Krupka Sontje, Aldehoff Alix Sarah, Goerdeler Cornelius, Engelmann Beatrice, Rolle-Kampczyk Ulrike, Schubert Kristin, Klöting Nora, von Bergen Martin, Blüher Matthias
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Centre München at the University of Leipzig Germany; Department of Endocrinology Nephrology Rheumatology University Hospital Leipzig Medical Research Center Leipzig Germany.
Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ) Leipzig Germany.
Environ Int. 2025 Feb;196:109306. doi: 10.1016/j.envint.2025.109306. Epub 2025 Jan 26.
Plastic materials are ubiquitous, leading to constant human exposure to plastic additives such as plasticizers. There is growing evidence that plasticizers may contribute to obesity due to their disruptive effects on metabolism. Alternatives like diisononylcyclohexane-1,2-dicarboxylate (DINCH) are replacing traditional phthalates such as di-(2-ethylhexyl) phthalate (DEHP), which are now banned due to their proven harmful health effects. While DINCH is considered a safer alternative to DEHP and no adipogenic effects have been demonstrated in in vivo studies, recent research suggests that the primary metabolite, monoisononylcyclohexane-1,2-dicarboxylic acid ester (MINCH), promotes adipocyte differentiation and dysfunction in vitro. However, metabolic and molecular effects are not fully understood in vivo. Here, we performed a comprehensive in vivo analysis using C57BL/6N mice to investigate the effects of DINCH on adipose tissue physiology and function. Mice were exposed to two doses of DINCH for 16 weeks, followed by a 10-week recovery period. Tissue analysis confirmed the presence of DINCH and MINCH in liver and adipose tissue after treatment and recovery. After the recovery period, elevated DINCH concentrations in adipose tissue depots indicated possible bioaccumulation. Although no changes were observed in body composition and energy expenditure, sex-specific metabolic effects were identified. Female mice exhibited impaired whole-body insulin sensitivity and higher triglyceride levels, while male mice showed an altered insulin/C-peptide ratio and elevated cholesterol, HDL, and LDL levels. Proteomic profiling of serum, adipose and liver tissues revealed changes in pathways related to central energy metabolism and immune response, highlighting the systemic impact of DINCH, potentially on inflammatory processes. Most effects of DINCH, such as changes in insulin response and serum lipid levels, were diminished after the recovery period. Despite many findings consistent with the existing literature suggesting DINCH as a safer DEHP substitute, the observed sex-specific effects on insulin sensitivity, lipid metabolism and inflammatory processes, as well as potential bioaccumulation and long-term metabolic effects of DINCH exposure warrant careful consideration in further risk assessment.
塑料材料无处不在，导致人类持续接触增塑剂等塑料添加剂。越来越多的证据表明，增塑剂可能因其对新陈代谢的破坏作用而导致肥胖。二异壬基环己烷-1,2-二羧酸酯（DINCH）等替代品正在取代传统邻苯二甲酸盐，如邻苯二甲酸二（2-乙基己基）酯（DEHP），后者因已证实的有害健康影响而被禁用。虽然DINCH被认为是比DEHP更安全的替代品，且体内研究未显示其有促脂肪生成作用，但最近的研究表明，其主要代谢产物单异壬基环己烷-1,2-二羧酸酯（MINCH）在体外可促进脂肪细胞分化和功能障碍。然而，其在体内的代谢和分子效应尚未完全明确。在此，我们使用C57BL/6N小鼠进行了全面的体内分析，以研究DINCH对脂肪组织生理和功能的影响。小鼠暴露于两种剂量的DINCH中16周，随后有10周的恢复期。组织分析证实，在治疗和恢复后，肝脏和脂肪组织中存在DINCH和MINCH。恢复期后，脂肪组织库中DINCH浓度升高表明可能存在生物蓄积。虽然未观察到身体组成和能量消耗的变化，但发现了性别特异性的代谢效应。雌性小鼠表现出全身胰岛素敏感性受损和甘油三酯水平升高，而雄性小鼠则表现出胰岛素/C肽比值改变以及胆固醇、高密度脂蛋白和低密度脂蛋白水平升高。血清、脂肪和肝脏组织的蛋白质组分析揭示了与中枢能量代谢和免疫反应相关途径的变化，突出了DINCH的全身影响，可能对炎症过程产生影响。DINCH的大多数效应，如胰岛素反应和血清脂质水平的变化，在恢复期后有所减轻。尽管许多研究结果与现有文献一致，表明DINCH是更安全的DEHP替代品，但观察到的DINCH对胰岛素敏感性、脂质代谢和炎症过程的性别特异性影响，以及DINCH暴露可能的生物蓄积和长期代谢效应，在进一步的风险评估中值得仔细考虑。
