RESUMO
There is solid epidemiological evidence that arsenic exposure leads to cognitive impairment, while experimental work supports the hypothesis that it also contributes to neurodegeneration. Energy deficit, oxidative stress, demyelination, and defective neurotransmission are demonstrated arsenic effects, but it remains unclear whether synaptic structure is also affected. Employing both a triple-transgenic Alzheimer's disease model and Wistar rats, the cortical microstructure and synapses were analyzed under chronic arsenic exposure. Male animals were studied at 2 and 4 months of age, after exposure to 3 ppm sodium arsenite in drinking water during gestation, lactation, and postnatal development. Through nuclear magnetic resonance, diffusion-weighted images were acquired and anisotropy (integrity; FA) and apparent diffusion coefficient (dispersion degree; ADC) metrics were derived. Postsynaptic density protein and synaptophysin were analyzed by means of immunoblot and immunohistochemistry, while dendritic spine density and morphology of cortical pyramidal neurons were quantified after Golgi staining. A structural reorganization of the cortex was evidenced through high-ADC and low-FA values in the exposed group. Similar changes in synaptic protein levels in the 2 models suggest a decreased synaptic connectivity at 4 months of age. An abnormal dendritic arborization was observed at 4 months of age, after increased spine density at 2 months. These findings demonstrate alterations of cortical synaptic connectivity and microstructure associated to arsenic exposure appearing in young rodents and adults, and these subtle and non-adaptive plastic changes in dendritic spines and in synaptic markers may further progress to the degeneration observed at older ages.
Assuntos
Intoxicação por Arsênico/patologia , Córtex Cerebral/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Intoxicação por Arsênico/diagnóstico por imagem , Western Blotting , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Imagem de Tensor de Difusão , Feminino , Masculino , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Wistar , Sinapses/patologiaRESUMO
Inorganic arsenic is among the major contaminants of groundwater in the world. Worldwide population-based studies demonstrate that chronic arsenic exposure is associated with poor cognitive performance among children and adults, while research in animal models confirms learning and memory deficits after arsenic exposure. The aim of this study was to investigate the long-term effects of environmentally relevant arsenic exposure in the myelination process of the prefrontal cortex (PFC) and corpus callosum (CC). A longitudinal study with repeated follow-up assessments was performed in male Wistar rats exposed to 3â¯ppm sodium arsenite in drinking water. Animals received the treatment from gestation until 2, 4, 6, or 12â¯months of postnatal age. The levels of myelin basic protein (MBP) were evaluated by immunohistochemistry/histology and immunoblotting from the PFC and CC. As plausible alterations associated with demyelination, we considered mitochondrial mass (VDAC) and two axonal damage markers: amyloid precursor protein (APP) level and phosphorylated neurofilaments. To analyze the microstructure of the CC in vivo, we acquired diffusion-weighted images at the same ages, from which we derived metrics using the tensor model. Significantly decreased levels of MBP were found in both regions together with significant increases of mitochondrial mass and slight axonal damage at 12â¯months in the PFC. Ultrastructural imaging demonstrated arsenic-associated decreases of white matter volume, water diffusion anisotropy, and increases in radial diffusivity. This study indicates that arsenic exposure is associated with a significant and persistent negative impact on microstructural features of white matter tracts.
Assuntos
Intoxicação por Arsênico/patologia , Doenças Desmielinizantes/patologia , Envelhecimento , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Intoxicação por Arsênico/diagnóstico por imagem , Arsenitos/toxicidade , Axônios/patologia , Corpo Caloso/patologia , Doenças Desmielinizantes/diagnóstico por imagem , Imagem de Tensor de Difusão , Água Potável , Imuno-Histoquímica , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína Básica da Mielina/metabolismo , Proteínas de Neurofilamentos/metabolismo , Córtex Pré-Frontal/patologia , Ratos , Ratos Wistar , Compostos de Sódio/toxicidade , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
For the first time, juvenile toxicity of inorganic arsenic (As) was investigated in male rats, focusing on reproductive effects. As is a metalloid naturally occurring in the environment, being the inorganic forms the most toxics. Contaminated drinking water and agricultural products are the main prospectors of intoxication for general population. In the present study, Wistar male rats (21 days old) were distributed into three groups (n = 10/group): control (received vehicle-filtered drinking water), As1 (received AsNaO2 at 0.01 mg L-1 ) and As2 (received AsNaO2 at 10 mg L-1 ). The animals were euthanized on PND 53. Testicular damages increased in As1 and As2 compared to control (ie, presence of vacuolization, acidophilic cells, and epithelium degeneration). Testicular interstitium of As1 and As2 presented fluid's increase and intense inflammatory infiltration. In the epididymis there was reduction of sperm amount in the lumen, besides epithelium areas presenting cribriform aspect in As1 and As2, exfoliation of cells in the light (in As1) and vacuoles (in As2). In epididymis interstitium, inflammatory infiltrates were observed in initial segment of As1 and As2. AsNaO2 changed immunolabeling pattern for androgen receptor in epididymis of As2, although serum testosterone levels was statistically comparable to control. Mass spectrometry revealed higher As concentrations in testis and epididymis of As2 compared to As1 and Control. These results indicate compromise of spermatogenesis and epididymal histophysiology in AsNaO2 -treated animals, possibly impairing sperm quality and fertility in long-term, even at low levels of exposure. Investigations about the reversibility of reproductive damages are necessary to better understand the mechanisms of As reproductive toxicity.
Assuntos
Arsenitos/toxicidade , Epididimo/efeitos dos fármacos , Epididimo/patologia , Maturidade Sexual/efeitos dos fármacos , Compostos de Sódio/toxicidade , Espermatogênese/efeitos dos fármacos , Animais , Intoxicação por Arsênico/patologia , Intoxicação por Arsênico/fisiopatologia , Arsenitos/farmacologia , Fertilidade/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Reprodução/efeitos dos fármacos , Compostos de Sódio/farmacologia , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testes de Toxicidade , Poluentes Químicos da Água/toxicidadeRESUMO
En las áreas costeras del norte de Chile es común encontrar en el agua para consumo humano niveles medios o altos de arsénico. La exposición al arsénico puede ir asociada a efectos agudos o crónicos. El objetivo de esta investigación fue determinar el daño histológico que provoca el trióxido de arsénico a nivel de los compartimentos del timo de ratas Sprague-Dawley. Se utilizaron 24 ratas de ambos sexos de 55 días de vida. Las ratas fueron pesadas y divididas en 3 grupos (4 hembras y 4 machos). A los grupos tratados se les aplicó 5 mg y 10 mg de As2O3 respectivamente, en dosis única diaria vía intraperitoneal por 15 días. Al grupo control se le aplicó agua destilada sin arsénico. Después del tratamiento los animales fueron sacrificados y retirado el timo de ellos, los cuales fueron lavados, pesados y seccionados en dos, luego se fijaron en formol tamponado al 10 por ciento. Mediante técnica histológica convencional se obtuvieron 4 muestras seriadas de cada timo, de 5 um de espesor y separadas por 100 um entre si, luego fueron teñidas con H-E. Se analizaron 30 campos (120 campos por órgano). Los resultados muestran que el As2O3 provoca la pérdida de celularidad en ambos compartimentos del timo, tanto en la corteza como en la médula, viéndose más afectado el compartimento medular (junto a la unión corticomedular). Se observó una reducción significativa del tamaño de la zona medular en ambos grupos tratados (5 y 10 mg de As2O3 respectivamente), siendo probablemente la disminución de este tejido el responsable de la atrofia del timo. Además se observó un aumento del tamaño de la corteza en las ratas hembras tratadas con 10 mg de As2O3. La unión corticomedular de las ratas tratadas se observó difusa o difícil de distinguir.
In coastal areas of northern Chile medium or high levels of arsenic are commonly found in drinking water. Arsenic exposure may be associated with acute or chronic effects. The objective of this investigation was to determine the histological damage caused by arsenic trioxide level of the compartments of the thymus of Sprague-Dawley rats. We used 24 rats of both sexes of 55 days of life. The rats were weighed and divided into 3 groups (4 females and 4 males). In the treated groups were administered 5 mg and 10 mg of As2O3 respectively, in a single daily dose for 15 days intraperitoneally. The control group was administered distilled water without arsenic. After treatment the animals were sacrificed and the thymus removed, washed, weighed and divided into two, then fixed in 10 percent buffered formalin. By conventional histology samples were obtained serially every 4 thymus, 5 microns thick and separated by 100 microns each, then were stained with HE. We analyzed 30 fields (120 fields per organ). The results showed that As2O3 causes loss of cellularity in both compartments of the thymus, both in the cortex and in the bone, medullary compartment was more affected (near the corticomedullary junction). There was a significant reduction in the size of the medulla in both groups (5 and 10 mg As2O3 respectively), probably the decrease of the tissue responsible for thymic atrophy. We observed an increase in the size of the cortex in female rats treated with 10 mg of As2O3. The corticomedullary junction of the treated rats showed diffuse or difficult to distinguish.
Assuntos
Animais , Feminino , Ratos , Arsênio/toxicidade , Timo , Timo/patologia , Atrofia , Arsênio/administração & dosagem , Intoxicação por Arsênico/patologia , Óxidos/toxicidade , Peso Corporal , Ratos Sprague-DawleyRESUMO
BACKGROUND: The Camarones River Valley, located in the extreme north of Chile, is characterized by high environmental arsenic levels and an arid desert. It has been inhabited by humans for the past 7,000 years. Evidence exists for chronic arsenic poisoning in both prehispanic and present populations residing in the area. Chronic arsenic exposure causes multi-systemic problems and can induce congenital malformations, in particular neural tube development defects such as spina bifida. AIM: To study the prevalence of spina bifida among prehispanic mummies of the area. MATERIAL AND METHODS: One hundred and twenty prehistoric adult individuals were analyzed for evidence of spina bifda occulta of the sacrum in skeletal samples from the sites of Camarones 8, Camarones 9, Azapa 140 and Lluta 54, held in repository at the Museo Universidad de Tarapacá de Arica- San Miguel de Azapa. A diagnosis was considered positive when at least S1, S2 or S3 were affected. As controls, mummies of individuals that resided in Lluta and Azapa valley, with a low arsenic exposure, were analyzed. RESULTS: The frequency of spina bifida occulta among samples from the Camarones coast and Lluta and Azapa Valley were 13.5 and 2.4% respectively. CONCLUSIONS: Considering these were contemporaneous samples, and are believed to have had no other differences in diet or other factors, the differential exposures to arsenic could have produced the observed differences in spina bifida frequencies.
Assuntos
Intoxicação por Arsênico/história , Exposição Ambiental/história , Múmias , Espinha Bífida Oculta/história , Adulto , Determinação da Idade pelo Esqueleto , Intoxicação por Arsênico/etiologia , Intoxicação por Arsênico/patologia , Chile , Exposição Ambiental/efeitos adversos , Feminino , História Antiga , Humanos , Masculino , Pessoa de Meia-Idade , Paleopatologia , Sacro/patologia , Espinha Bífida Oculta/induzido quimicamente , Espinha Bífida Oculta/patologiaRESUMO
Background: The Camarones River Valley, located in the extreme north of Chile, is characterized by high environmental arsenic levels and an arid desert. It has been inhabited by humans for the past 7,000 years. Evidence exists for chronic arsenic poisoning in both prehispanic and present populations residing in the area. Chronic arsenic exposure causes multi-systemic problems and can induce congenital malformations, in particular neural tube development defects such as spina bifda. Aim: To study the prevalence of spina bifda among prehispanic mummies of the area. Material and Methods: Onehundred and twenty prehistoric adult individuals were analyzed for evidence of spina bifda occulta of the sacrum in skeletal samples from the sites of Camarones 8, Camarones 9, Azapa 140 and Lluta 54, held in repository at the Museo Universidad de Tarapacá de Arica- San Miguel de Azapa. A diagnosis was considered positive when at least S1, S2 or S3 were affected. As controls, mummies of individuals that resided in Lluta and Azapa valley, with a low arsenic exposure, were analyzed. Results: The frequency of spina bifda occulta among samples from the Camarones coast and Lluta and Azapa Valley were 13.5 and 2.4 percent respectively. Conclusions: Considering these were contemporaneous samples, and are believed to have had no other differences in diet or other factors, the differential exposures to arsenic could have produced the observed differences in spina bifda frequencies.
Assuntos
Adulto , Feminino , História Antiga , Humanos , Masculino , Pessoa de Meia-Idade , Intoxicação por Arsênico/história , Exposição Ambiental/história , Múmias , Espinha Bífida Oculta/história , Determinação da Idade pelo Esqueleto , Intoxicação por Arsênico/etiologia , Intoxicação por Arsênico/patologia , Chile , Exposição Ambiental/efeitos adversos , Paleopatologia , Sacro/patologia , Espinha Bífida Oculta/induzido quimicamente , Espinha Bífida Oculta/patologiaRESUMO
Methylation has an important role in the synthesis of myelin basic protein (MBP), an essential component that confers compactness to myelin, and the correct synthesis and assembling of myelin are fundamental in the development of the central nervous system. Since arsenic metabolism requires a high consumption of S-adenosylmethionine, the main donor of methyl groups in the organism, it has been proposed that arsenic exposure can lead to a demethylation status in the organism comprising DNA and protein hypomethylation. This study documents myelin alterations in brain and changes in levels of methylated arginines in brain and serum of adult female Wistar rats exposed to arsenic (3 and 36 ppm, drinking water) from gestation throughout lactation, development and until 1, 2, 3 and 4 months of age. Morphological characteristics were analyzed by means of light microscopy and methylated arginines were analyzed through HPLC. Arsenic intake resulted in myelin damage reflected as empty spaces in fiber tracts of the exposed animals. The low exposure group (approximately 0.4 mg/kg/day) did not present myelin damage during the first 2 months, only moderate alterations in the third and fourth months. By contrast, animals exposed to 36 ppm (approximately 4 mg/kg/day) showed moderate to severe damage to nerve tracts from the first month of age. These alterations were accompanied by significant lower levels of dimethyl arginine in both exposed groups, as compared with the controls, in the third and fourth months of age and exposure. These data demonstrate that myelin composition is a target of arsenic through interference with arginine methylation, and they suggest that disturbances in nervous transmission through myelinated fibers are an important component of arsenic neurotoxicity.
Assuntos
Arginina/metabolismo , Intoxicação por Arsênico/patologia , Arsênio/toxicidade , Bainha de Mielina/efeitos dos fármacos , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Masculino , Metilação/efeitos dos fármacos , Bainha de Mielina/patologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Exposure of several human populations to arsenic has been associated with a high incidence of detrimental dermatological and carcinogenic effects. To date, studies examining the immunotoxic effects of arsenic in humans, and specifically in children, are lacking. Therefore, we evaluated several parameters of immunological status in a group of children exposed to arsenic through their drinking water. Peripheral blood mononuclear cells (PBMCs) of 90 children (6 to 10 years old) were collected. Proportions of lymphocyte subpopulations, PBMC mitogenic proliferative response, and urinary arsenic levels were evaluated. Increased urine arsenic levels were associated with a reduced proliferative response to phytohemaglutinin (PHA) stimulation (P=0.005), CD4 subpopulation proportion (P=0.092), CD4/CD8 ratio (P=0.056), and IL-2 secretion levels (P=0.003). Increased arsenic exposure was also associated with an increase in GM-CSF secretion by mononucleated cells (P=0.000). We did not observe changes in CD8, B, or NK cell proportions, nor did we observe changes in the secretion of IL-4, IL-10, or IFN-gamma by PHA-activated PBMCs. These data indicate that arsenic exposure could alter the activation processes of T cells, such that an immunosuppression status that favors opportunistic infections and carcinogenesis is produced together with increased GM-CSF secretion that may be associated with chronic inflammation.
Assuntos
Intoxicação por Arsênico/imunologia , Arsênio/toxicidade , Citocinas/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismo , Arsênio/administração & dosagem , Arsênio/urina , Intoxicação por Arsênico/patologia , Criança , Estudos Transversais , Feminino , Humanos , Masculino , México , Subpopulações de Linfócitos T/citologia , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/urinaRESUMO
In the Old World, several researchers have indicated that adverse health effects were associated with exposure to arsenic, and that this influenced a change in the use of copper-arsenic alloys to others less toxic. This hypothesis was evaluated for three Pre-Columbian metallurgy traditions: Central Andes, Intermediate Area, and West Mexico. The metal artifacts from the Central Andes showed arsenic concentrations similar to those in the Old World (0.5%-1.0%). In the Intermediate Area the values were smallest; however, in West Mexico the arsenic content was very high (7%-25%). In Central Andes arsenical bronze was used initially, but copper-tin alloys when introduced were preferred and distributed throughout the Inca Empire. Osteological and artistic evidences of foot amputations among Moche individuals from Central Andes support the presence of "black foot disease" (a condition associated with arsenic poisoning) among Pre-Columbian populations. In conclusion, the adverse effects of arsenic have been observed in the New World, and that these effects promoted a change toward the use of less toxic alloys.