Science for Life Laboratory, Department of Environmental Science, Stockholm University, 11418 Stockholm, Sweden.
Int J Mol Sci. 2022 Aug 5;23(15):8718. doi: 10.3390/ijms23158718.
Studies indicate that phthalates are endocrine disruptors affecting reproductive health. One of the most commonly used phthalates, di-n-butyl phthalate (DBP), has been linked with adverse reproductive health outcomes in men, but the mechanisms behind these effects are still poorly understood. Here, adult male mice were orally exposed to DBP (10 or 100 mg/kg/day) for five weeks, and the testis and adrenal glands were collected one week after the last dose, to examine more persistent effects. Quantification of testosterone, androstenedione, progesterone and corticosterone concentrations by liquid chromatography-mass spectrometry showed that testicular testosterone was significantly decreased in both DBP treatment groups, whereas the other steroids were not significantly altered. Western blot analysis of testis revealed that DBP exposure increased the levels of the steroidogenic enzymes CYP11A1, HSD3β2, and CYP17A1, the oxidative stress marker nitrotyrosine, and the luteinizing hormone receptor (LHR). The analysis further demonstrated increased levels of the germ cell marker DAZL, the Sertoli cell markers vimentin and SOX9, and the Leydig cell marker SULT1E1. Overall, the present work provides more mechanistic understanding of how adult DBP exposure can induce effects on the male reproductive system by affecting several key cells and proteins important for testosterone biosynthesis and spermatogenesis, and for the first time shows that these effects persist at least one week after the last dose. It also demonstrates impairment of testosterone biosynthesis at a lower dose than previously reported.
研究表明邻苯二甲酸酯是影响生殖健康的内分泌干扰物。邻苯二甲酸二丁酯（DBP）是最常用的邻苯二甲酸酯之一，它与男性生殖健康不良结局有关，但这些影响的机制仍知之甚少。在这里，成年雄性小鼠经口暴露于 DBP（10 或 100mg/kg/天）五周后，末次给药后一周收集睾丸和肾上腺，以检查更持久的影响。通过液相色谱-质谱法定量检测睾丸中的睾酮、雄烯二酮、孕酮和皮质酮浓度表明，DBP 处理组的睾丸睾酮均显著降低，而其他类固醇未显著改变。睾丸的 Western blot 分析显示，DBP 暴露增加了类固醇生成酶 CYP11A1、HSD3β2 和 CYP17A1、氧化应激标志物硝基酪氨酸和促黄体生成素受体（LHR）的水平。分析进一步表明，生殖细胞标志物 DAZL、支持细胞标志物波形蛋白和 SOX9 以及间质细胞标志物 SULT1E1 的水平增加。总的来说，本研究提供了更多关于成年 DBP 暴露如何通过影响几个关键细胞和蛋白质来影响雄性生殖系统的机制理解，这些细胞和蛋白质对于睾酮生物合成和精子发生很重要，并且首次表明这些影响在末次给药后至少一周仍持续存在。它还表明，在低于先前报道的剂量下，睾酮生物合成受损。
