Agonistic and antagonistic effects of phthalates and their urinary metabolites on the steroid hormone receptors ERα, ERβ, and AR
Agonistic and antagonistic effects of phthalates and their urinary metabolites on the steroid hormone receptors ERα, ERβ, and AR
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DOI：
10.1016/j.toxlet.2017.05.028
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发表时间：
2017-08-01
影响因子：
3.5
通讯作者：
Lampen, Alfonso
中科院分区：
文献类型：
--
作者：
Engel, Anika;Buhrke, Thorsten;Lampen, Alfonso
据报道，邻苯二甲酸酯增塑剂通过激活雌激素受体ER α和ER β以及抑制雄激素受体AR作为分子起始事件而产生不良反应。经口摄入后，邻苯二甲酸酯代谢为相应的单酯，随后代谢为氧化的邻苯二甲酸单酯衍生物，后者又与葡萄糖醛酸结合，最终随尿液排出。与母体邻苯二甲酸酯相比，关于其初级和次级代谢产物的毒理学数据很少。本研究旨在通过使用报告基因试验监测人ER α、ER β和AR活性，表征15种邻苯二甲酸酯和19种邻苯二甲酸酯代谢物的潜在内分泌效应。在这些体外试验中，邻苯二甲酸酯刺激或抑制ER α和ER α活性并抑制AR活性，而邻苯二甲酸酯代谢产物对这些人激素受体的活性无影响。相比之下，邻苯二甲酸二（2-乙基己基）酯（DEHP）的代谢物在类似的报告基因试验中刺激了人类过氧化物酶体增殖物激活受体PPAR α和PPAR γ的反式激活，尽管DEHP本身并不激活这些核受体。因此，与母体化合物相比，邻苯二甲酸酯的初级和次级代谢产物似乎在分子水平上发挥不同的作用。
Phthalate plasticizers have been reported to exert adverse effects via activation of the estrogen receptors ER alpha and ER beta and inhibition of the androgen receptor AR as molecular initiating events. After oral uptake, phthalates are metabolized to their corresponding monoesters and subsequently to oxidized phthalate monoester derivatives, which are in turn conjugated to glucuronic acid and finally excreted with the urine. In contrast to the parent phthalates, toxicological data regarding their primary and secondary metabolites are rare. The present study aimed at the characterization of potential endocrine effects of 15 phthalates and 19 phthalate metabolites by using reporter gene assays to monitor human ER alpha, ER beta, and AR activity. In these in vitro assays, the phthalates either stimulated or inhibited ERa and ERa activity and inhibited AR activity, whereas the phthalate metabolites had no impact on the activity of these human hormone receptors. In contrast, the metabolites of di-(2-ethylhexyl) phthalate (DEHP) stimulated transactivation of the human peroxisome proliferator-activated receptors PPAR alpha and PPAR gamma in analogous reporter gene assays, although DEHP itself did not activate these nuclear receptors. Therefore, primary and secondary phthalate metabolites appear to exert different effects at the molecular level compared to the parent compounds.