Obesogens and Male Fertility: a Threat to Sertoli Cell Function?
Autor(a) principal: | |
---|---|
Data de Publicação: | 2016 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.6/5768 |
Resumo: | In the last decades, several studies evidenced a negative correlation between life expectancy and sperm quality in developed countries. Although the etiology of this trend in male fertility remains a matter of debate, environmental compounds that predispose to weight gain, namely obesogens, are appointed as pivotal contributors due to their action as endocrine disruptors. Obesogens can be found virtually everywhere, including in high-energy diets or in the surrounding environment. Tributyltin arises as the obesogen model, being considered one of the most toxic compounds ever introduced into the environment. Tributyltin presents lipophilic characteristics and high affinity to accumulate in tissues with high lipid contents, as is the case of testes. Once stored in these organs, tributyltin can affect testicular physiology and metabolism, which are crucial for spermatogenesis. Disruption of these tightly regulated metabolic pathways may be the molecular basis of adverse reproductive outcomes, such as increased oxidative stress or even sperm defects. The appropriate development of germ cells is highly dependent on the nutritional support provided by Sertoli cells, which metabolism present some unique features. Sertoli cells metabolize glucose, being the majority of it converted to lactate, the main fuel for developing germ cells. Thus, the regulation of Sertoli cell glycolytic metabolism plays a central role on spermatogenesis. Interestingly, these cells were already proven to be a target for environmental toxicants, being these compounds able to alter their structure and/or function. Herein, we evaluated the impact of tributyltin on Sertoli cell metabolism, with a particular focus on glycolytic metabolism. In order to achieve it, we selected 3 different concentrations of tributyltin: 0.1 nM, a subtoxic dose but to which weigh gain and retinoid X receptor- peroxisome proliferator-activated receptor ? activation were already described; 10 nM, a dose within the range of concentrations reported in serum and tissues of humans; and 1000 nM, a dose from which broad cytotoxic effects have already been evidenced. Our results evidenced that the exposure to the highest concentration of tributyltin (1000 nM) induce severe cytotoxic effects in rat Sertoli cells, decreasing their proliferation to 28%, when compared with the control group. Since the lower concentrations of tributyltin (10 nM and 0.1 nM) did not induced cytotoxic effects, we investigated possible changes in Sertoli cells maturation markers through the analysis of inhibin B and androgens receptor. However, for the adopted concentrations, significant changes were not observed in the expression of these transcripts. However, both concentrations (10 and 0.1 nM) revealed to affect glycolysis and lactate production-related events. Indeed, the glycolytic pathway was favored in Sertoli cells exposed to tributyltin 10 nM, since the increased glucose and pyruvate consumption was followed by an increase in lactate production. However, the protein expression of glucose transporters 1, 2 and 3 remain unaltered, while the expression of lactate dehydrogenase was decreased when compared to control. In addition, Sertoli cells exposed to this concentration of tributyltin revealed also an increased expression of monocarboxylate transporter isoform 4 when compared to control, which had probably contributed to a higher lactate export. Concerning to Sertoli cells exposed to the lowest concentration of tributyltin (0.1 nM), significant changes in glucose consumption were not observed, even though a decreased expression of glucose transporters 1 and 2 was evidenced in this experimental group. Similarly, also the pyruvate consumption was significantly lower when compared with the group of Sertoli cells exposed to tributyltin 10 nM. The absence of significant changes in lactate production may be due to the decreased lactate dehydrogenase expression. Besides, we also observed a significant decrease in alanine levels in both groups of Sertoli cells exposed to tributyltin, which favors a high cytosolic oxidative redox state, predisposing the cells to a possible oxidative environment. In conclusion, this study showed that tributyltin, in addition to induce significant cytotoxic effects in rat Sertoli cells when administered at a high dose, also promotes several changes in one of the main functions of differentiated Sertoli cells, the glycolytic metabolism. In this regard, tributyltin may affect spermatogenesis and thus male fertility. |
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Obesogens and Male Fertility: a Threat to Sertoli Cell Function?Células de SertoliFertilidade MasculinaMetabolismo Glicolítico.ObesogénicosTributilestanhoIn the last decades, several studies evidenced a negative correlation between life expectancy and sperm quality in developed countries. Although the etiology of this trend in male fertility remains a matter of debate, environmental compounds that predispose to weight gain, namely obesogens, are appointed as pivotal contributors due to their action as endocrine disruptors. Obesogens can be found virtually everywhere, including in high-energy diets or in the surrounding environment. Tributyltin arises as the obesogen model, being considered one of the most toxic compounds ever introduced into the environment. Tributyltin presents lipophilic characteristics and high affinity to accumulate in tissues with high lipid contents, as is the case of testes. Once stored in these organs, tributyltin can affect testicular physiology and metabolism, which are crucial for spermatogenesis. Disruption of these tightly regulated metabolic pathways may be the molecular basis of adverse reproductive outcomes, such as increased oxidative stress or even sperm defects. The appropriate development of germ cells is highly dependent on the nutritional support provided by Sertoli cells, which metabolism present some unique features. Sertoli cells metabolize glucose, being the majority of it converted to lactate, the main fuel for developing germ cells. Thus, the regulation of Sertoli cell glycolytic metabolism plays a central role on spermatogenesis. Interestingly, these cells were already proven to be a target for environmental toxicants, being these compounds able to alter their structure and/or function. Herein, we evaluated the impact of tributyltin on Sertoli cell metabolism, with a particular focus on glycolytic metabolism. In order to achieve it, we selected 3 different concentrations of tributyltin: 0.1 nM, a subtoxic dose but to which weigh gain and retinoid X receptor- peroxisome proliferator-activated receptor ? activation were already described; 10 nM, a dose within the range of concentrations reported in serum and tissues of humans; and 1000 nM, a dose from which broad cytotoxic effects have already been evidenced. Our results evidenced that the exposure to the highest concentration of tributyltin (1000 nM) induce severe cytotoxic effects in rat Sertoli cells, decreasing their proliferation to 28%, when compared with the control group. Since the lower concentrations of tributyltin (10 nM and 0.1 nM) did not induced cytotoxic effects, we investigated possible changes in Sertoli cells maturation markers through the analysis of inhibin B and androgens receptor. However, for the adopted concentrations, significant changes were not observed in the expression of these transcripts. However, both concentrations (10 and 0.1 nM) revealed to affect glycolysis and lactate production-related events. Indeed, the glycolytic pathway was favored in Sertoli cells exposed to tributyltin 10 nM, since the increased glucose and pyruvate consumption was followed by an increase in lactate production. However, the protein expression of glucose transporters 1, 2 and 3 remain unaltered, while the expression of lactate dehydrogenase was decreased when compared to control. In addition, Sertoli cells exposed to this concentration of tributyltin revealed also an increased expression of monocarboxylate transporter isoform 4 when compared to control, which had probably contributed to a higher lactate export. Concerning to Sertoli cells exposed to the lowest concentration of tributyltin (0.1 nM), significant changes in glucose consumption were not observed, even though a decreased expression of glucose transporters 1 and 2 was evidenced in this experimental group. Similarly, also the pyruvate consumption was significantly lower when compared with the group of Sertoli cells exposed to tributyltin 10 nM. The absence of significant changes in lactate production may be due to the decreased lactate dehydrogenase expression. Besides, we also observed a significant decrease in alanine levels in both groups of Sertoli cells exposed to tributyltin, which favors a high cytosolic oxidative redox state, predisposing the cells to a possible oxidative environment. In conclusion, this study showed that tributyltin, in addition to induce significant cytotoxic effects in rat Sertoli cells when administered at a high dose, also promotes several changes in one of the main functions of differentiated Sertoli cells, the glycolytic metabolism. In this regard, tributyltin may affect spermatogenesis and thus male fertility.Nas últimas décadas, diversos estudos têm evidenciado uma correlação inversa entre o aumento da esperança de vida e a qualidade espermática dos indivíduos residentes nos países desenvolvidos. Embora a etiologia desta tendência na fertilidade masculina ainda seja um assunto que suscite grande debate, os obesogénicos, compostos ambientais que predispõem para o ganho de peso, têm sido apontados como importantes causadores, sobretudo devido à sua ação enquanto desreguladores endócrinos. Os obesogénicos podem ser encontrados praticamente em todo o lado, inclusive em dietas altamente calóricas ou no meio ambiente. O tributilestanho surge como o obesogénico modelo, sendo mesmo considerado um dos compostos mais tóxicos alguma vez introduzidos no ecossistema. Este apresenta caraterísticas lipofílicas e revela uma grande afinidade para se acumular em tecidos com elevado teor lipídico, como é o caso dos testículos. Uma vez armazenado nestes órgãos, o tributilestanho pode afetar a fisiologia e o próprio metabolismo testicular, função fulcral para a espermatogénese. A desregulação destas vias metabólicas pode estar na base molecular de efeitos reprodutivos adversos, como é o caso do aumento do stress oxidativo testicular ou de defeitos espermáticos. O adequado desenvolvimento das células germinativas é altamente dependente do suporte nutricional fornecido pelas células de Sertoli, cujo metabolismo revela características particulares. As células de Sertoli metabolizam a maioria da glucose a lactato que, por sua vez, constitui a principal fonte de energia das células germinativas em desenvolvimento. Assim, a regulação do metabolismo glicolítico das células de Sertoli tem um papel central no processo da espermatogénese. Curiosamente, já se evidenciou que estas células são um alvo preferencial para tóxicos ambientais capazes de alterar a sua estrutura e/ou função. O objetivo deste estudo passou por avaliar o impacto do tributilestanho no metabolismo das células de Sertoli, com um foco particular no metabolismo glicolítico. Para tal, recorreu-se a três concentrações do composto: 0.1 nM, uma dose considerada subtóxica, mas para a qual o ganho de peso e, particularmente, a ativação do heterodímero do recetor de retinoide X/recetor ativado pelo proliferador de peroxissoma ? foram demonstrados; 10 nM, pertencente ao intervalo de concentrações descritas no soro e tecidos de alguns indivíduos; e 1000 nM, uma concentração a partir da qual foram demonstrados efeitos citotóxicos. Os resultados obtidos demonstraram que a exposição à concentração mais elevada de tributilestanho (1000 nM) induz efeitos citotóxicos severos nas células de Sertoli de rato, reduzindo a sua proliferação para 28%, em comparação com o grupo controlo. Dada a ausência de efeitos citotóxicos nos grupos expostos às restantes concentrações de tributilestanho, investigaram-se eventuais alterações na expressão de marcadores de células de Sertoli maduras, através da análise da inibina B e do recetor de androgénios. Para as concentrações utilizadas, não se observaram alterações significativas na expressão dos transcritos destes marcadores. Contudo, em termos metabólicos, ambas as doses revelaram afetar as vias relacionadas com a glicólise e com a produção de lactato. De facto, a via glicolítica foi favorecida nas células de Sertoli expostas a 10 nM de tributilestanho, visto que o aumento do consumo de glucose e piruvato foi acompanhado por um aumento na produção de lactato. No entanto, não se verificou qualquer alteração na expressão dos transportadores de glucose 1, 2 e 3, ao passo que a expressão da enzima lactato desidrogenase se revelou diminuída em relação ao grupo controlo. Adicionalmente, constatou-se também que as células de Sertoli expostas a esta concentração de tributilestanho (10 nM) apresentavam uma maior expressão da isoforma 4 do transportador de monocarboxilatos, o que sugere um contributo para uma exportação de lactato mais elevada. Relativamente às células de Sertoli expostas à concentração mais baixa de tributilestanho (0.1 nM), estas não apresentaram diferenças no consumo da glucose, apesar de ter sido evidenciada uma diminuição da expressão dos transportadores de glucose 1 e 2 neste grupo experimental. De forma idêntica, também o consumo de piruvato foi significativamente inferior em comparação ao grupo de células expostas a 10 nM de tributilestanho. Não se verificaram alterações significativas na produção de lactato, facto que poderá ter resultado da diminuição da expressão da lactato desidrogenase. Paralelamente, verificou-se, em ambos os grupos, uma diminuição significativa dos níveis de alanina, o que favorece um aumento do estado redox citosólico, sujeitando as células a um possível ambiente oxidativo. Em conclusão, este estudo destacou que o tributilestanho, para além de induzir efeitos citotóxicos significativos nas células de Sertoli de rato quando administrado numa dose elevada, promove diversas alterações numa das principais funções das células de Sertoli diferenciadas, o metabolismo glicolítico, podendo, desta forma, afetar a espermatogénese e consequentemente a fertilidade masculina.Cavaco, José Eduardo BritesOliveira, Carlos Pedro FontesRato, Luís Pedro FerreirauBibliorumCardoso, Ana Margarida Nunes Ferreira Ribeiro2018-08-27T15:52:33Z2016-6-22016-06-282016-06-28T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10400.6/5768TID:201771454enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-12-15T09:43:56Zoai:ubibliorum.ubi.pt:10400.6/5768Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:46:37.018288Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Obesogens and Male Fertility: a Threat to Sertoli Cell Function? |
title |
Obesogens and Male Fertility: a Threat to Sertoli Cell Function? |
spellingShingle |
Obesogens and Male Fertility: a Threat to Sertoli Cell Function? Cardoso, Ana Margarida Nunes Ferreira Ribeiro Células de Sertoli Fertilidade Masculina Metabolismo Glicolítico. Obesogénicos Tributilestanho |
title_short |
Obesogens and Male Fertility: a Threat to Sertoli Cell Function? |
title_full |
Obesogens and Male Fertility: a Threat to Sertoli Cell Function? |
title_fullStr |
Obesogens and Male Fertility: a Threat to Sertoli Cell Function? |
title_full_unstemmed |
Obesogens and Male Fertility: a Threat to Sertoli Cell Function? |
title_sort |
Obesogens and Male Fertility: a Threat to Sertoli Cell Function? |
author |
Cardoso, Ana Margarida Nunes Ferreira Ribeiro |
author_facet |
Cardoso, Ana Margarida Nunes Ferreira Ribeiro |
author_role |
author |
dc.contributor.none.fl_str_mv |
Cavaco, José Eduardo Brites Oliveira, Carlos Pedro Fontes Rato, Luís Pedro Ferreira uBibliorum |
dc.contributor.author.fl_str_mv |
Cardoso, Ana Margarida Nunes Ferreira Ribeiro |
dc.subject.por.fl_str_mv |
Células de Sertoli Fertilidade Masculina Metabolismo Glicolítico. Obesogénicos Tributilestanho |
topic |
Células de Sertoli Fertilidade Masculina Metabolismo Glicolítico. Obesogénicos Tributilestanho |
description |
In the last decades, several studies evidenced a negative correlation between life expectancy and sperm quality in developed countries. Although the etiology of this trend in male fertility remains a matter of debate, environmental compounds that predispose to weight gain, namely obesogens, are appointed as pivotal contributors due to their action as endocrine disruptors. Obesogens can be found virtually everywhere, including in high-energy diets or in the surrounding environment. Tributyltin arises as the obesogen model, being considered one of the most toxic compounds ever introduced into the environment. Tributyltin presents lipophilic characteristics and high affinity to accumulate in tissues with high lipid contents, as is the case of testes. Once stored in these organs, tributyltin can affect testicular physiology and metabolism, which are crucial for spermatogenesis. Disruption of these tightly regulated metabolic pathways may be the molecular basis of adverse reproductive outcomes, such as increased oxidative stress or even sperm defects. The appropriate development of germ cells is highly dependent on the nutritional support provided by Sertoli cells, which metabolism present some unique features. Sertoli cells metabolize glucose, being the majority of it converted to lactate, the main fuel for developing germ cells. Thus, the regulation of Sertoli cell glycolytic metabolism plays a central role on spermatogenesis. Interestingly, these cells were already proven to be a target for environmental toxicants, being these compounds able to alter their structure and/or function. Herein, we evaluated the impact of tributyltin on Sertoli cell metabolism, with a particular focus on glycolytic metabolism. In order to achieve it, we selected 3 different concentrations of tributyltin: 0.1 nM, a subtoxic dose but to which weigh gain and retinoid X receptor- peroxisome proliferator-activated receptor ? activation were already described; 10 nM, a dose within the range of concentrations reported in serum and tissues of humans; and 1000 nM, a dose from which broad cytotoxic effects have already been evidenced. Our results evidenced that the exposure to the highest concentration of tributyltin (1000 nM) induce severe cytotoxic effects in rat Sertoli cells, decreasing their proliferation to 28%, when compared with the control group. Since the lower concentrations of tributyltin (10 nM and 0.1 nM) did not induced cytotoxic effects, we investigated possible changes in Sertoli cells maturation markers through the analysis of inhibin B and androgens receptor. However, for the adopted concentrations, significant changes were not observed in the expression of these transcripts. However, both concentrations (10 and 0.1 nM) revealed to affect glycolysis and lactate production-related events. Indeed, the glycolytic pathway was favored in Sertoli cells exposed to tributyltin 10 nM, since the increased glucose and pyruvate consumption was followed by an increase in lactate production. However, the protein expression of glucose transporters 1, 2 and 3 remain unaltered, while the expression of lactate dehydrogenase was decreased when compared to control. In addition, Sertoli cells exposed to this concentration of tributyltin revealed also an increased expression of monocarboxylate transporter isoform 4 when compared to control, which had probably contributed to a higher lactate export. Concerning to Sertoli cells exposed to the lowest concentration of tributyltin (0.1 nM), significant changes in glucose consumption were not observed, even though a decreased expression of glucose transporters 1 and 2 was evidenced in this experimental group. Similarly, also the pyruvate consumption was significantly lower when compared with the group of Sertoli cells exposed to tributyltin 10 nM. The absence of significant changes in lactate production may be due to the decreased lactate dehydrogenase expression. Besides, we also observed a significant decrease in alanine levels in both groups of Sertoli cells exposed to tributyltin, which favors a high cytosolic oxidative redox state, predisposing the cells to a possible oxidative environment. In conclusion, this study showed that tributyltin, in addition to induce significant cytotoxic effects in rat Sertoli cells when administered at a high dose, also promotes several changes in one of the main functions of differentiated Sertoli cells, the glycolytic metabolism. In this regard, tributyltin may affect spermatogenesis and thus male fertility. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-6-2 2016-06-28 2016-06-28T00:00:00Z 2018-08-27T15:52:33Z |
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info:eu-repo/semantics/publishedVersion |
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