Kersch Christian, Masutin Viktor, Kuhlmann Laura, Alsaleh Rasha, Kaifie Andrea, Schmitz-Spanke Simone
Institute and Outpatient Clinic of Occupational, Social, and Environmental Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, Henkestr. 9-11, 91054, Erlangen, Germany.
Arch Toxicol. 2025 Aug 25. doi: 10.1007/s00204-025-04155-4.
Dermal exposure to polycyclic aromatic hydrocarbons (PAHs) and UV irradiation in occupational and environmental settings poses a health risk by inducing skin toxicity, including immunomodulatory effects. This study investigated the effects of benzo[a]pyrene (B[a]P), a well-characterized PAH, at three concentrations (0.04 nM, 4 nM, and 4 µM) and UV irradiation on human monocytic U937 cells, employing both single and combined exposure scenarios. An integrated metabolomics and toxicological approach was utilized to assess cellular responses, with a focus on understanding the immunometabolic effects of these exposures. Our findings revealed that only the highest B[a]P concentration in combination with UV irradiation resulted in significant metabolic dysregulation and impaired cellular function. Notably, we observed a pronounced downregulation of glutaminolysis, a critical metabolic pathway for cellular energy production and biosynthesis. This was evidenced by decreased levels of glutamate and key intermediates within the tricarboxylic acid cycle (e.g., succinate, fumarate, malate, and citrate), as well as reduced levels of glycine, a precursor for glutathione synthesis. In parallel, toxicological assays revealed increased levels of oxidative stress markers, lipid peroxidation, and enhanced DNA damage. Furthermore, the combined exposure led to alterations in tryptophan metabolism and dysregulation of lipid species, particularly sphingolipids and phosphatidylinositols. These findings lead us to propose the hypothesis that metabolic disruption, specifically the impairment of glutaminolysis, initiated a cascade of events, including increased oxidative stress, lipid peroxidation, and ultimately, ferroptosis in our study. Our results indicate that the combined exposure to UV irradiation and B[a]P can induce immunometabolic reprogramming and significantly contribute to the pathogenesis of inflammatory skin diseases.
在职业和环境中，皮肤暴露于多环芳烃（PAHs）以及紫外线辐射会通过引发皮肤毒性（包括免疫调节作用）对健康构成风险。本研究调查了特征明确的多环芳烃苯并[a]芘（B[a]P）在三种浓度（0.04 nM、4 nM和4 µM）下以及紫外线辐射对人单核细胞U937细胞的影响，采用了单一暴露和联合暴露两种情况。运用综合代谢组学和毒理学方法来评估细胞反应，重点是了解这些暴露的免疫代谢效应。我们的研究结果表明，只有最高浓度的B[a]P与紫外线辐射联合才会导致显著的代谢失调和细胞功能受损。值得注意的是，我们观察到谷氨酰胺分解显著下调，这是细胞能量产生和生物合成的关键代谢途径。这表现为谷氨酸和三羧酸循环中的关键中间体（如琥珀酸、富马酸、苹果酸和柠檬酸）水平降低，以及谷胱甘肽合成前体甘氨酸水平降低。同时，毒理学分析显示氧化应激标志物水平升高、脂质过氧化增加以及DNA损伤增强。此外，联合暴露导致色氨酸代谢改变以及脂质种类失调，特别是鞘脂和磷脂酰肌醇。这些发现使我们提出一个假设，即代谢紊乱，特别是谷氨酰胺分解受损，引发了一系列事件，包括氧化应激增加、脂质过氧化，最终在我们的研究中导致铁死亡。我们的结果表明，紫外线辐射和B[a]P的联合暴露可诱导免疫代谢重编程，并显著促进炎症性皮肤病的发病机制。
