg in the cerebellum that culminated into motor functions deficits, which are associated with several molecular features and may be related to the clinical outcomes of people exposed to the toxicant.

Lung cancer represents the second-highest incidence of cancer worldwide and the leading cause of cancer-related deaths. Smoking is still the main risk factor, but other factors are also important, such as those associated with the large-scale exploitation of natural resources. This ecological study aimed to analyse the potential association between the spatial distribution of lung cancer and the natural vegetation cover in the state of Pará, Brazil. The study included 700 new cases of lung cancer taken from the Integrador Hospital Cancer Registries, a web-based system consolidating cancer data across Brazil. Spatial exploratory techniques were estimated by global and local spatial correlation coefficients and presented as thematic maps. The independent variables were socio-economic and environmental indicators. A significant variation was identified between different geographical areas and the distribution pattern of lung cancer incidence, with a negative correlation (I = - 0.12, p-value = < 0.001) between cancer rates and natural vegetation cover. The findings provide insights into the role of environmental factors that influence public health, ratifying the need for environmental conservation policies to promote health and prevent disease.

The potential of fluoride (F) as a neurotoxicant in humans is still controversial in the literature. However, recent studies have raised the debate by showing different mechanism of F-induced neurotoxicity, as oxidative stress, energy metabolism and inflammation in the central nervous system (CNS). In the present study, we investigated the mechanistic action of two F concentration (0.095 and 0.22 μg/ml) on gene and protein profile network using a human glial cell in vitro model over 10 days of exposure. A total of 823 genes and 2,084 genes were modulated after exposure to 0.095 and 0.22 μg/ml F, respectively. Among them, 168 were found to be modulated by both concentrations. The number of changes in protein expression induced by F were 20 and 10, respectively. Gene ontology annotations showed that the main terms were related to cellular metabolism, protein modification and cell death regulation pathways, such as the MAP kinase (MAPK) cascade, in a concentration independent manner. Proteomics confirmed the changes in energy metabolism and also provided evidence of F-induced changes in cytoskeleton components of glial cells. Our results not only reveal that F has the potential to modulate gene and protein profiles in human U87 glial-like cells overexposed to F, but also identify a possible role of this ion in cytoskeleton disorganization.

The alveolar bone is an important mineralized structure of the periodontal support apparatus, and information about the methylmercury (MeHg) effects on the structural integrity is scarce. Therefore, this study aimed to investigate whether systemic, chronic, and low-dose exposure to MeHg can change the alveolar bone microstructure of rats. Adult Wistar rats (n = 30) were exposed to 0.04 mg/kg/day of MeHg or vehicle through intragastric gavage. The animals were euthanized after 60 days, and blood samples were collected for trolox equivalent antioxidant capacity (TEAC), glutathione (GSH), lipid peroxidation (LPO), and comet assays. The mandible of each animal was collected and separated into hemimandibles that were used to determine the total Hg level in the bone and to analyze microstructural damage and alveolar bone loss in terms of trabecular number (Tb.N), trabecular thickness (Tb.Th), bone volume fraction (BV/TV), and exposed root area of the second molars. MeHg exposure triggered oxidative stress in blood represented by lower levels of GSH and TEAC and the increase in LPO and DNA damage of the blood cells. High total Hg levels were found in the alveolar bone, and the microstructural analyses showed a reduction in Tb.N, Tb.Th, and BV/TV, which resulted in an increase in the exposed root area and a decrease in bone height. Long-term MeHg exposure promotes a systemic redox imbalance associated with microstructural changes and alveolar bone loss and may indicate a potential risk indicator for periodontal diseases.