RESUMEN
There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Microcefalia , Recién Nacido , Humanos , Femenino , Lactante , Masculino , Discapacidad Intelectual/genética , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Tamizaje Neonatal , Estudios Transversales , Factor de Maduración de la Glia , Aminoácidos de Cadena Ramificada/metabolismo , Microcefalia/genéticaRESUMEN
Multiresistance plasmids belonging to the IncI incompatibility group have become one of the most pervasive plasmid types in extended-spectrum beta-lactamase-producing Escherichia coli of animal origin. The extent of the burden imposed on the bacterial cell by these plasmids seems to modulate the emergence of "epidemic" plasmids. However, in vivo data in the natural environment of the strains are scarce. Here, we investigated the cost of a bla CTX-M-1-IncI1 epidemic plasmid in a commensal E. coli animal strain, UB12-RC, before and after oral inoculation of 15 6- to 8-week- old specific-pathogen-free pigs. Growth rate in rich medium was determined on (i) UB12-RC and derivatives, with or without plasmid, in vivo and/or in vitro evolved, and (ii) strains that acquired the plasmid in the gut during the experiment. Although bla CTX-M-1-IncI1 plasmid imposed no measurable burden on the recipient strain after conjugation and during the longitudinal carriage in the pig's gut, we observed a significant difference in the bacterial growth rate between IncI1 plasmid-carrying and plasmid-free isolates collected during in vivo carriage. Only a few mutations on the chromosome of the UB12-RC derivatives were detected by whole-genome sequencing. RNA-Seq analysis of a selected set of these strains showed that transcriptional responses to the bla CTX-M-1-IncI1 acquisition were limited, affecting metabolism, stress response, and motility functions. Our data suggest that the effect of IncI plasmid on host cells is limited, fitness cost being insufficient to act as a barrier to IncI plasmid spread among natural population of E. coli in the gut niche.
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Infecciones por Escherichia coli , Escherichia coli , Animales , Porcinos , Antibacterianos , Plásmidos/genética , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Infecciones por Escherichia coli/microbiologíaRESUMEN
Over the last several years human sperm quality was found to be significantly reduced and the role environmental contaminants play in this phenomenon remain to be determined. Mercury (Hg) is one of the most widespread contaminants; however the correlation between metal exposure and adverse consequences on human and animals fertility are not completely established. The aim of this study was to determine the effects of direct exposure to inorganic Hg on male gametes using spermatozoa (bovine sperm) which characteristically resemble human sperm. Sperm were divided and incubated for 0.5, 1 or 2 h at low levels of Hg: i) Control: without exposure; ii) Hg8 nM: mercury chloride (HgCl2) at 8 nM and iii) Hg8 µM: HgCl2 at 8 µM. Sperm kinetics, morphology, sperm membrane integrity, and in vitro fertilization were assessed. In addition the levels of reactive oxygen species (ROS), lipid peroxidation and total antioxidant capacity were measured. Hg exposure for 2 h impaired sperm morphology and membrane integrity as well as kinetic parameters including curvilinear velocity and straight-line velocity, which are needed for fertilization as evidenced by the reduced fertilization rate in 8 µM Hg-treated gametes. Hg enhanced oxidative stress in male sperm as reflected by elevated levels of ROS and lipid peroxidation and decreased antioxidant capacity. Data demonstrated that low levels of Hg when incubated with spermatozoa are sufficient to increase oxidative stress, adversely affect sperm quality parameters, subsequently impairing sperm fertility capacity.
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Contaminantes Ambientales/análisis , Contaminantes Ambientales/toxicidad , Fertilidad/efectos de los fármacos , Mercurio/análisis , Mercurio/toxicidad , Motilidad Espermática/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Adulto , Animales , Bovinos , Monitoreo del Ambiente , Humanos , Masculino , Persona de Mediana Edad , Modelos Animales , Recuento de EspermatozoidesRESUMEN
Mercury is a ubiquitous environmental pollutant and mercury contamination and toxicity are serious hazards to human health. Some studies have shown that mercury impairs male reproductive function, but less is known about its effects following exposure at low doses and the possible mechanisms underlying its toxicity. Herein we show that exposure of rats to mercury chloride for 30 days (first dose 4.6µgkg-1, subsequent doses 0.07µgkg-1day-1) resulted in mean (±s.e.m.) blood mercury concentrations of 6.8±0.3ngmL-1, similar to that found in human blood after occupational exposure or released from removal of amalgam fillings. Even at these low concentrations, mercury was deposited in reproductive organs (testis, epididymis and prostate), impaired sperm membrane integrity, reduced the number of mature spermatozoa and, in the testes, promoted disorganisation, empty spaces and loss of germinal epithelium. Mercury increased levels of reactive oxygen species and the expression of glutathione peroxidase (GPx) 1 and GPx4. These results suggest that the toxic effects of mercury on the male reproductive system are due to its accumulation in reproductive organs and that the glutathione system is its potential target. The data also suggest, for the first time, a possible role of the selenoproteins GPx1 and GPx4 in the reproductive toxicity of mercury chloride.
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Glutatión Peroxidasa/metabolismo , Mercurio/farmacología , Motilidad Espermática/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Animales , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Glutatión/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Espermatozoides/metabolismo , Testículo/metabolismoRESUMEN
AIMS: Aluminum (Al) is an important environmental contaminant; however, there are not enough evidences of Al-induced cardiovascular dysfunction. We investigated the effects of acute exposure to aluminum chloride (AlCl3) on blood pressure, vascular reactivity and oxidative stress. METHODS AND RESULTS: Male Wistar rats were divided into two groups: Untreated: vehicle (ultrapure water, ip) and AlCl3: single dose of AlCl3 (100mg/kg,ip). Concentration-response curves to phenylephrine in the absence and presence of endothelium, the nitric oxide synthase inhibitor l-NAME, the potassium channel blocker tetraethylammonium, and the NADPH oxidase inhibitor apocynin were performed in segments from aortic and mesenteric resistance arteries. NO released was assessed in aorta and reactive oxygen species (ROS), malondialdehyde, non-protein thiol levels, antioxidant capacity and enzymatic antioxidant activities were investigated in plasma, aorta and/or mesenteric arteries. After one hour of AlCl3 exposure serum Al levels attained 147.7±25.0µg/L. Al treatment: 1) did not affect blood pressure, heart rate and vasodilator responses induced by acetylcholine or sodium nitroprusside; 2) decreased phenylephrine-induced vasoconstrictor responses; 3) increased endothelial modulation of contractile responses, NO release and vascular ROS production from NADPH oxidase; 4) increased plasmatic, aortic and mesenteric malondialdehyde and ROS production, and 5) decreased antioxidant capacity and affected the antioxidant biomarkers non-protein thiol levels, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and catalase enzymatic activities. CONCLUSION: AlCl3-acute exposure reduces vascular reactivity. This effect is associated with increased NO production, probably acting on K+ channels, which seems to occur as a compensatory mechanism against Al-induced oxidative stress. Our results suggest that Al exerts toxic effects to the vascular system.
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Aluminio/toxicidad , Arterias/efectos de los fármacos , Resistencia Vascular , Animales , Arterias/metabolismo , Arterias/fisiología , Masculino , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVE: To investigate the relation between pelvic floor muscle strength and sexual function among women with higher and lower pelvic floor muscle strength. DESIGN: A cross-sectional study was performed among employees and students of the University. SETTING: Urogynecology department, Federal University of Pampa, Brazil, carried out between January and July of 2012. POPULATION: Forty women, aged 20-28 years. METHODS: Forty-nine women were screened and nine were excluded. Baseline information of the participants was obtained. The Female Sexual Function Index questionnaire was applied and pelvic floor muscle strength was randomly measured by transvaginal palpation according to the Ortiz scale, and by perineometry. Women were allocated into two groups according to muscle strength. MAIN OUTCOME MEASURES: Index of sexual function and pelvic floor muscle strength RESULTS: Women with stronger pelvic floor muscles scored higher in the following domains: desire, excitement, orgasm and general score of the questionnaire (4.9 ± 0.73 vs. 3.8 ± 0.58; 5.0 ± 0.35 vs. 4.3 ± 0.82; 5.8 ± 0.21 vs. 4.0 ± 1.00 and 32.4 ± 0.77 vs. 27.6 ± 3.29, p < 0.001). There was a moderate correlation between pelvic floor muscle pressure and both sexual satisfaction (r = 0.47, p = 0.03) and lubrication (r = -0.69, p = 0.001) as well as the manual evaluation of pelvic floor muscle strength, graded by the Ortiz and perineometry, which were interrelated (r = 0.65, p = 0.001). CONCLUSION: Our findings suggest that women with stronger pelvic floor muscles have better sexual function.
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Fuerza Muscular , Diafragma Pélvico/fisiología , Sexualidad/fisiología , Adulto , Secreciones Corporales/fisiología , Estudios Transversales , Femenino , Humanos , Manometría , Contracción Muscular , Orgasmo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Mercury (Hg) is a widespread environmental pollutant that adversely affects the male reproductive system. The precise mechanisms underlying mercuric chloride (HgCl2)-induced toxicity are not fully understood; however, evidence indicates that oxidative stress may be involved in this process. Although the adverse effects of high levels of inorganic Hg on the male reproductive system have been investigated, the effects of low levels of exposure are unknown. Therefore, the aim of this study was to investigate the effects of chronic exposure to low concentrations of HgCl2 on sperm parameters, lipid peroxidation, and antioxidant activity of male rats. Three-month-old male Wistar rats were treated for 30 d and divided into groups: control (saline, i.m.) and HgCl2 group (i.m., first dose 4.6 µg/kg, subsequent doses 0.07 µg/kg/d). Sperm parameters (count, motility and morphology) and biomarkers of oxidative stress in testis, epididymis, prostate, and vas deferens were analyzed. Mercury treatment produced a reduction in sperm quantity (testis and epididymis) and daily sperm production, following by decrease in sperm motility and increase on head and tail morphologic abnormalities. HgCl2 exposure was correlated with enhanced oxidative stress in reproductive organs, represented not only by augmented lipid peroxidation but also by changes in antioxidant enzymes activity superoxide dismutase (SOD) and catalase (CAT) and nonprotein thiol levels. In conclusion, chronic exposure to low doses of Hg impaired sperm quality and adversely affected male reproductive functions, which may be due, at least in part, to enhanced oxidative stress.
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Contaminantes Ambientales/toxicidad , Cloruro de Mercurio/toxicidad , Estrés Oxidativo/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Recuento de Espermatozoides , Motilidad Espermática/efectos de los fármacos , Espermatozoides/patología , Espermatozoides/fisiología , Pruebas de Toxicidad CrónicaRESUMEN
Importance: Sleep disorders are one of the most frequent comorbidities in children with autism spectrum disorder (ASD). However, the link between neurodevelopmental effects in ASD children with their underlying sleep microarchitecture is not well understood. An improved understanding of etiology of sleep difficulties and identification of sleep-associated biomarkers for children with ASD can improve the accuracy of clinical diagnosis. Objectives: To investigate whether machine learning models can identify biomarkers for children with ASD based on sleep EEG recordings. Design setting and participants: Sleep polysomnogram data were obtained from the Nationwide Children' Health (NCH) Sleep DataBank. Children (ages: 8-16 yrs) with 149 autism and 197 age-matched controls without neurodevelopmental diagnosis were selected for analysis. An additional independent age-matched control group (n = 79) selected from the Childhood Adenotonsillectomy Trial (CHAT) was also used to validate the models. Furthermore, an independent smaller NCH cohort of younger infants and toddlers (age: 0.5-3 yr.; 38 autism and 75 controls) was used for additional validation. Main outcomes and measures: We computed periodic and non-periodic characteristics from sleep EEG recordings: sleep stages, spectral power, sleep spindle characteristics, and aperiodic signals. Machine learning models including the Logistic Regression (LR) classifier, Support Vector Machine (SVM), and Random Forest (RF) model were trained using these features. We determined the autism class based on the prediction score of the classifier. The area under the receiver operating characteristics curve (AUC), accuracy, sensitivity, and specificity were used to evaluate the model performance. Results: In the NCH study, RF outperformed two other models with a 10-fold cross-validated median AUC of 0.95 (interquartile range [IQR], [0.93, 0.98]). The LR and SVM models performed comparably across multiple metrics, with median AUC 0.80 [0.78, 0.85] and 0.83 [0.79, 0.87], respectively. In the CHAT study, three tested models have comparable AUC results: LR: 0.83 [0.76, 0.92], SVM: 0.87 [0.75, 1.00], and RF: 0.85 [0.75, 1.00]. Sleep spindle density, amplitude, spindle-slow oscillation (SSO) coupling, aperiodic signal's spectral slope and intercept, as well as the percentage of REM sleep were found to be key discriminative features in the predictive models. Conclusion and relevance: Our results suggest that integration of EEG feature engineering and machine learning can identify sleep-based biomarkers for ASD children and produce good generalization in independent validation datasets. Microstructural EEG alterations may help reveal underlying pathophysiological mechanisms of autism that alter sleep quality and behaviors. Machine learning analysis may reveal new insight into the etiology and treatment of sleep difficulties in autism.
RESUMEN
BACKGROUND: Metabolic syndrome (Met-S) is considered one of the most important health problems of the 21st century. It includes a group of metabolic disorders that increase the risk of cardiovascular diseases such as overweight and obesity, elevated lipid profile and blood pressure and insulin resistance (IR). Based on the information mentioned above in which there seems to be a relationship between IR and Met-S, the objective of this work was twofold: on the one hand, to assess the relationship between the values of different insulin resistance risk scales and Met-S determined with three different scales, and on the other, to determine whether any of the components of Met-S predispose more to the appearance of IR. METHODS: A descriptive cross-sectional study of 418,343 workers. Waist circumference was measured and evaluated together with six formulas to assess the insulin resistance index. Categorical variables were evaluated by calculating the frequency and distribution of each one. For quantitative variables, mean and standard deviation were determined, and Student's t-test was applied, while for qualitative variables, the chi-square test was performed. The usefulness of the different risk scales for insulin resistance for predicting metabolic syndrome was evaluated using ROC curves, the area under the curve (AUC), as well as their cut-off points for sensitivity, specificity, and the Youden index. RESULTS: People with metabolic syndrome applying any criteria had higher values in the IR risk scales. The different IR scales made it possible to adequately classify people with metabolic syndrome. Of the three definitions of Met-S, the one that showed the greatest relationship with IR was IDF. CONCLUSIONS: Most risk scales for insulin resistance enable the presence of metabolic syndrome to be adequately classified, finding the best ones if the International Diabetes Federation (IDF) criteria are applied. Of the elements included in the Met-S, the one that seems to increase the risk of presenting IR the most is waist circumference; hence, the Met-S definition that is most related to IR is that of the IDF, which is the only one of the three in which a high value of waist circumference is necessary to be able to diagnose Met-S. Waist circumference can be considered the central essential component for detecting insulin resistance and, therefore, the early detection of metabolic syndrome.
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Resistencia a la Insulina , Síndrome Metabólico , Adulto , Humanos , Síndrome Metabólico/diagnóstico , Resistencia a la Insulina/fisiología , Circunferencia de la Cintura/fisiología , Estudios Transversales , Obesidad/complicaciones , Obesidad/diagnóstico , Obesidad/metabolismo , Factores de RiesgoRESUMEN
Aluminum (Al) is a non-essential metal omnipresent in human life and is considered an environmental toxicant. Al increases reactive oxygen production and triggers immune responses, contributing to chronic systemic inflammation development. Here, we have tested whether an egg white hydrolysate (EWH) with potential bioactive properties can protect against changes in reproductive function in rats exposed to long-term Al dietary levels at high and low doses. Male Wistar rats received orally: low aluminum level group-AlCl3 at 8.3 mg/kg b.w. for 60 days with or without EWH (1 g/kg/day); high aluminum level group-AlCl3 at 100 mg/kg b.w. for 42 days with or without EWH (1 g/kg/day). The co-administration of EWH prevented the increased Al deposition surrounding the germinative cells, reducing inflammation and oxidative stress in the reproductive organs. Furthermore, the daily supplementation with EWH maintained sperm production and sperm quality similar to those found in control animals, even after Al exposure at a high dietary contamination level. Altogether, our results suggest that EWH could be used as a protective agent against impairment in the reproductive system produced after long-term exposure to Al at low or high human dietary levels.
RESUMEN
Aluminum (Al) is toxic for humans and animals. Here, we have tested the potential for Egg White Hydrolysate (EWH) to protect against cardiovascular changes in rats exposed to both high and low dietary levels of Al. Indeed, EWH has been previously shown to improve cardio metabolic dysfunctions induced by chronic exposure to heavy metals. Male Wistar rats received orally: Group 1) Low aluminum level (AlCl3 at a dose of 8.3â¯mg/kg b.w. during 60 days) with or without EWH treatment (1â¯g/kg/day); Group 2) High aluminum level (AlCl3 at a dose of 100â¯mg/kg b.w. during 42 days) with or without EWH treatment. After Al treatment, rats co-treated with EWH did not show vascular dysfunction or increased blood pressure as was observed in non EWH-cotreated animals. Indeed, co-treatment with EWH prevented the following effects observed in both aorta and mesenteric arteries: the increased vascular responses to phenylephrine (Phe), the decreased ACh-induced relaxation, the reduction on endothelial modulation of vasoconstrictor responses and the nitric oxide bioavailability, as well as the increased reactive oxygen species production from NAD(P)H oxidase. Altogether, our results suggest that EWH could be used as a protective agent against the harmful vascular effects after long term exposure to Al.
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Antioxidantes/farmacología , Proteínas del Huevo/farmacología , Clara de Huevo/química , Hidrolisados de Proteína/farmacología , Enfermedades Vasculares/prevención & control , Aluminio , Animales , Antioxidantes/química , Ciclooxigenasa 2/metabolismo , Proteínas del Huevo/química , Endotelio Vascular/efectos de los fármacos , Hidrólisis , Masculino , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Tromboxano-A Sintasa/metabolismo , Enfermedades Vasculares/inducido químicamente , Vasoconstricción/efectos de los fármacosRESUMEN
Aluminum (Al), which is omnipresent in human life, is a potent neurotoxin. Here, we have tested the potential for Egg White Hydrolysate (EWH) to protect against changes in cognitive function in rats exposed to both high and low levels of Al. Indeed, EWH has been previously shown to improve the negative effects induced by chronic exposure to heavy metals. Male Wistar rats received orally: Group 1) Low aluminum level (AlCl3 at a dose of 8.3 mg/kg b.w. during 60 days) with or without EWH treatment (1 g/kg/day); Group 2) High aluminum level (AlCl3 at a dose of 100 mg/kg b.w. during 42 days) with or without EWH treatment (1 g/kg/day). After 60 or 42 days of exposure, rats exposed to Al and EWH did not show memory or cognitive dysfunction as was observed in Al-treated animals. Indeed, co-treatment with EWH prevented catalepsy, hippocampal oxidative stress, cholinergic dysfunction and increased number of activated microglia and COX-2-positive cells induced by Al exposure. Altogether, since hippocampal inflammation and oxidative damage were partially prevented by EWH, our results suggest that it could be used as a protective agent against the detrimental effects of long term exposure to Al.
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Aluminio/toxicidad , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/prevención & control , Clara de Huevo , Alimentos Funcionales , Hidrolisados de Proteína/uso terapéutico , Acetilcolinesterasa/metabolismo , Animales , Antioxidantes/metabolismo , Conducta Animal , Peso Corporal , Ciclooxigenasa 2/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Aluminum (Al) is a neurotoxic associated with a number of chronic human diseases. We investigated the effects of Al exposure at doses similar to human dietary levels and at a high level exposure to Al on the peripheral nervous system. Wistar male rats were divided into two major groups and received orally: 1) First group - Low level - rats were subdivided and treated for 60days: a) Control - received ultrapure water; b) AlCl3 - received Al at 8.3mg/kg body weight (bw) for 60days; and 2) Second group - High level - rats were subdivided and treated for 42days: C) Control - received ultrapure water through oral gavage; d) AlCl3 - received Al at 100mg/kg bw for 42days. Von Frey hair test, plantar test, the presence of catalepsy and the spontaneous motor activity were investigated. Reactive oxygen species, lipid peroxidation and total antioxidant capacity, immunohistochemistry to investigate the nerve inflammation and, the specific presence of Al in the sciatic nerve fibers were investigated. Al exposure at a representative human dietary level promotes the development of mechanical allodynia, catalepsy, increased inflammation in the sciatic nerve, systemic oxidative stress and, is able to be retained in the sciatic nerve. The effects of low-dose Al were similar to those found in rats exposed to Al at a dose much higher (100mg/kg). Our findings suggest that Al may be considered toxic for the peripheral nervous system, thus inducing peripheral dysfunction.
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Aluminio/toxicidad , Neuritis/etiología , Síndromes de Neurotoxicidad/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/etiología , Sistema Nervioso Periférico/efectos de los fármacos , Contaminantes del Agua/toxicidad , Aluminio/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Catalepsia/etiología , Relación Dosis-Respuesta a Droga , Hiperalgesia/etiología , Peroxidación de Lípido/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Neuritis/inmunología , Neuritis/metabolismo , Neuritis/fisiopatología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Sistema Nervioso Periférico/inmunología , Sistema Nervioso Periférico/fisiopatología , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ratas Wistar , Especies Reactivas de Oxígeno/sangre , Especies Reactivas de Oxígeno/metabolismo , Nervio Ciático/efectos de los fármacos , Nervio Ciático/inmunología , Nervio Ciático/metabolismo , Nervio Ciático/patología , Factores de Tiempo , Distribución Tisular , Pruebas de Toxicidad Crónica , Toxicocinética , Contaminantes del Agua/administración & dosificaciónRESUMEN
Aluminum (Al) is a significant environmental contaminant. While a good deal of research has been conducted on the acute neurotoxic effects of Al, little is known about the effects of longer-term exposure at human dietary Al levels. Therefore, the purpose of this study was to investigate the effects of 60-day Al exposure at low doses for comparison with a model of exposure known to produce neurotoxicity in rats. Three-month-old male Wistar rats were divided into two major groups: (1) low aluminum levels, and (2) a high aluminum level. Group 1 rats were treated orally by drinking water for 60 days as follows: (a) control-received ultrapure drinking water; (b) aluminum at 1.5 mg/kg b.w., and (c) aluminum at 8.3 mg/kg b.w. Group 2 rats were treated through oral gavages for 42 days as follows: (a) control-received ultrapure water; (b) aluminum at 100 mg/kg b.w. We analyzed cognitive parameters, biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in hippocampus and prefrontal cortex. Al treatment even at low doses promoted recognition memory impairment seen in object recognition memory testing. Moreover, Al increased hippocampal reactive oxygen species and lipid peroxidation, reduced antioxidant capacity, and decreased AChE activity. Our data demonstrate that 60-day subchronic exposure to low doses of Al from feed and added to the water, which reflect human dietary Al intake, reaches a threshold sufficient to promote memory impairment and neurotoxicity. The elevation of oxidative stress and cholinergic dysfunction highlight pathways of toxic actions for this metal.
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Aluminio/toxicidad , Trastornos de la Memoria/inducido químicamente , Acetilcolinesterasa/metabolismo , Administración Oral , Animales , Antioxidantes/metabolismo , Dieta , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Agua Potable , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/metabolismo , Actividad Motora/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Contaminantes del Agua/toxicidad , Contaminación Química del AguaRESUMEN
Concerns about environmental aluminum (Al) and reproductive health have been raised. We investigated the effects of Al exposure at a human relevant dietary level and a high level exposure to Al. Experiment 1 (Lower level) rats were treated orally for 60 days: a) controls - ultrapure water; b) aluminum at 1.5mg/kg bw/day and c) aluminum at 8.3mg/kg bw/day. Experiment 2 (High level) rats were treated for 42 days: a) controls - ultrapure water; b) aluminum at 100mg/kg bw/day. Al decreased sperm count, daily sperm production, sperm motility, normal morphological sperm, impaired testis histology; increased oxidative stress in reproductive organs and inflammation in testis. Our study shows the specific presence of Al in the germinative cells and, that low concentrations of Al in testes (3.35µg/g) are sufficient to impair spermatogenesis and sperm quality. Our findings provide a better understanding of the reproductive health risk of Al.
Asunto(s)
Aluminio/toxicidad , Espermatozoides/efectos de los fármacos , Animales , Dieta , Epidídimo/efectos de los fármacos , Epidídimo/patología , Humanos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Recuento de Espermatozoides , Motilidad Espermática/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Espermatozoides/anomalías , Espermatozoides/fisiología , Testículo/efectos de los fármacos , Testículo/patologíaRESUMEN
Aluminum (Al) is a non-essential metal and a significant environmental contaminant and is associated with a number of human diseases including cardiovascular disease. We investigated the effects of Al exposure at doses similar to human dietary levels on the cardiovascular system over a 60day period. Wistar male rats were divided into two major groups and received orally: 1) Low aluminum level - rats were subdivided and treated for 60days as follows: a) Untreated - ultrapure water; b) AlCl3 at a dose of 8.3mg/kg bw for 60days, representing human Al exposure by diet; and 2) High aluminum level - rats were subdivided and treated for 42days as follows: C) Untreated - ultrapure water; d) AlCl3 at 100mg/kg bw for 42days, representing a high level of human exposure to Al. Effects on systolic blood pressure (SBP) and vascular function of aortic and mesenteric resistance arteries (MRA) were studied. Endothelium and smooth muscle integrity were evaluated by concentration-response curves to acetylcholine (ACh) and sodium nitroprusside. Vasoconstrictor responses to phenylephrine (Phe) in the presence and absence of endothelium and in the presence of the NOS inhibitor L-NAME, the potassium channels blocker TEA, the NAD(P)H oxidase inhibitor apocynin, superoxide dismutase (SOD), the non-selective COX inhibitor indomethacin and the selective COX-2 inhibitor NS 398 were analyzed. Vascular reactive oxygen species (ROS), lipid peroxidation and total antioxidant capacity, were measured. The mRNA expressions of eNOS, NAD(P)H oxidase 1 and 2, SOD1, COX-2 and thromboxane A2 receptor (TXA-2 R) were also investigated. Al exposure at human dietary levels impaired the cardiovascular system and these effects were almost the same as Al exposure at much higher levels. Al increased SBP, decreased ACh-induced relaxation, increased response to Phe, decreased endothelial modulation of vasoconstrictor responses, the bioavailability of nitric oxide (NO), the involvement of potassium channels on vascular responses, as well as increased ROS production from NAD(P)H oxidase and contractile prostanoids mainly from COX-2 in both aorta and mesenteric arteries. Al exposure increased vascular ROS production and lipid peroxidation as well as altered the antioxidant status in aorta and MRA. Al decreased vascular eNOS and SOD1 mRNA levels and increased the NAD(P)H oxidase 1, COX-2 and TXA-2 R mRNA levels. Our results point to an excess of ROS mainly from NAD(P)H oxidase after Al exposure and the increased vascular prostanoids from COX-2 acting in concert to decrease NO bioavailability, thus inducing vascular dysfunction and increasing blood pressure. Therefore, 60-day chronic exposure to Al, which reflects common human dietary Al intake, appears to pose a risk for the cardiovascular system.
Asunto(s)
Compuestos de Aluminio/toxicidad , Presión Sanguínea/efectos de los fármacos , Cloruros/toxicidad , Ciclooxigenasa 2/metabolismo , Dieta , Endotelio Vascular/efectos de los fármacos , Hipertensión/inducido químicamente , NADH NADPH Oxidorreductasas/metabolismo , Vasoconstricción/efectos de los fármacos , Cloruro de Aluminio , Animales , Inhibidores de la Ciclooxigenasa 2/farmacología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/enzimología , Endotelio Vascular/fisiopatología , Humanos , Hipertensión/enzimología , Hipertensión/genética , Hipertensión/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Masculino , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/genética , NADPH Oxidasa 1 , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Receptores de Tromboxano A2 y Prostaglandina H2/efectos de los fármacos , Receptores de Tromboxano A2 y Prostaglandina H2/genética , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismo , Medición de Riesgo , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Factores de TiempoRESUMEN
Oxidative stress in known to contribute to the male reproductive dysfunction induced by mercury (Hg). Our study tested the hypothesis that the egg white hydrolysate (EWH), a potent antioxidant in vitro, is able to prevent the effects of prolonged Hg exposure on male reproductive system in rats. For this, rats were treated for 60 days with: a) Untreated - saline solution (i.m.); b) Hydrolysate - EWH (1 g/kg/day, gavage); c) Mercury - HgCl2 (1st dose 4.6 µg/kg, subsequent doses 0.07 µg/kg/day, i.m.); d) Hydrolysate-Mercury. At the end of the treatment, sperm motility, count and morphological studies were performed; Reactive Oxygen Species (ROS) levels, lipid peroxidation, antioxidant capacity, histological and immunohistochemical assays on testis and epididymis were also carried out. As results, HgCl2-treatment decreased sperm number, increased sperm transit time in epididymis and impaired sperm morphology. However, these harmful effects were prevented by EWH. HgCl2-treatment also increased ROS levels, lipid peroxidation and antioxidant capacity in testis and epididymis as well as promoted testicular inflammation and histological changes in epididymis. EWH improved histological and immunohistochemical alterations, probably due to its antioxidant property. In conclusion, the EWH could represent a powerful natural alternative to protect the male reproductive system against Hg-induced sperm toxicity.
Asunto(s)
Antioxidantes/metabolismo , Clara de Huevo/química , Inflamación/tratamiento farmacológico , Intoxicación por Mercurio/tratamiento farmacológico , Mercurio/toxicidad , Fragmentos de Péptidos/farmacología , Reproducción/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Epidídimo/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/patología , Masculino , Intoxicación por Mercurio/etiología , Intoxicación por Mercurio/patología , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/uso terapéutico , Ratas , Ratas Wistar , Recuento de Espermatozoides , Motilidad Espermática/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/patología , Testículo/efectos de los fármacos , Testículo/patologíaRESUMEN
The study aimed to investigate whether the Egg White Hydrolysate (EWH) is able to prevent the recognition memory disorders associated with long-term Hg exposure in rats. For this, male Wistar rats were treated for 60 days with: a) Untreated: saline solution (i.m.); b) Hydrolysate: EWH (1 g/kg/day, gavage); c) Mercury: HgCl2 (1st dose 4.6 µg/kg, subsequent doses 0.07 µg/kg/day, i.m.); d) Hydrolysate-Mercury. Object recognition memory test was performed to verify Short (STM) and Long-Term Memory (LTM) and Open Field, Plus Maze and Tail Flick tests were performed as control for behavioural experiments. Reactive Oxygen Species (ROS) in the hippocampus were determined by the dichlorofluorescein diacetate (DCFH-DA) method, malondialdehyde (MDA) levels by TBARS, antioxidant power by FRAP assay and total Hg concentration by atomic fluorescence spectrometry. We confirm that the STM and LTM were impaired in adult rats exposed to Hg at low concentrations, which may be related to the increased metal deposition, ROS production and subsequent oxidative damage in the hippocampus. In addition, we demonstrated for the first time that EWH treatment is able to prevent memory impairment induced by Hg exposure, reducing Hg content and ROS production in the hippocampus. In conclusion, EWH prevents memory impairments induced by chronic exposure to low doses of Hg. These findings may represent a good public health strategy since they indicate that EWH is a promising candidate as a new natural therapy for heavy metal intoxication.
Asunto(s)
Antioxidantes/farmacología , Peroxidación de Lípido/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Mercurio/farmacología , Hidrolisados de Proteína/metabolismo , Animales , Clara de Huevo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Especies Reactivas de Oxígeno/farmacologíaRESUMEN
Mercury is a toxic and bio-accumulative heavy metal of global concern. While good deals of research have been conducted on the toxic effects of mercury, little is known about the mechanisms involved in the pathogenesis of male reproductive dysfunction induced by mercury. Therefore, the purpose of this study was to assess the effects and underlying mechanisms of chronic mercury exposure at low levels on male reproductive system of rats. Three-month-old male Wistar rats were divided into two groups and treated for 60 days with saline (i.m., Control) and HgCl2 (i.m. 1st dose: 4.6 µg/kg, subsequent doses 0.07 µg/kg/day). We analyzed sperm parameters, hormonal levels and biomarkers of oxidative stress in testis, epididymis, prostate and vas deferens. Mercury treatment decreased daily sperm production, count and motility and increased head and tail morphologic abnormalities. Moreover, mercury treatment decreased luteinizing hormone levels, increased lipid peroxidation on testis and decreased antioxidant enzymes activities (superoxide dismutase and catalase) on reproductive organs. Our data demonstrate that 60-day chronic exposure to low concentrations of HgCl2 impairs sperm quality and promotes hormonal imbalance. The raised oxidative stress seems to be a potential mechanism involved on male reproductive toxicity by mercury.