The urinary metabolites of DINCH® have an impact on the activities of the human nuclear receptors ERα ERβ, AR, PPARα and PPARγ
The urinary metabolites of DINCH® have an impact on the activities of the human nuclear receptors ERα ERβ, AR, PPARα and PPARγ
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DOI：
10.1016/j.toxlet.2018.02.006
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发表时间：
2018-05-01
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
DINCH（R）（环己烷-1，2-二羧酸二异壬酯）是一种非邻苯二甲酸酯增塑剂，已开发用于替代邻苯二甲酸酯增塑剂，如DEHP（邻苯二甲酸二-2-乙基己酯）或DINP（邻苯二甲酸二异壬酯）。DINCH（R）代谢为相应的单酯，随后代谢为氧化的单酯衍生物。它们与葡萄糖醛酸结合并经尿排泄。与DINCH（R）相反，几乎没有关于其初级和次级代谢产物的毒理学数据。本研究旨在通过使用报告基因测定来监测体外人核受体ER α、ER β、AR、PPAR α和PPAR γ的活性，表征DINCH（R）和五种DINCH（R）代谢物的潜在内分泌特性。DINCH（R）本身对这些受体的活性没有任何影响，而DINCH（R）代谢物显示出激活所有这些受体。在AR的情况下，DINCH（R）代谢物主要增强二氢睾酮刺激的AR活性。在H295 R类固醇生成试验中，DINCH（R）及其任何代谢产物均不影响雌二醇或睾酮的合成。总之，与DINCH（R）本身相比，初级和次级DINCH（R）代谢物在分子水平上发挥不同的作用。然而，DINCH（R）代谢物的所有这些体外作用仅在高浓度（例如10 μ M或更高）下观察到，所述高浓度比人尿液中报道的DINCH（R）代谢物浓度高约三个数量级。因此，体外数据不支持DINCH（R）或任何研究的代谢物在相关人体暴露水平下可能在体内产生相当大的内分泌效应的观点。
DINCH (R) (di-isononyl cyclohexane-1,2-dicarboxylate) is a non-phthalate plasticizer that has been developed to replace phthalate plasticizers such as DEHP (di-2-ethylhexyl phthalate) or DINP (di-isononyl phthalate). DINCH (R) is metabolized to its corresponding monoester and subsequently to oxidized monoester derivatives. These are conjugated to glucuronic acid and subject to urinary excretion. In contrast to DINCH (R), there are almost no toxicological data available regarding its primary and secondary metabolites. The present study aimed at the characterization of potential endocrine properties of DINCH (R) and five DINCH (R) metabolites by using reporter gene assays to monitor the activity of the human nuclear receptors ER alpha, ER beta, AR, PPAR alpha and PPAR gamma in vitro. DINCH (R) itself did not have any effect on the activity of these receptors whereas DINCH (R) metabolites were shown to activate all these receptors. In the case of AR, DINCH (R) metabolites predominantly enhanced dihydrotestosterone-stimulated AR activity. In the H295R steroidogenesis assay, neither DINCH (R) nor any of its metabolites affected estradiol or testosterone synthesis. In conclusion, primary and secondary DINCH (R) metabolites exert different effects at the molecular level compared to DINCH (R) itself. All these in vitro effects of DINCH (R) metabolites, however, were only observed at high concentrations such as 10 iM or above which is about three orders of magnitude above reported DINCH (R) metabolite concentrations in human urine. Thus, the in vitro data do not support the notion that DINCH (R) or any of the investigated metabolites may exert considerable endocrine effects in vivo at relevant human exposure levels.