RESUMO
Anemia is the most widespread hematological disease, therefore the search for new approaches to erythropoiesis regulation in the body remains an extremely urgent problem. We studied the effect of long-term reduction of deuterium level in the internal milieu of the body on hemoglobin production and parameters of erythropoiesis in sexually mature male Wistar rats. The animals consumed water with deuterium content decreased to 10 ppm for 2 months. After 1 month, an increase of hemoglobin synthesis in erythrocytes was detected, and after 2 months we observed intensification of erythropoiesis. Since the observed processes occurred in healthy animals with initially normal indices of hematopoiesis, the obtained data allow us to consider the reduction of deuterium level in the internal milieu of the body as a factor of erythropoiesis regulation and a possible option of its alternative non-pharmacological regulators.
Assuntos
Deutério , Eritropoese , Hemoglobinas , Ratos Wistar , Animais , Eritropoese/efeitos dos fármacos , Eritropoese/fisiologia , Masculino , Hemoglobinas/metabolismo , Ratos , Eritrócitos/metabolismo , Eritrócitos/efeitos dos fármacosRESUMO
We studied features of age-related changes in the thymus of mature male Wistar rats developmentally exposed to the endocrine disruptor dichlorodiphenyltrichloroethane (DDT). The study was carried out at the stage of early thymus involution. Differences in the thymus morphology associated with imbalance of morphogenetic processes in the cortex and medulla were observed after puberty in rats developmentally exposed to DDT. Increased proliferation of thymocytes, higher content of lymphoblasts, and concomitant decrease in T-cell migration in comparison with the control were found. Our findings indicate lower functional maturity of the thymus and prolonged disorders in the program of postnatal thymus development induced by the endocrine disruptor DDT.
Assuntos
DDT , Disruptores Endócrinos , Ratos , Animais , Masculino , Ratos Wistar , DDT/farmacologia , Disruptores Endócrinos/farmacologia , Maturidade Sexual , TimoRESUMO
Regulation of morphogenetic processes during postnatal development of the rat adrenal medulla was studied. Termination of the adrenal medulla growth was found to be associated with decreased chromaffin cell proliferation, activation of canonical Wnt-signaling pathway, and enhanced expression of Sonic Hedgehog ligand. Analysis of transcription factors associated with pluripotency revealed increased percentage of Oct4-expressing cells by the end of medulla growth and no signs of Sox2 expression. All the cells demonstrating activation of Wnt-signaling and expression of Oct4 and Sonic Hedgehog were found to be highly differentiated chromaffin cells actively producing tyrosine hydroxylase. These findings allow considering the formation of the cell pools for dedifferentiation as a putative mechanism for physiological regeneration of the adrenal medulla.
Assuntos
Medula Suprarrenal , Células Cromafins , Ratos , Animais , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Medula Suprarrenal/metabolismo , Células Cromafins/metabolismo , Fatores de Transcrição/metabolismo , Diferenciação Celular , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
We studied changes in the secretion of thyroid hormones and pituitary thyroid-stimulating hormone (TSH) in young mature male Wistar rats during gradual decrease in deuterium body content. The rats received deuterium-depleted water ([D]=10 ppm) instead of tap water for 21 days. As soon as after 1 day, an increase in the secretion of thyroid hormones was recorded. On day 14, secondary hypothyroidism due to a sharp decrease in TSH secretion by the pituitary gland was found. By day 21, secretion of the thyroid hormones increased, and the reciprocal dependence between the concentrations of thyroid hormones and TSH was restored. Thus, the thyroid gland showed a higher sensitivity to a decrease in the deuterium content in the body than the hypothalamic-pituitary complex. The second difference was in type of response: activation of the secretory processes in the thyroid gland and a transient decrease in the secretory activity of pituitary gland thyrotropes to a decrease in deuterium content.
Assuntos
Hipófise , Glândula Tireoide , Masculino , Ratos , Animais , Glândula Tireoide/fisiologia , Deutério , Ratos Wistar , Tireotropina , Hormônios Tireóideos , TiroxinaRESUMO
The development of the spleen in newborn male Wistar rats exposed to low-dose endocrine disruptor dichlorodiphenyltrichloroethane during the prenatal period was studied. Histological examination of the spleen revealed a more active development of periarterial lymphoid sheaths and lower granulocyte content in the organ. Cytofluorimetry showed a significantly lower content of B cells. Thus, low-dose exposure of the endocrine disruptor dichlorodiphenyltrichloroethane on the developing organism during the prenatal period induced changes in spleen morphogenesis resulting in extensive development of lymphoid formations and a lower intensity of lymphocyte and granulocyte differentiation.
Assuntos
Disruptores Endócrinos , Gravidez , Feminino , Ratos , Animais , Masculino , Ratos Wistar , Animais Recém-Nascidos , Disruptores Endócrinos/toxicidade , Baço , DDT/toxicidadeRESUMO
We analyzed the expression of the transcription factor Oct4 in the chromaffin cells during the postnatal development of the adrenal glands in rats. Single Oct4+-chromaffin cells with nuclear localization of the protein were found in the medulla, and their number increased in parallel with a decrease in the proliferative activity of cells. In postnatal development, 100% of chromaffin cells demonstrated high expression of tyrosine hydroxylase, which attested to their differentiation and functional activity. It was found that all Oct4+ cells were differentiated chromaffin cells. An increase in the pool of Oct4-expressing cells after the completion of organ growth suggests the formation of a potential source for the physiological and reparative regeneration of the adrenal medulla.
Assuntos
Medula Suprarrenal , Células Cromafins , Animais , Ratos , Glândulas Suprarrenais/metabolismo , Medula Suprarrenal/metabolismo , Diferenciação Celular , Células Cromafins/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
We studied changes in thymic lymphocytopoiesis induced by a short-term decrease in deuterium content in the body. The experiment was performed on adult male Wistar rats receiving water with lower deuterium content [D]=10 ppm. Increased relative weight of thymus was found after 24 h of consumption. Flow cytometry revealed higher percentage of undifferentiated cells and mature T cells, especially cytotoxic T cells. Hence, lymphocytopoiesis in the thymus is highly sensitive to short-term decrease in deuterium body content. A decrease in the content of deuterium stimulates proliferation of lymphoblasts in the thymus and slows down migration of differentiated T cells. Enhanced generation of cytotoxic T cells under these conditions attests to the role of deuterium in selection of double-positive thymocytes. The revealed shifts are reactive, and their pattern can change later, which requires further research.
Assuntos
Linfopoese , Linfócitos T Citotóxicos , Animais , Deutério , Masculino , Ratos , Ratos Wistar , Timo , ÁguaRESUMO
We studied the mechanisms underlying decreased production of epinephrine by adrenal glands in rats developmentally exposed to endocrine disruptor DDT was performed on the basis of assessment of morphology, fine structure, and function of the adrenal medulla and medullary cells. It was found that the main mechanisms of disruptive action of DDT leading to a decrease in epinephrine secretion into systemic circulation are a decrease in the growth rate of the adrenal medulla, a decrease in the number of mitochondria in adrenal cells, especially under the outer cytoplasmic membrane, destructive changes in mitochondria, and a progressive decrease in the synthesis of tyrosine hydroxylase. The decrease in the number of mitochondria and suppression tyrosine hydroxylase synthesis in adrenal cells predominate during the pubertal period, while slowdown of the growth of the adrenal medulla and progressive decrease in the synthesis of tyrosine hydroxylase seem to be the most evident mechanisms after puberty.
Assuntos
Medula Suprarrenal , DDT , Animais , DDT/toxicidade , Epinefrina , Ratos , Maturidade Sexual , Tirosina 3-Mono-OxigenaseRESUMO
We studied the expression of pluripotency factor Oct-4 and the intensity of apoptosis in the uterus during spontaneous and immune abortions in mice. Increased expression of factor Bax and reduced protein Bcl-2 synthesis in cells of the decidual membrane and decreased Oct-4 expression in the myometrium and perimetrium were detected. Thus, both spontaneous and immune-dependent abortions impair the apoptosis processes in the decidua and the formation of a pool of Oct-4+ cells in the uterus. In immune-dependent abortions, the intensity of apoptosis of decidual cells was lower than in spontaneous abortion. Low expression of the transcription factor Oct-4 in the myometrium and perimetrium characterizes pregnancy failure irrespective of its mechanisms.
Assuntos
Aborto Espontâneo , Fator 3 de Transcrição de Octâmero , Útero , Aborto Espontâneo/imunologia , Animais , Apoptose , Decídua/metabolismo , Feminino , Humanos , Camundongos , Fator 3 de Transcrição de Octâmero/biossíntese , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/imunologia , Gravidez , Útero/imunologiaRESUMO
We studied functional changes in rat pituitary-thyroid axis after a short-term shift in deuterium body content. Male Wistar rats consumed deuterium-enriched (500,000 ppm) or deuterium-depleted water (10 ppm) for 24 h. Rats of both experimental groups demonstrated elevated concentration of bound with transport proteins thyroxine and reduced level of thyroid-stimulating hormone in serum. No changes in the rate of thyroxine conversion to triiodothyronine were found. Thus, both the increase and reduction of deuterium body content produced similar changes in the function of the pituitary-thyroid axis with primary affection of the thyroid gland, indicative of its higher sensitivity to shift in deuterium levels.
Assuntos
Deutério/farmacologia , Deslocamentos de Líquidos Corporais/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Animais , Líquidos Corporais/química , Líquidos Corporais/efeitos dos fármacos , Líquidos Corporais/metabolismo , Peso Corporal/efeitos dos fármacos , Deutério/metabolismo , Deslocamentos de Líquidos Corporais/fisiologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Hipófise/metabolismo , Ratos , Ratos Wistar , Glândula Tireoide/metabolismo , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
The study examined transcriptional regulation of adrenal zona reticularis development in male Wistar rats exposed to low doses of endocrine disruptor dichlorodiphenyltrichloroethane (DDT) prenatally and postnatally. At pubertal age, zona reticularis demonstrated a retarded growth with a low proliferative activity of its cells. At this age, zona reticularis was characterized with overexpression of ß-catenin by steroid-producing cells; a high percentage of cells with membrane and cytoplasmic localization of ß-catenin, and reduced number of cells with nuclear ß-catenin attesting to insufficient activation of Wnt signaling. Expression of transcriptional factor Oct4 by reticularis cells was down-regulated indicating their diminished proliferative potency. No significant alterations in Sonic Hedgehog expression were observed. Thus, DDT-provoked disorders of transcriptional regulation result in abnormal development of zona reticularis thereby disturbing sexual maturation in males.
Assuntos
DDT/farmacologia , Disruptores Endócrinos/farmacologia , Zona Reticular/efeitos dos fármacos , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Via de Sinalização Wnt/efeitos dos fármacos , Zona Reticular/metabolismoRESUMO
The role of stable hydrogen isotopes in the thermoregulation and its regulation is poorly studied. We analyzed fluctuations in body temperature and changes in thermoregulation parameters in mice under conditions of reduced deuterium intake. The study was performed on male C57BL/6 mice that consumed water with a low (10 ppm) and normal (146 ppm) deuterium content. In 7 days, fluctuations of body temperature, locomotor activity, and oxygen uptake were assessed. Deuterium depletion in the body reduced the mean value of minute fluctuations of body temperature and the mean spectral density of minute fluctuations in body temperature in the 2-20-min periods. This attested to a stabilizing effect of deuterium depletion on the rhythms of body temperature fluctuations, without significant shifts in the thermogenesis parameters. Thus, drinking water with reduced deuterium content makes them less sensitive to external influences.
Assuntos
Regulação da Temperatura Corporal , Deutério/farmacocinética , Comportamento de Ingestão de Líquido/fisiologia , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Regulação da Temperatura Corporal/efeitos dos fármacos , Regulação da Temperatura Corporal/fisiologia , Deutério/análise , Deutério/farmacologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Termogênese/efeitos dos fármacos , Termogênese/fisiologia , Água/química , Água/metabolismo , Água/farmacologiaRESUMO
We studied the formation of proliferative response of thymic lymphocytes to T-cell mitogen in rats exposed to endocrine disrupter DDT during prenatal and postnatal ontogeny. Developmental exposure to the endocrine disruptor was found to attenuate proliferative response during puberty and adulthood due to maintenance of higher proliferation rate of thymic lymphocytes in comparison with age-matched controls. Insufficient proliferative response to mitogens in rats developmentally exposed to the endocrine disrupter increases the risk of impairment of cell-mediated reactions of adaptive immunity.
Assuntos
Proliferação de Células/efeitos dos fármacos , DDT/toxicidade , Crescimento e Desenvolvimento/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Timócitos/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Embrião de Mamíferos , Disruptores Endócrinos/toxicidade , Feminino , Crescimento e Desenvolvimento/imunologia , Linfopoese/efeitos dos fármacos , Masculino , Mitógenos/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Ratos , Ratos Wistar , Linfócitos T/fisiologia , Timócitos/fisiologia , Testes de ToxicidadeRESUMO
The study is aimed at elucidation of ultrastructural mechanisms underlying impaired aldosterone synthesis by glomerulosa cells in Wistar rats exposed to low doses of endocrine disrupter DDT during prenatal and postnatal development. Analysis of rat zona glomerulosa histology and function during the pubertal and postpubertal periods showed that exposure to endocrine disrupter DDT disturbs its development and reduced the production of aldosterone. Electron microscopy showed that changes in the aldosterone synthesis are related to impaired reorganization of the mitochondrial apparatus, one of the leading factors in the regulation of steroidogenesis, in glomerulosa cells in DDT-exposed rats during puberty.
Assuntos
Aldosterona/sangue , DDT/toxicidade , Disruptores Endócrinos/toxicidade , Mitocôndrias/ultraestrutura , Efeitos Tardios da Exposição Pré-Natal/patologia , Zona Glomerulosa/ultraestrutura , Animais , Feminino , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Wistar , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/fisiologia , Zona Glomerulosa/efeitos dos fármacos , Zona Glomerulosa/metabolismo , Zona Glomerulosa/patologiaRESUMO
We studied the expression of transcriptional factors regulating postnatal morphogenesis of the adrenal zona fasciculata in rats after developmental exposure to endocrine disruptor DDT. It was found that tissue reparation after trophic disorders and cell death triggered by prenatal and postnatal exposure to DDT was accompanied by an increase in the number of Oct4- and Shh-expressing cells forming a pool located outside the regeneration zones and involved in the maintenance of tissue homeostasis in the zona fasciculata. DDT exposure also disrupted the expression of antiproliferative factor Hhex. The data showed that proliferation of fasciculata cells after termination of adrenal cortex growth was downregulated by inhibition of the expression of Oct4 and Shh and suppression of canonical Wnt signaling, i.e. due to a decrease in the reserve cell pool essential for physiological regeneration, which can reduce the reactive potential of the zona fasciculata.
Assuntos
DDT/farmacologia , Células Endócrinas/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Efeitos Tardios da Exposição Pré-Natal/genética , Transcrição Gênica/efeitos dos fármacos , Zona Fasciculada/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Proliferação de Células/efeitos dos fármacos , Células Endócrinas/citologia , Células Endócrinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Masculino , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Via de Sinalização Wnt , Zona Fasciculada/citologia , Zona Fasciculada/crescimento & desenvolvimento , Zona Fasciculada/metabolismoRESUMO
We studied histophysiology of the adrenal medulla in adult (70-day-old) male Wistar rats developmentally exposed to low doses of endocrine disruptor DDT. It was found that exposure to DDT during the prenatal and postnatal ontogeny decelerated the development of the adrenal medulla and reduced the synthesis of tyrosine hydroxylase, the rate-liming enzyme of catecholamine synthesis, in chromaffin cells, which led to a decrease in epinephrine secretion into the blood.
Assuntos
Medula Suprarrenal/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Medula Suprarrenal/metabolismo , Animais , Catecolaminas/metabolismo , Células Cromafins/efeitos dos fármacos , Células Cromafins/metabolismo , DDT/farmacologia , Epinefrina/sangue , Masculino , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
We analyzed the expression of transcriptional factor Oct4 in rat adrenal cortical cells during postnatal development. It was found that Oct4 is expressed by typical cortical cells of the zona glomerulosa, zona fasciculata, and zona reticularis in pubertal and postpubertal periods. The maximum number of Oct4+ cells was found in the zona glomerulosa. An inverse correlation between the number of Oct4+ glomerulosa cells and serum level of aldosterone both in pubertal and postpubertal periods was revealed. After puberty, the number of Oct4+ glomerulosa cells directly correlated with the number of Ki-67+ cells. A hypothesis was put forward that Oct4 is involved in postnatal morphogenesis, regeneration, and functioning of the adrenal cortex.
Assuntos
Córtex Suprarrenal/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Córtex Suprarrenal/citologia , Glândulas Suprarrenais/citologia , Glândulas Suprarrenais/metabolismo , Animais , Fator 3 de Transcrição de Octâmero/genética , Ratos , Ratos Wistar , Zona Glomerulosa/citologia , Zona Glomerulosa/metabolismoRESUMO
The effects of endocrine disrupters of transcriptional control of morphogenesis are poorly studied. Changes in the expression of transcriptional factor PRH and proliferation of adrenal cortical cells were analyzed in pubertal and postpubertal rats exposed prenatally and postnatally to low doses of endocrine disrupter DDT. In rats exposed to DDT, the expression of PRH and proliferation of adrenal cortical cells differed from those in control rats. Association between these parameters was weakened in the zona glomerulosa and zona reticularis and was absent in the zona fasciculata. These findings suggest that exposure to DDT in pre- and postnatal periods impairs the regulation of proliferative processes by transcriptional factor PRH in all zones of rat adrenal cortex, which can be a mechanism of the disruptive action of DDT.
Assuntos
Córtex Suprarrenal/crescimento & desenvolvimento , Proliferação de Células/efeitos dos fármacos , DDT/toxicidade , Disruptores Endócrinos/toxicidade , Proteínas de Homeodomínio/metabolismo , Córtex Suprarrenal/citologia , Animais , Masculino , Ratos , Ratos Wistar , Zona Fasciculada/crescimento & desenvolvimento , Zona Glomerulosa/crescimento & desenvolvimento , Zona Reticular/crescimento & desenvolvimentoRESUMO
The structure of the thymus in newborn rats exposed in utero to endocrine disruptor DDT was studied. We found that exposure to low doses of DDT during pregnancy does not disturb thymus formation in the offspring, but leads to changes in its structure than manifested as slower lobulation, wider epithelium-free areas in the cortex, and lower number of thymic corpuscles in the medulla. The results attest to sensitivity of the reticuloepithelial stroma of the thymus to the effects of endocrine disruptor.
Assuntos
DDT/toxicidade , Disruptores Endócrinos/toxicidade , Timo/efeitos dos fármacos , Timo/embriologia , Animais , Animais Recém-Nascidos , Feminino , Organogênese/efeitos dos fármacos , Gravidez , Ratos , Ratos WistarRESUMO
Prenatal and postnatal exposure to low doses of the endocrine disruptor dichlorodiphenyltrichloroethane (DDT) leads to delayed activation of the canonical ß-catenin/Wnt signaling in zona glomerulosa and zona reticularis of the adrenal cortex in rats, which changed the rate of their postnatal development. Suppression of the Wnt pathway in zona fasciculata promotes its regeneration after DDT-induced blood circulation disorders and cell death.