DINCH® (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® 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®, 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® and five DINCH® metabolites by using reporter gene assays to monitor the activity of the human nuclear receptors ERα, ERβ, AR, PPARα and PPARγ in vitro. DINCH® itself did not have any effect on the activity of these receptors whereas DINCH® metabolites were shown to activate all these receptors. In the case of AR, DINCH® metabolites predominantly enhanced dihydrotestosterone-stimulated AR activity. In the H295R steroidogenesis assay, neither DINCH® nor any of its metabolites affected estradiol or testosterone synthesis. In conclusion, primary and secondary DINCH® metabolites exert different effects at the molecular level compared to DINCH® itself. All these in vitro effects of DINCH® metabolites, however, were only observed at high concentrations such as 10 μM or above which is about three orders of magnitude above reported DINCH® metabolite concentrations in human urine. Thus, the in vitro data do not support the notion that DINCH® or any of the investigated metabolites may exert considerable endocrine effects in vivo at relevant human exposure levels.

中文翻译：

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DINCH ® 的尿代谢物对人核受体 ERα、ERβ、AR、PPARα 和 PPARγ 的活性有影响

DINCH®（环己烷-1,2-二异壬酯）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，例如 DEHP（邻苯二甲酸二-2-乙基己酯）或 DINP（邻苯二甲酸二异壬酯）。DINCH® 被代谢为其相应的单酯，随后被代谢为氧化的单酯衍生物。它们与葡萄糖醛酸结合并受尿排泄。与 DINCH® 相比，几乎没有关于其初级和次级代谢物的毒理学数据。本研究旨在通过使用报告基因检测来监测体外人核受体 ERα、ERβ、AR、PPARα 和 PPARγ 的活性来表征 DINCH® 和五种 DINCH® 代谢物的潜在内分泌特性。DINCH® 本身对这些受体的活性没有任何影响，而 DINCH® 代谢物显示可以激活所有这些受体。在 AR 的情况下，DINCH® 代谢物主要增强了双氢睾酮刺激的 AR 活性。在 H295R 类固醇生成试验中，DINCH® 或其任何代谢物均不影响雌二醇或睾酮的合成。总之，与 DINCH® 本身相比，初级和次级 DINCH® 代谢物在分子水平上发挥不同的作用。然而，DINCH® 代谢物的所有这些体外效应仅在高浓度（例如 10 μM 或更高）下观察到，这比人类尿液中报告的 DINCH® 代谢物浓度高出约三个数量级。因此，