| dc.description.abstract | Plasticizers are widely present in people′s daily life, found in items such as cling film, cosmetics, pharmaceuticals, medical equipment, and health food capsules. Among them, Di (2-ethylhexyl) phthalate (DEHP) is the most common plasticizer, which is easily leached out from PVC products. Once it enters the human body, it is rapidly metabolized to mono-2-ethylhexyl phthalate (MEHP) and then enters the circulatory system, affecting physiological functions such as endocrine system, reproductive, growth, and metabolism. Previous studies have shown that MEHP represses skeletal muscle (SKM) differentiation. Cancer cachexia is an irreversible wasting syndrome of muscle and fat induced by signals from cancer and immune cells. Given the high levels of DEHP exposure in long-term hospitalized cancer patients due to continuous contact with PVC tubing and medical equipment, we hypothesize that DEHP exposure exacerbates muscle wasting in cancer patients. Here I found that cancer cachexia factors contained in the C26 colon cancer cells conditioned medium (C26M) differentially modulate the promoter activity and mRNA stability of E3 ligases MuRF1 and Atrogin1, resulting in decreased MuRF1 expression and increased Atrogin 1 expression in C2C12 myoblasts and myotubes. Moreover, MEHP and C26M synergistically inhibited the myogenic capacity of C2C12 and the mRNA expression of muscle differentiation factors (MyoG, Mef2c), along with elevated ROS levels in these cells. In vivo experiments showed that DEHP caused further atrophy of the gastrocnemius (GC) muscle in mice with C26 tumor (C26 mice). Of note, soleus atrophy was only observed in mice treated with DEHP/C26. In contrast to the observations in C2C12 myoblasts, the mRNA expression of MuRF1 and Atrogin 1 was both increased in the GC muscle of C26 mice, suggesting the involvement of other cell types, such as neuron and immune cells, in vivo. Additionally, C26 mice exhibited significant splenomegaly compared to normal mice, indicating severe inflammatory responses. Culturing with Raw264.7 macrophage conditioned medium (RM) and C26M-stimulated macrophage conditioned medium (RC) intensified myotube atrophy in C2C12, suggesting a potential role of immune cells in regulating E3 ubiquitin ligase mRNA expression. In conclusion, DEHP/MEHP exacerbates muscle wasting in cancer cachexia, contributing to its deterioration. | en_US |