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BACKGROUND: By identifying the molecular mechanisms underlying sodium selenite (Na2SeO3) cytotoxicity during exposure in non-tumor cells (HaCaT cells), we will improve the current understanding of its antiproliferative effects and modulation of gene expression in the main pathways related to the cell cycle, cell death, oxidative stress, and DNA damage and repair. METHODS: Non-tumor HaCaT cells were treated with Na2SeO3 to induce cytotoxicity, and the effects were investigated using an MTT assay (cell viability), real-time cell analysis (profiling the cell index), flow cytometry (membrane integrity, cell cycle disruption, and apoptosis), a comet assay (genotoxicity, i.e., DNA damage), and RT-qPCR (mRNA expression of genes). RESULTS: Treatment with Na2SeO3 was cytotoxic at 10 µM, producing morphological changes in cells (cytoplasmic granulations); however, it did not have a genotoxic effect. Na2SeO3 induced cell membrane damage, cell death, and cell cycle arrest in HaCaT cells. It also altered the mRNA expression levels of PUMA, ATR, and mTOR genes. However, it had no effect on the mRNA expression of caspases or PARP1, BIRC5, BECN1, and c-MYC genes, suggesting that Na2SeO3 causes PUMA-dependent apoptosis in HaCaT cells. The mRNA expression of specific genes related to oxidative stress, DNA damage and repair, and cell cycle control were unchanged by Na2SeO3. CONCLUSIONS: We demonstrated the cytotoxic effect of Na2SeO3 in HaCaT cells by analyzing mRNA expression patterns, changes in cell morphology, and proliferation kinetics.

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Following a case of iatrogenic selenium poisoning in a young pig, an experimental study was carry out. Sodium selenite was orally and parenterally administered to 13 pigs that were subdivided into three groups (G1, G2 and G3). The animals in groups G1 and G3 received sodium selenite intramuscularly (IM), G1 received a comercial formula, and G3 received sodium selenite mixed with distilled water at different dosages, and those in group G2 were fed commercial sodium selenite. Acute and subacute poisoning was observed in both groups, although the onset of clinical signs was slower in group G2. Only one pig (in group G1) that had received the highest dose showed a peracute course. Apathy, anorexia, dyspnea, vomiting, muscular tremors, proprioceptive deficit, ataxia and paresis of the hind limbs progressing to the front limbs evolving to tetraplegia were observed. Postmortem findings differed whether the animals received the injected (G1 and G3) or oral (G2) sodium selenite. The liver was moderately atrophic in some animals of G2. Some of the animals in groups G1 and G3 presented with lung edema. One pig in G3 had yellowish-brown areas in the ventral horns of the cervical intumescences of the spinal cord. The most important histological changes were present in the ventral horns of the cervical and lumbar intumescences of the spinal cord. In one animal, changes were present in the brainstem and mesencephalon. The initial lesion was a perivascular and astrocyte edema that progressing to lysis and death of astrocytes and neurons. In the chronic stage of the lesions, there were extensive areas of liquefaction necrosis with perivascular lymphocytic and histiocytic infiltration and occasional eosinophils. It seems that disruption of the blood-brain barrier due to astrocyte edema is the most likely mechanism of CNS lesion.(AU)

A partir de um caso de intoxicação iatrogênica por selenito de sódio injetável em suíno verificaram-se alguns aspectos patogenéticos não esclarecidos, o que ensejou o estudo experimental. Selenito de sódio foi administrado pelas vias oral e parenteral a 13 suínos, subdivididos em três grupos (G1, G2 e G3). Os grupos G1 e G3 receberam selenito de sódio por via intra-muscular (IM); (G1 - fórmula comercial e G3 - selenito de sódio misturado à água destilada, em diversas dosagens) e o grupo G2, por via oral (VO), misturado à ração. Quadros de evolução aguda e subaguda foram observados em todos os grupos, embora o início dos sintomas tenha sido mais lento no grupo G2. Um único porco (do grupo G1), que havia recebido a dose mais alta, apresentou evolução superaguda. Apatia, anorexia, dispneia, vômito, tremores musculares, déficit proprioceptivo, ataxia e paresia dos membros posteriores com progressão para os anteriores e evolução para tetraplegia foram observados. Os achados de necropsia foram diferentes entre os animais que receberam o selenito de sódio injetável (IM - G1 e G3) e oral (G2). Havia moderada atrofia hepática em alguns animais do G2. Parte dos animais dos grupos G1 e G3 apresentaram edema pulmonar. Em um suíno (G3) notaram-se áreas marrom-amareladas nos cornos ventrais da intumescência cervical. As alterações histológicas mais importantes ocorreram nos cornos ventrais do "H" medular das intumescências cervical e lombar. Em um animal, as alterações envolviam o tronco cerebral e o mesencéfalo. Inicialmente, a lesão caracterizava-se por edema perivascular e astrocitário que progredia para lise e necrose de astrócitos e neurônios. O estágio crônico das lesões caracterizava-se por extensas áreas de necrose liquefativa e infiltração perivascular linfocítica e histiocítica, com raros eosinófilos. Sugere-se que a ruptura da barreira hematoencefálica por edema astrocitário seja o mecanismo mais provável da lesão no SNC.(AU)

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RESUMEN

Following a case of iatrogenic selenium poisoning in a young pig, an experimental study was carry out. Sodium selenite was orally and parenterally administered to 13 pigs that were subdivided into three groups (G1, G2 and G3). The animals in groups G1 and G3 received sodium selenite intramuscularly (IM), G1 received a comercial formula, and G3 received sodium selenite mixed with distilled water at different dosages, and those in group G2 were fed commercial sodium selenite. Acute and subacute poisoning was observed in both groups, although the onset of clinical signs was slower in group G2. Only one pig (in group G1) that had received the highest dose showed a peracute course. Apathy, anorexia, dyspnea, vomiting, muscular tremors, proprioceptive deficit, ataxia and paresis of the hind limbs progressing to the front limbs evolving to tetraplegia were observed. Postmortem findings differed whether the animals received the injected (G1 and G3) or oral (G2) sodium selenite. The liver was moderately atrophic in some animals of G2. Some of the animals in groups G1 and G3 presented with lung edema. One pig in G3 had yellowish-brown areas in the ventral horns of the cervical intumescences of the spinal cord. The most important histological changes were present in the ventral horns of the cervical and lumbar intumescences of the spinal cord. In one animal, changes were present in the brainstem and mesencephalon. The initial lesion was a perivascular and astrocyte edema that progressing to lysis and death of astrocytes and neurons. In the chronic stage of the lesions, there were extensive areas of liquefaction necrosis with perivascular lymphocytic and histiocytic infiltration and occasional eosinophils. It seems that disruption of the blood-brain barrier due to astrocyte edema is the most likely mechanism of CNS lesion.(AU)

A partir de um caso de intoxicação iatrogênica por selenito de sódio injetável em suíno verificaram-se alguns aspectos patogenéticos não esclarecidos, o que ensejou o estudo experimental. Selenito de sódio foi administrado pelas vias oral e parenteral a 13 suínos, subdivididos em três grupos (G1, G2 e G3). Os grupos G1 e G3 receberam selenito de sódio por via intra-muscular (IM); (G1 - fórmula comercial e G3 - selenito de sódio misturado à água destilada, em diversas dosagens) e o grupo G2, por via oral (VO), misturado à ração. Quadros de evolução aguda e subaguda foram observados em todos os grupos, embora o início dos sintomas tenha sido mais lento no grupo G2. Um único porco (do grupo G1), que havia recebido a dose mais alta, apresentou evolução superaguda. Apatia, anorexia, dispneia, vômito, tremores musculares, déficit proprioceptivo, ataxia e paresia dos membros posteriores com progressão para os anteriores e evolução para tetraplegia foram observados. Os achados de necropsia foram diferentes entre os animais que receberam o selenito de sódio injetável (IM - G1 e G3) e oral (G2). Havia moderada atrofia hepática em alguns animais do G2. Parte dos animais dos grupos G1 e G3 apresentaram edema pulmonar. Em um suíno (G3) notaram-se áreas marrom-amareladas nos cornos ventrais da intumescência cervical. As alterações histológicas mais importantes ocorreram nos cornos ventrais do "H" medular das intumescências cervical e lombar. Em um animal, as alterações envolviam o tronco cerebral e o mesencéfalo. Inicialmente, a lesão caracterizava-se por edema perivascular e astrocitário que progredia para lise e necrose de astrócitos e neurônios. O estágio crônico das lesões caracterizava-se por extensas áreas de necrose liquefativa e infiltração perivascular linfocítica e histiocítica, com raros eosinófilos. Sugere-se que a ruptura da barreira hematoencefálica por edema astrocitário seja o mecanismo mais provável da lesão no SNC.(AU)

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The aim of this study was to analyze the effects of chronic toxicity of sodium selenite (Na2SeO3 SE4+) on juvenile Nile tilapia Oreochromis niloticus. Therefore, a toxicity test was carried out with three sub-lethal concentrations of that salt (0.4 mgSe L-1, 0.04 mgSe L-1 and 0.01 mgSe L-1), plus a control group. The experiment was carried out for 14 days, sampling six individuals per treatment in intervals of 0, 3, 7, 10 and 14 days. Effects of chronic sublethal concentrations of selenite were evaluated by routine haematological and histopathological analysis. There were significant differences (P 0.05) in the rate of hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) and an increase of the total number of leukocytes, mainly due to the increased number of lymphocytes, monocytes, and neutrophils. Severe gill hyperplasia was found on the fourteenth day. Nephrosis were found in the cephalic kidney, characterized by glomerulonephritis and tubular vacuolar degeneration, which was a result of the necrosis or secondary infection, glomerular atrophy and glomerulosclerosis, proliferative glomerulonephritis, nephrosis, nephrosclerosis, tubular calcification, edema and hemorrhage. It was found that selenite, at the tested concentrations despite being sublethal, caused histological and hematological changes in Nile tilapia.

Este trabalho teve como objetivo analisar os efeitos da toxicidade crônica do selenito de sódio (Na2SeO3 Se4+) em jovens de tilápia-do-nilo Oreochromis niloticus. Para tanto, um teste de toxicidade foi realizado com três concentrações sub-letais deste sal (0,4 mgSe L-1, 0,04 mgSe L-1 e 0,01 mgSe L-1) e 0 mgSe L-1 (controle). O experimento foi conduzido por 14 dias, com amostragem de seis indivíduos por tratamento nos intervalos 0, 3, 7, 10 e 14 dias para a avaliação dos efeitos crônicos sub-letais por meio de análises hematológicas de rotina e análises histopatológicas. Diferença significativa (P 0,05) ocorreu na concentração de hemoglobina, volume corpuscular médio (VCM), hemoglobina corpuscular média (HCM) e concentração de hemoglobina corpuscular média (CHCM) e aumento do número total de leucócitos, causados principalmente pelo aumento do número de linfócitos, monócitos e neutrófilos. Nas brânquias dos peixes expostos ao selenito de sódio foi encontrada hiperplasia grave no décimo quarto dia. No rim cefálico ocorreu nefrose caracterizada pela degeneração vacuolar tubular e glomerulonefrite, atrofia glomerular e glomeruloesclerose, glomerulonefrite proliferativa, nefroesclerose, calcificação tubular, edema e hemorragia. Conclui-seo selenito de sódio nas concentrações utilizadas provocaram alterações hematológicas e histológicasem tilápia-do-nilo, embora tenham sido usadas concentrações sub-letais neste ensaio.

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The aim of this study was to analyze the effects of chronic toxicity of sodium selenite (Na2SeO3 SE4+) on juvenile Nile tilapia Oreochromis niloticus. Therefore, a toxicity test was carried out with three sub-lethal concentrations of that salt (0.4 mgSe L-1, 0.04 mgSe L-1 and 0.01 mgSe L-1), plus a control group. The experiment was carried out for 14 days, sampling six individuals per treatment in intervals of 0, 3, 7, 10 and 14 days. Effects of chronic sublethal concentrations of selenite were evaluated by routine haematological and histopathological analysis. There were significant differences (P 0.05) in the rate of hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) and an increase of the total number of leukocytes, mainly due to the increased number of lymphocytes, monocytes, and neutrophils. Severe gill hyperplasia was found on the fourteenth day. Nephrosis were found in the cephalic kidney, characterized by glomerulonephritis and tubular vacuolar degeneration, which was a result of the necrosis or secondary infection, glomerular atrophy and glomerulosclerosis, proliferative glomerulonephritis, nephrosis, nephrosclerosis, tubular calcification, edema and hemorrhage. It was found that selenite, at the tested concentrations despite being sublethal, caused histological and hematological changes in Nile tilapia.(AU)

Este trabalho teve como objetivo analisar os efeitos da toxicidade crônica do selenito de sódio (Na2SeO3 Se4+) em jovens de tilápia-do-nilo Oreochromis niloticus. Para tanto, um teste de toxicidade foi realizado com três concentrações sub-letais deste sal (0,4 mgSe L-1, 0,04 mgSe L-1 e 0,01 mgSe L-1) e 0 mgSe L-1 (controle). O experimento foi conduzido por 14 dias, com amostragem de seis indivíduos por tratamento nos intervalos 0, 3, 7, 10 e 14 dias para a avaliação dos efeitos crônicos sub-letais por meio de análises hematológicas de rotina e análises histopatológicas. Diferença significativa (P 0,05) ocorreu na concentração de hemoglobina, volume corpuscular médio (VCM), hemoglobina corpuscular média (HCM) e concentração de hemoglobina corpuscular média (CHCM) e aumento do número total de leucócitos, causados principalmente pelo aumento do número de linfócitos, monócitos e neutrófilos. Nas brânquias dos peixes expostos ao selenito de sódio foi encontrada hiperplasia grave no décimo quarto dia. No rim cefálico ocorreu nefrose caracterizada pela degeneração vacuolar tubular e glomerulonefrite, atrofia glomerular e glomeruloesclerose, glomerulonefrite proliferativa, nefroesclerose, calcificação tubular, edema e hemorragia. Conclui-seo selenito de sódio nas concentrações utilizadas provocaram alterações hematológicas e histológicasem tilápia-do-nilo, embora tenham sido usadas concentrações sub-letais neste ensaio.(AU)

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RecBCD and RecFOR homologous recombination pathways induced bacterial chromosomal duplication-segregation by sodium selenite (SSe) at sub-inhibitory concentrations. This evidence suggests that SSe induces both, double and single DNA strand damage with a concomitant DNA repair response, however the strong dependence for recombinogenic activity of RecB product suggests that the main DNA repair pathway copes with dsDNA breaks. A role for SSe recombinogenic induction is proposed to explain its effect on DNA instability.

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Many works have reported the interaction between selenium and mercury in the mammalian body and that chalcogen seems to have a protective effect against mercury toxicity. The aim of this study was to investigate the hemolytic effects of sodium selenite and/or mercuric chloride in human blood under in vitro conditions. For this, total venous blood from healthy subjects (males and females) was heparinized and incubated at 37 degrees C for 90 min with different concentrations of sodium selenite and/or mercuric chloride. The hemolytic effects of compounds were evaluated by measuring plasma hemoglobin concentration after centrifugation. In addition, 2-thiobarbituric acid reactive substances (TBARS) from plasma and erythrocytes, as well as erythrocyte nonprotein thiols (NPSH), were also evaluated in order to investigate molecular mechanisms related to selenite- or mercury-induced hemolysis. Mercuric chloride and sodium selenite, alone (400 microM), promoted a small in vitro hemolytic effect in human erythrocytes. However, when blood was exposed to both compounds (200 microM of each), there was an extremely high synergistic hemolytic effect. The exposure of blood to sodium selenite (400 microM), mercuric chloride (400 microM), and both compounds (200 microM each) did not alter erythrocyte TBARS levels. Sodium selenite presented a high oxidant effect toward erythrocyte NPSH; however, this effect was inhibited by mercuric chloride. The current results point to a synergistic hemolytic effect of sodium selenite and mercuric chloride in human blood, suggesting new understanding on the selenium-mercury antagonism. Moreover, this observed hemolysis seems to be not related to lipoperoxidation or thiol depletion.

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Mercury is known to interact with selenite and when the two are co-administered, one reduces the toxicity of the other. The main goal of this study was to investigate the simultaneous in vitro effects of sodium selenite (Se(4+)) and mercuric chloride (Hg(2+)) on the activity of hepatic, renal and cerebral delta-aminolevulinate dehydratase (delta-ALA-D) of adult male mice (Swiss albino). Hg(2+) inhibited delta-ALA-D from tissue supernatants and the IC(50) values for hepatic, renal and cerebral enzyme inhibition were 38+/-4.2, 67.5+/-4.3 and 46.2+/-3.7 microM, respectively. Se(4+) displayed a higher inhibitory action toward delta-ALA-D activity than Hg(2+). Simultaneous addition of Se(4+) and Hg(2+) to the delta-ALA-D assay increased the inhibition of the enzyme. Se(4+) and Hg(2+) oxidized total -SH groups from hepatic, renal and cerebral supernatants, although the effect of Se(4+) decreased in the presence of increasing concentrations of Hg(2+). The oxidation of -SH groups from a dithiol (DTT), a monothiol glutathione (GSH) and a protein (albumin) increased in the presence of Hg(2+). Only DTT was oxidized by Se(4+) and the oxidation decreased in the presence of Hg(2+), suggesting the formation of a chemical complex. This complex did not inhibit delta-ALA-D. These results suggest a similar inhibitory mechanism of Se(4+) and Hg(2+) on delta-ALA-D in which oxidation of sulfhydryl groups located at the active site of the enzyme is an essential step. Furthermore, decreasing oxidative effects of selenite on sulfhydryl groups from DTT in the presence of mercury are believed to occur as the result of the formation of an inactive ternary complex of the thiol-Hg-Se type, which does not inhibit delta-ALA-D.

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Vinte e cinco cordeiros não castrados, de 4 meses de idade e peso vivo médio de 30,2 kg, foram colocados em gaiolas metabólicas individuais de plástico e, após 14 dias de adaptação, receberam um dos seguintes tratamentos, por 90 dias: um controle (C) com 0,1 mg/kg Se na dieta `maisï pré-mistura mineral com 1 por cento de S, mais quatro tratamentos contendo o mesmo nível potencialmente tóxico de Se na dieta (5 mg/kg) e níveis crescentes de S na pré-mistura mineral, 1 por cento, 6 por cento, 11 por cento ou 26 por cento de S (respectivamente tratamentos I, II, III e IV). Num delineamento inteiramente casualizado, estudou-se o efeito antagônico do S na forma de flor de enxofre sobre o Se como selenito de sódio em nível potencialmente tóxico, através da análise dos teores de Se no soro, na lã, nas fezes, na urina e nos tecidos (fígado, rim, coração e músculo), hematócrito total e ganho de peso...

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