The urinary metabolites of DINCH® have an impact on the activities of the human nuclear receptors ERα, ERβ, AR, PPARα and PPARγ

• Published in: Toxicology letters Vol. 287; pp. 83 - 91
• Main Authors: Engel, Anika, Buhrke, Thorsten, Kasper, Stefanie, Behr, Anne-Cathrin, Braeuning, Albert, Jessel, Sönke, Seidel, Albrecht, Völkel, Wolfgang, Lampen, Alfonso
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2018
• Subjects: Androgen receptor; DINCH; Estrogen receptor; PPAR activation; Steroidogenesis; Estrogen receptor; PPAR activation; Steroidogenesis; DINCH; Androgen receptor; DINCH(®)
• ISSN: 0378-4274; 1879-3169; 1879-3169
• DOI: 10.1016/j.toxlet.2018.02.006

•DINCH® does not activate the human hormone receptors ERα, ERβ and AR.•DINCH® metabolites stimulate ERα,ERβ and AR activity.•DINCH® metabolites activate the nuclear receptors PPARα and PPARγ.•DINCH® and its metabolites exert different molecular biological activities. 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.