Biological effects of a copper-based fungicide on the fruit fly, Drosophila melanogaster.

The increased consumption of pesticides can have a negative environmental impact by increasing the essential metals to toxic levels. Bordasul® is a commonly used fungicide in Brazil and it is composed of 20% Cu, 10% sulfur, and 3.0% calcium. The study of fungicides in vivo in non-target model organisms can predict their environmental impact more broadly. The Drosophila melanogaster is a unique model due to its ease of handling and maintenance. Here, the potential toxicity of Bordasul® was investigated by assessing the development, survival, and behavior of exposed flies. Exposure to Bordasul® impaired the development (p < 0.01) and caused a significant reduction in memory retention (p < 0.05) and locomotor ability (p < 0.001). Fungicides are needed to assure the world's food demand; however, Bordasul® was highly toxic to D. melanogaster. Therefore, Bordasul® may be potentially toxic to non-target invertebrates and new environmentally-safe biofertilizers have to be developed to preserve the biota.

Interplay between diphenyl diselenide and copper: Impact on D. melanogaster survival, behavior, and biochemical parameters.

Copper (Cu2+) is a biologically essential element that participates in numerous physiological processes. However, elevated concentrations of copper have been associated with cellular oxidative stress and neurodegenerative diseases. Organo­selenium compounds such as diphenyl diselenide (DPDS) have in vitro and in vivo antioxidant properties. Hence, we hypothesized that DPDS may modulate the toxicity of Cu2+ in Drosophila melanogaster. The acute effects (4 days of exposure) caused by a high concentration of Cu2+ (3 mM) were studied using endpoints of toxicity such as survival and behavior in D. melanogaster. The potential protective effect of low concentration of DPDS (20 µM) against Cu2+ was also investigated. Adult flies aged 1-5 days post-eclosion (both sexes) were divided into four groups: Control, DPDS (20 µM), CuSO4 (3 mM), and the combined exposure of DPDS (20 µM) and CuSO4 (3 mM). Survival, biochemical, and behavioral parameters were determined. Co-exposure of DPDS and CuSO4 increased acetylcholinesterase (AChE) activity and the generation of reactive oxygen species (ROS as determined by DFCH oxidation). Contrary to our expectation, the co-exposure reduced survival, body weight, locomotion, catalase activity, and cell viability in relation to control group. Taken together, DPDS potentiated the Cu2+ toxicity.

Multibiomarker approach to assess the magnitude of occupational exposure and effects induced by a mixture of metals.

Metals and metalloids including lead (Pb), arsenic (As) and manganese (Mn) can occur as mixtures in occupational contexts, such as mines. These chemicals are all known to be neurotoxic and provoke changes in heme metabolism also known to induce neurotoxicity. The objective of this work was to propose a multi-biomarker (BM) methodology to screen subjects exposed to the mixture of Pb, As and Mn and assess the severity of their exposure/effects, in an individual basis. The urinary levels of the metals, dela-aminolevulinic acid (ALA) and porphyrins were determined in Portuguese miners and in a control group. The combination of Pb and As urinary levels had the highest capability to identify subjects occupationally exposed to this mixture in mines, as evaluated through Receiver Operating Characteristic (ROC) (A = 98.2%; p < 0.05), allowing that 94.2% of 86 studied subjects were properly identified and the generation of an equation indicating the odd of a subject be considered as exposed to the metal mixture. The combination of urinary ALA and porphyrins revealed to be best one to be applied in the assessment of subjects with high, intermediate, and low magnitudes of exposure/effects, with 95.7% of 46 miners classified correctly according to their severity sub-group and allowing to generate equations, which can be applied in new subjects. The proposed methodology showed a satisfactory performance, evaluating in an integrated manner the magnitude of exposure/effects of the exposed workers, may contributing to improve the control of their health.

Assessing the neurotoxicity of the carbamate methomyl in Caenorhabditis elegans with a multi-level approach.

The neurotoxicity and developmental effects of a widely applied insecticide (methomyl) was investigated by a multi-level approach (behavior and biometry, biochemical alterations and neurodegeneration) in Caenorhabditis elegans upon a short-term exposure (1 h) and a post-exposure period (48 h). The 1-h exposure to sub-lethal concentrations of methomyl (lower than 0.320 g L-1; i.e. below the estimated LC10) triggered significant changes on motor behavior and development impairment. The type of movement was significantly altered in methomyl-exposed worms, as well as biometric parameters (worms frequently idle and moving more backwards than controls; small body area, length and wavelength). These effects were followed by an increase of acetylcholine levels. Interestingly, after the 48-h recovery period, movement of previously exposed worms was similar to controls, and a concentration-dependent reversion of biometric endpoints was recorded, pointing out the transient action of the carbamate in line with an apparent absence of cholinergic neurons damage. This study provided new insight on the neurotoxicity of methomyl by showing that effects on movement and development were transient, and apparently did not result in neurodegeneration in cholinergic neurons. Moreover, these findings reinforced the advantages of using C. elegans in a multi-level approach for pesticide effects assessment.

Caenorhabditis elegans as a tool for environmental risk assessment: emerging and promising applications for a "nobelized worm".

Caenorhabditis elegans has been an invaluable model organism in research fields such as developmental biology and neurobiology. Neurotoxicity is one of the subfields greatly profiting from the C. elegans model within biomedical context, while the corresponding potential of the organism applied to environmental studies is relevant but has been largely underexplored. Within the biomedical scope, the implication of metals and organic chemicals with pesticide activity (hereinafter designated as pesticides) in the etiology of several neurodegenerative diseases has been extensively investigated using this nematode as a primary model organism. Additionally, as a well-known experimental model bearing high sensitivity to different contaminants and representing important functional levels in soil and aquatic ecosystems, C. elegans has high potential to be extensively integrated within Environmental Risk Assessment (ERA) routines. In spite of the recognition of some regulatory agencies, this actual step has yet to be made. The purpose of this review is to discuss the major advantages supporting the inclusion of C. elegans in lower tiers of ERA. Special emphasis was given to its sensitivity to metals and pesticides, which is similar to that of other model organisms commonly used in ERA (e.g. Daphnia magna and Eisenia sp.), and to the large array of endpoints that can be tested with the species, both concerning the aquatic and the soil compartments. The inclusion of C. elegans testing may hence represent a relevant advance in ERA, providing ecologically relevant insights toward improvement of the regulatory capacity for establishing appropriate environmental protection benchmarks.

Mechanisms involved in anti-aging effects of guarana (Paullinia cupana) in Caenorhabditis elegans.

Guarana (Paullinia cupana) is habitually ingested by people in the Amazon region and is a key ingredient in various energy drinks consumed worldwide. Extension in longevity and low prevalence of chronic age-related diseases have been associated to habitual intake of guarana. Anti-aging potential of guarana was also demonstrated in Caenorhabditis elegans; however, the mechanisms involved in its effects are not clear. Herein, we investigated the putative pathways that regulate the effects of guarana ethanolic extract (GEE) on lifespan using C. elegans. The major known longevity pathways were analyzed through mutant worms and RT-qPCR assay (DAF-2, DAF-16, SKN-1, SIR-2.1, HSF-1). The possible involvement of purinergic signaling was also investigated. This study demonstrated that GEE acts through antioxidant activity, DAF-16, HSF-1, and SKN-1 pathways, and human adenosine receptor ortholog (ADOR-1) to extend lifespan. GEE also downregulated skn-1, daf-16, sir-2.1 and hsp-16.2 in 9-day-old C. elegans, which might reflect less need to activate these protective genes due to direct antioxidant effects. Our results contribute to the comprehension of guarana effects in vivo, which might be helpful to prevent or treat aging-associated disorders, and also suggest purinergic signaling as a plausible therapeutic target for longevity studies.

Assessment of occupational exposures to multiple metals with urinary porphyrin profiles.

Chronic occupational exposures to low levels of metal mixtures necessitates biomonitoring of exposed workers. However, a single biomarker (BM) is rarely sufficient to ascertain the exposure of an individual to a complex mixture, with multiparameter analysis of the same sample considered recently as a preferred approach. Porphyrins are formed as intermediates of heme biosynthesis and different metals can exert their effects at different points of this metabolic pathway, leading to changed urinary porphyrins excretion profiles. The aim of this work was to develop a model that could serve to identify, on an individual basis, multiple metal exposure resulting from mining work, by using urinary porphyrin profiles. Urine samples of workers were obtained from a Portuguese mining company and a non-occupationally exposed group was used as control. The levels of uro-, hepta-, hexa-, penta-, copro- and protoporphyrins were determined by HPLC. It was observed that only heptaporphyrin levels in miners were significantly (p<0.05) different from controls. However, when the concentrations of all porphyrins were combined by binary logistic regression, their ability to discriminate between miners and controls was higher than each one of the porphyrins alone, as indicated by a greater curve' area under a ROC curve. Moreover, when the combined porphyrins were used to calculate the probability of each subject fit in the occupationally exposed group, 83% of 47 individuals were correctly identified with respect to their type of exposure. These results suggest that the integration of the urinary porphyrin profile is a promising tool for the detection of subjects exhibiting biochemical modifications due to occupational exposure to metals in mines.

Mechanisms involved in anti-aging effects of guarana (Paullinia cupana) in Caenorhabditis elegans

Guarana (Paullinia cupana) is habitually ingested by people in the Amazon region and is a key ingredient in various energy drinks consumed worldwide. Extension in longevity and low prevalence of chronic age-related diseases have been associated to habitual intake of guarana. Anti-aging potential of guarana was also demonstrated in Caenorhabditis elegans; however, the mechanisms involved in its effects are not clear. Herein, we investigated the putative pathways that regulate the effects of guarana ethanolic extract (GEE) on lifespan using C. elegans. The major known longevity pathways were analyzed through mutant worms and RT-qPCR assay (DAF-2, DAF-16, SKN-1, SIR-2.1, HSF-1). The possible involvement of purinergic signaling was also investigated. This study demonstrated that GEE acts through antioxidant activity, DAF-16, HSF-1, and SKN-1 pathways, and human adenosine receptor ortholog (ADOR-1) to extend lifespan. GEE also downregulated skn-1, daf-16, sir-2.1 and hsp-16.2 in 9-day-old C. elegans, which might reflect less need to activate these protective genes due to direct antioxidant effects. Our results contribute to the comprehension of guarana effects in vivo, which might be helpful to prevent or treat aging-associated disorders, and also suggest purinergic signaling as a plausible therapeutic target for longevity studies.

Chemical Speciation of Selenium and Mercury as Determinant of Their Neurotoxicity.

The antagonism of mercury toxicity by selenium has been well documented. Mercury is a toxic metal, widespread in the environment. The main target organs (kidneys, lungs, or brain) of mercury vary depending on its chemical forms (inorganic or organic). Selenium is a semimetal essential to mammalian life as part of the amino acid selenocysteine, which is required to the synthesis of the selenoproteins. This chapter has the aim of disclosing the role of selenide or hydrogen selenide (Se-2 or HSe-) as central metabolite of selenium and as an important antidote of the electrophilic mercury forms (particularly, Hg2+ and MeHg). Emphasis will be centered on the neurotoxicity of electrophile forms of mercury and selenium. The controversial participation of electrophile mercury and selenium forms in the development of some neurodegenerative disease will be briefly presented. The potential pharmacological use of organoseleno compounds (Ebselen and diphenyl diselenide) in the treatment of mercury poisoning will be considered. The central role of thiol (-SH) and selenol (-SeH) groups as the generic targets of electrophile mercury forms and the need of new in silico tools to guide the future biological researches will be commented.

Neurotoxicity of Metal Mixtures.

Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull's, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels. The Substance Priority List of Agency for Toxic Substances and Disease Registry (ATSDR) ranked substances based on a combination of their frequency, toxicity, and potential for human exposure. In this list, As, Pb, Hg, and Cd occupy the first, second, third, and seventh positions, respectively (ATSDR, Priority list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 2016). Besides existing individually, these metals are also (or mainly) found as mixtures in various parts of the ecosystem (Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L, Chemosphere 132:79-86, 2015). Interactions among components of a mixture may change toxicokinetics and toxicodynamics (Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Stürzenbaum SR, Sci Total Environ 408:3725-3734, 2010) and may result in greater (synergistic) toxicity (Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ, Environ Int 37:663-670, 2011). This is particularly worrisome when the components of the mixture individually attack the same organs. On the other hand, metals such as manganese [Mn], iron [Fe], copper [Cu], and zinc [Zn] are essential metals, and their presence in the body below or above homeostatic levels can also lead to disease states (Annangi B, Bonassi S, Marcos R, Hernández A, Mutat Res 770(Pt A):140-161, 2016). Pb, As, Cd, and Hg can induce Fe, Cu, and Zn dyshomeostasis, potentially triggering neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, changes in heme synthesis have been associated with neurodegeneration, supported by evidence that a decline in heme levels might explain the age-associated loss of Fe homeostasis (Atamna H, Killile DK, Killile NB, Ames BN, Proc Natl Acad Sci U S A 99(23):14807-14812, 2002).The sources, disposition, transport to the brain, mechanisms of toxicity, and effects in the central nervous system (CNS) and in the hematopoietic system of each one of these metals will be described. More detailed information on Pb, Mn, Al, Hg, Cu, and Zn is available in other chapters. A major focus of the chapter will be on Pb toxicity and its interaction with other metals.

Imaging metals in Caenorhabditis elegans.

Systemic trafficking and storage of essential metal ions play fundamental roles in living organisms by serving as essential cofactors in various cellular processes. Thereby metal quantification and localization are critical steps in understanding metal homeostasis, and how their dyshomeostasis might contribute to disease etiology and the ensuing pathologies. Furthermore, the amount and distribution of metals in organisms can provide insight into their underlying mechanisms of toxicity and toxicokinetics. While in vivo studies on metal imaging in mammalian experimental animals are complex, time- and resource-consuming, the nematode Caenorhabditis elegans (C. elegans) provides a suitable comparative and complementary model system. Expressing homologous genes to those inherent to mammals, including those that regulate metal homeostasis and transport, C. elegans has become a powerful tool to study metal homeostasis and toxicity. A number of recent technical advances have been made in the development and application of analytical methods to visualize metal ions in C. elegans. Here, we briefly summarize key findings and challenges of the three main techniques and their application to the nematode, namely sensing fluorophores, microbeam synchrotron radiation X-ray fluorescence as well as laser ablation (LA) coupled to inductively coupled plasma-mass spectrometry (ICP-MS).

Neuroprotective and Therapeutic Strategies for Manganese-Induced Neurotoxicity.

Manganese (Mn) is an essential element required for growth, development and general maintenance of health. However, chronic or high occupational and environmental exposure to excessive levels of Mn has long been known to lead to a progressive neurological disorder similar to Parkinsonism. Manganism patients display a variety of symptoms, including mental, cognitive and behavioural impediments, as well as motor dysfunctions that are associated with basal ganglia dysfunction. Taking into account the pharmacokinetics and Mn-related toxicity mechanisms, several neuroprotective compounds and therapeutic approaches have been investigated to assess their efficacy in mitigating its neurotoxicity. Here, we will briefly address some of the toxic mechanisms of Mn, followed by neuroprotective strategies and therapeutic approaches aiming to reduce or treat Mn induced neurotoxicity. Natural and synthetic antioxidants, anti-inflammatory compounds, ATP/ADP ratio protectors and glutamate protectors have been introduced in view of decreasing Mn-induced neurotoxicity. In addition, the efficacy and mechanisms of several therapeutic interventions such as levodopa, ethylene-diamine-tetraacetic acid (EDTA) and para-aminosalicylic acid (PAS), aimed at ameliorating Mn neurotoxic symptoms in humans, will be reviewed.

Clinical practice guideline for the prevention, early detection, diagnosis, management and follow up of type 2 diabetes mellitus in adults / Guía de práctica clínica para la prevención, diagnóstico, tratamiento y seguimiento de la diabetes mellitus tipo 2 en la población mayor de 18 años

In Colombia, diabetes mellitus is a public health program for those responsible for creating and implementing strategies for prevention, diagnosis, treatment, and follow-up that are applicable at all care levels, with the objective of establishing early and sustained control of diabetes. A clinical practice guide has been developed following the broad outline of the methodological guide from the Ministry of Health and Social Welfare, with the aim of systematically gathering scientific evidence and formulating recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The current document presents in summary form the results of this process, including the recommendations and the considerations taken into account in formulating them. In general terms, what is proposed here is a screening process using the Finnish Diabetes Risk Score questionnaire adapted to the Colombian population, which enables early diagnosis of the illness, and an algorithm for determining initial treatment that can be generalized to most patients with diabetes mellitus type 2 and that is simple to apply in a primary care context. In addition, several recommendations have been made to scale up pharmacological treatment in those patients that do not achieve the objectives or fail to maintain them during initial treatment. These recommendations also take into account the evolution of weight and the individualization of glycemic control goals for special populations. Finally, recommendations have been made for opportune detection of micro- and macrovascular complications of diabetes.

En Colombia la Diabetes Mellitus es un problema de salud pública por lo que deben generarse e implementarse estrategias de prevención, diagnóstico, tratamiento y seguimiento, aplicables en todos los niveles de atención con miras a establecer el control de la diabetes en forma temprana y sostenida. Se elaboró una guía de práctica clínica siguiendo los lineamientos de la guía metodológica del Ministerio de Salud y Protección Social para recolectar de forma sistemática la evidencia científica y formular las recomendaciones utilizando la metodología GRADE. El presente documento muestra, de forma resumida, el resultado de ese proceso, incluyendo las recomendaciones y las consideraciones tenidas en cuenta para llegar a ellas. En términos generales, se propone un proceso de tamización mediante el cuestionario FINDRISC adaptado a población Colombiana que permite llegar a un diagnóstico temprano de la enfermedad y un algoritmo para el manejo inicial que es generalizable a la gran mayoría de los pacientes con diabetes mellitus tipo 2 y que es sencillo de aplicar en atención primaria. También se hacen unas recomendaciones para escalar el tratamiento farmacológico de los pacientes que no alcanzan la meta o la pierden con el manejo inicial, teniendo en cuenta principalmente la evolución del peso y la individualización de la meta de control glucémico en poblaciones especiales. Finalmente se proponen algunas recomendaciones para la detección oportuna de las complicaciones micro y macrovasculares de la diabetes.

The role of autophagy in modulation of neuroinflammation in microglia.

Microglia have multiple functions in regulating homeostasis in the central nervous system (CNS), and microglial inflammation is thought to play a role in the etiology of the neurodegenerative diseases. When endogenous or exogenous stimuli trigger disorders in microenvironmental homeostasis in CNS, microglia critically determine the fate of other neural cells. Recently, it was reported that autophagy might influence inflammation and activation of microglia. Though the interaction between autophagy and macrophages has been reported and reviewed in length, the role of autophagy in microglia has yet to be reviewed. Herein, we will highlight recent advances on the emerging role of autophagy in microglia, focusing on the regulation of autophagy during microglial inflammation, and the possible mechanism involved.

Lead, Arsenic, and Manganese Metal Mixture Exposures: Focus on Biomarkers of Effect.

The increasing exposure of human populations to excessive levels of metals continues to represent a matter of public health concern. Several biomarkers have been studied and proposed for the detection of adverse health effects induced by lead (Pb), arsenic (As), and manganese (Mn); however, these studies have relied on exposures to each single metal, which fails to replicate real-life exposure scenarios. These three metals are commonly detected in different environmental, occupational, and food contexts and they share common neurotoxic effects, which are progressive and once clinically apparent may be irreversible. Thus, chronic exposure to low levels of a mixture of these metals may represent an additive risk of toxicity. Building upon their shared mechanisms of toxicity, such as oxidative stress, interference with neurotransmitters, and effects on the hematopoietic system, we address putative biomarkers, which may assist in assessing the onset of neurological diseases associated with exposure to this metal mixture.

An uncommon pattern of polyneuropathy induced by lifetime exposures to drift containing organophosphate pesticides.

The natural history of chronic peripheral polyneuropathy following lifetime low-level organophosphate (OP) exposure was investigated. A pilot study (1984-1987) conducted in rural communities in Israel detected subtle reversible in-season changes in nerve conduction patterns of 17 field workers out of 214 residents exposed to seasonal drift containing OP's. We examined 60 individuals (males: 50/60; 83.3%) from the original cohort still residing (more than 40 years) in the same communities. Exposure assessment was based on reports by Israeli institutions and the Bureau of Statistics. Information on personal status, work experience, exposures and symptoms was collected by questionnaires. The nervous system was systematically studied, evaluating cortical upper motor neurons, corticospinal tracts, lower motor neurons and peripheral nerves. Electrophysiological studies included conduction velocities, amplitudes and distal latencies of sensory and motor median, ulnar, tibial and sural nerves; F-waves for proximal nerve functions; thermal and pain thresholds for small thinly-myelinated and non-myelinated fibers; transcranial magnetic stimulation for large fibers. Clinical and electrophysiological features of Carpal Tunnel Syndrome were found in 18% of the subjects, atypically in males only. Fingertips' tingling correlated with both axonal and myelin-dependent parameters (lower wave amplitudes and prolonged latency periods, respectively) in the sensory median nerves bilaterally. OP exposure significantly correlated to prolonged distal latency in the right median sensory nerve (r=0.29; p=0.052; n=45) and lower wave amplitude in the right sural nerve (p=0.031). These findings attest to subtle, predominantly sensory peripheral polyneuropathy following lifetime low-level exposures to drifts containing OP.

Arsenic and manganese alter lead deposition in the rat.

Lead (Pb) continues to be a major toxic metal in the environment. Pb exposure frequently occurs in the presence of other metals, such as arsenic (As) and manganese (Mn). Continued exposure to low levels of these metals may lead to long-term toxic effects due to their accumulation in several organs. Despite the recognition that metals in a mixture may alter each other's toxicity by affecting deposition, there is dearth of information on their interactions in vivo. In this work, we investigated the effect of As and Mn on Pb tissue deposition, focusing on the kidney, brain, and liver. Wistar rats were treated with eight doses of each single metal, Pb (5 mg/Kg bw), As (60 mg/L), and Mn 10 mg/Kg bw), or the same doses in a triple metal mixture. The kidney, brain, liver, blood, and urine Pb, As, and Mn concentrations were determined by graphite furnace atomic absorption spectrophotometry. The Pb kidney, brain, and liver concentrations in the metal-mixture-treated group were significantly increased compared to the Pb-alone-treated group, being more pronounced in the kidney (5.4-fold), brain (2.5-fold), and liver (1.6-fold). Urinary excretion of Pb in the metal-mixture-treated rats significantly increased compared with the Pb-treated group, although blood Pb concentrations were analogous to the Pb-treated group. Co-treatment with As, Mn, and Pb alters Pb deposition compared to Pb alone treatment, increasing Pb accumulation predominantly in the kidney and brain. Blood Pb levels, unlike urine, do not reflect the increased Pb deposition in the kidney and brain. Taken together, the results suggest that the nephro- and neurotoxicity of "real-life" Pb exposure scenarios should be considered within the context of metal mixture exposures.

Manganese toxicity in the central nervous system: the glutamine/glutamate-γ-aminobutyric acid cycle.

Manganese (Mn) is an essential trace element that is required for maintaining proper function and regulation of numerous biochemical and cellular reactions. Despite its essentiality, at excessive levels Mn is toxic to the central nervous system (CNS). Increased accumulation of Mn in specific brain regions, such as the substantia nigra, globus pallidus and striatum, triggers neurotoxicity resulting in a neurological brain disorder, termed manganism. Mn has been also implicated in the pathophysiology of several other neurodegenerative diseases. Its toxicity is associated with disruption of the glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle (GGC) between astrocytes and neurons, thus leading to changes in Glu-ergic and/or GABAergic transmission and Gln metabolism. Here we discuss the common mechanisms underlying Mn-induced neurotoxicity and their relationship to CNS pathology and GGC impairment.

Prolactin is a peripheral marker of manganese neurotoxicity.

UNLABELLED: Excessive exposure to Mn induces neurotoxicity, referred to as manganism. Exposure assessment relies on Mn blood and urine analyses, both of which show poor correlation to exposure. Accordingly, there is a critical need for better surrogate biomarkers of Mn exposure. The aim of this study was to examine the relationship between Mn exposure and early indicators of neurotoxicity, with particular emphasis on peripheral biomarkers. Male Wistar rats (180-200g) were injected intraperitoneally with 4 or 8 doses of Mn (10mg/kg). Mn exposure was evaluated by analysis of Mn levels in brain and blood along with biochemical end-points (see below). RESULTS: Brain Mn levels were significantly increased both after 4 and 8 doses of Mn compared with controls (p<0.001). Blood levels failed to reflect a dose-dependent increase in brain Mn, with only the 8-dose-treated group showing significant differences (p<0.001). Brain glutathione (GSH) levels were significantly decreased in the 8-dose-treated animals (p<0.001). A significant and dose-dependent increase in prolactin levels was found for both treated groups (p<0.001) compared to controls. In addition, a decrease in motor activity was observed in the 8-dose-treated group compared to controls. CONCLUSIONS: (1) The present study demonstrates that peripheral blood level is a poor indicator of Mn brain accumulation and exposure; (2) Mn reduces GSH brain levels, likely reflecting oxidative stress; (3) Mn increases blood prolactin levels, indicating changes in the integrity of the dopaminergic system. Taken together these results suggest that peripheral prolactin levels may serve as reliable predictive biomarkers of Mn neurotoxicity.