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首页> 外文学位 >In utero exposure to di-(2-ethylhexyl) phthalate reveals the presence of an adrenal-testis axis regulating androgen formation.
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In utero exposure to di-(2-ethylhexyl) phthalate reveals the presence of an adrenal-testis axis regulating androgen formation.

机译：在子宫内暴露于邻苯二甲酸二-（2-乙基己基）酯时，表明存在调节雄激素形成的肾上腺-睾丸轴。

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摘要

Phthalates are endocrine disruptors with short- and long- term antiadrogenic properties. In the adult, in utero exposure to di-(2-ethylhexyl) phthalate (DEHP) results in decreased testosterone levels despite normal serum levels of LH, proteins and enzymes involved in cholesterol transport and biosynthesis, suggesting that the effects of DEHP are independent of the classic steroidogenic pathway. The purpose of this body of work is to identify the mechanism mediating this antiandrogenic effect of DEHP. The mineralocorticoid receptor (NR3C2; MR) mediates testosterone production and we show that in utero exposure to DEHP decreases MR-expression in Leydig cells. The reduced MR expression was accompanied by a decrease in circulating levels of aldosterone biosynthesized in the adrenal gland and was similar in magnitude to the decrease seen in testosterone. In search of the mechanism underlying the reduced aldosterone formation, we observed that DEHP decreases the expression of angiotensin II (ATII) receptors despite normal serum levels of the main aldosterone stimulants, ATII and potassium. The ATII receptor decrease did not have an impact on the proteins and enzymes involved in aldosterone biosynthesis. Paradoxically, the pathways for extracellular cholesterol and de novo cholesterol synthesis were up regulated and were accompanied with accumulation of lipid droplets in the zona glomerulosa.;Global gene expression of post-natal day 60 (PND60) adrenals showed an up regulation of genes involved in the potassium response and resulted in the identification of the potassium channels Kcnk5 and Kcnn2 as novel targets of DEHP exposure. The deregulation of potassium sensing pathway was confirmed in vitro using NCI-H295R human adrenal cortical tumor cells exposed to the bioactive DEHP metabolite mono-2-ethylhexyl phthalate (MEHP).;The data obtained suggest that a deregulation in potassium channel gene expression can lead to a chronic activation of the adrenal zona glomerulosa, leading to reduction of ATII receptor expression and inhibition of aldosterone production. Reduction of circulating aldosterone levels together with a decrease of MR levels in Leydig cells could account for the antiandrogenic effects of DEHP in testis.;Taken together these results demonstrate that in utero exposure to DEHP induces long lasting effects on the endocrine system in the rat and unveiled the presence of adrenal-testis interactions driving androgen formation.
机译：邻苯二甲酸酯是具有短期和长期抗雄激素特性的内分泌干扰物。在成年人中，尽管血清中的LH，胆固醇和胆固醇的转运和生物合成所涉及的蛋白质和酶的水平正常，但在子宫内接触邻苯二甲酸二（2-乙基己基）酯（DEHP）会导致睾丸激素水平降低，这表明DEHP的作用与经典的类固醇生成途径。该工作的目的是确定介导DEHP抗雄激素作用的机制。盐皮质激素受体（NR3C2; MR）介导睾丸激素的产生，我们表明子宫内暴露于DEHP会降低Leydig细胞的MR表达。 MR表达的降低伴随着肾上腺中生物合成的醛固酮循环水平的降低，其幅度与睾丸激素的降低相似。在寻找降低醛固酮形成的潜在机制时，我们观察到DEHP降低了血管紧张素II（ATII）受体的表达，尽管主要醛固酮兴奋剂，ATII和钾的血清水平正常。 ATII受体的减少对醛固酮生物合成中涉及的蛋白质和酶没有影响。矛盾的是，细胞外胆固醇和从头胆固醇合成的途径被上调，并伴随着脂质液滴在肾小球中的积累。；出生后第60天（PND60）肾上腺的整体基因表达表明，参与该过程的基因的上调钾反应，并确定钾通道Kcnk5和Kcnn2是DEHP暴露的新靶标。使用暴露于生物活性DEHP代谢物邻苯二甲酸单-2-乙基己基酯（MEHP）的NCI-H295R人肾上腺皮质肿瘤细胞在体外确认了钾传感通路的失调;;获得的数据表明钾通道基因表达的失调可以导致导致肾上腺肾小球的慢性活化，导致ATII受体表达降低和醛固酮生成抑制。循环醛固酮水平的降低以及Leydig细胞中MR水平的降低可以解释DEHP在睾丸中的抗雄激素作用。总而言之，这些结果表明子宫内暴露于DEHP会对大鼠和大鼠的内分泌系统产生长期的影响。揭示了驱动雄激素形成的肾上腺-睾丸相互作用的存在。

著录项

  • 作者

    Martinez Arguelles, Daniel B.;

  • 作者单位

    Georgetown University.;

  • 授予单位 Georgetown University.;
  • 学科 Biology Endocrinology.;Environmental Health.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 209 p.
  • 总页数 209
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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