苯并[a]芘暴露在肌肉中会通过芳香烃受体介导的活性氧产生引发肌肉减少症。
Benzo[a]pyrene exposure in muscle triggers sarcopenia through aryl hydrocarbon receptor-mediated reactive oxygen species production.
机构信息
Department of Dermatology, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei City, Taiwan (R.O.C); Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei City, Taiwan (R.O.C); Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, Taipei, Taiwan (R.O.C).
Department of Biochemistry, National Defense Medical Center, Taiwan (R.O.C).
出版信息
Ecotoxicol Environ Saf. 2022 Jul 1;239:113599. doi: 10.1016/j.ecoenv.2022.113599. Epub 2022 May 11.
BACKGROUND
Benzo[a]pyrene (BaP), a toxic carcinogen, is associated with various adverse effects but is rarely discussed in muscle-related disorders. This study investigated in vitro and in vivo effects triggered by BaP exposure in muscles and hypothesized that exposure might induce conditions similar to sarcopenia due to the shared mechanism of oxidative stress. In vitro experiments used C2C12 mouse myoblasts to examine effects induced by BaP exposure in control (untreated) and BaP-treated (10 µM/ml) muscle cells. An established TNF-α-treated sarcopenia model was utilized to verify our results. In vivo experiments compared immunohistochemical staining of sarcopenia-related markers in rats exposed to clean air and polluted air.
RESULTS
In C2C12 cells, after 2-72 h of BaP exposure, elevated mRNA and protein expressions were observed in aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1, subsequently in ROS (NOX2 and NOX4) production, inflammatory cytokines (IL-6, TNF-α, and NF-kB), and proteins mediating apoptotic cell death (caspase-3 and PARP). Two myokines also altered mRNA and protein expressions akin to changes in sarcopenia, namely decreased irisin levels and increased myostatin levels. In addition, N-acetylcysteine, a well-known antioxidant, led to decrease in oxidative markers induced by BaP. The validation by TNF-α-treated sarcopenia model revealed comparable biological responses in either TNF-α or BaP treated C2C12 cells. In vivo experiments with rats exposed to air pollution showed increased expression of BaP, AhR, 8-hydroxydeoxyguanosine, and myostatin and decreased irisin expression in immunohistochemical staining.
CONCLUSIONS
Our results suggest that BaP exerts deleterious effects on the muscle, leading to conditions indicative of sarcopenia. Antioxidant supplementation may be a treatment option for BaP-induced sarcopenia, but further validation studies are needed.
背景
苯并[a]芘（BaP）是一种有毒的致癌物质，与各种不良反应有关，但在肌肉相关疾病中很少被提及。本研究调查了 BaP 暴露在肌肉中引起的体外和体内效应，并假设由于氧化应激的共同机制，暴露可能会导致类似于肌肉减少症的情况。体外实验使用 C2C12 小鼠成肌细胞，研究 BaP 暴露对对照（未处理）和 BaP 处理（10 μM/ml）肌肉细胞的诱导作用。利用已建立的 TNF-α 诱导的肌肉减少症模型验证了我们的结果。体内实验比较了暴露于清洁空气和污染空气中的大鼠与肌肉减少症相关标志物的免疫组织化学染色。
结果
在 C2C12 细胞中，BaP 暴露 2-72 小时后，芳烃受体（AhR）和细胞色素 P450 1A1 的 mRNA 和蛋白表达升高，随后 ROS（NOX2 和 NOX4）产生、炎症细胞因子（IL-6、TNF-α 和 NF-kB）和介导细胞凋亡的蛋白（caspase-3 和 PARP）升高。两种肌生成素的 mRNA 和蛋白表达也发生了类似于肌肉减少症的变化，即鸢尾素水平降低和肌肉生长抑制素水平升高。此外，N-乙酰半胱氨酸是一种众所周知的抗氧化剂，可减少 BaP 诱导的氧化标志物。用 TNF-α 处理的肌肉减少症模型验证表明，无论是 TNF-α 还是 BaP 处理的 C2C12 细胞，都有类似的生物学反应。用暴露于空气污染的大鼠进行的体内实验显示，BaP、AhR、8-羟基脱氧鸟苷和肌肉生长抑制素的表达增加，免疫组织化学染色中鸢尾素的表达减少。
结论
我们的结果表明，BaP 对肌肉有有害影响，导致类似于肌肉减少症的情况。抗氧化剂补充可能是 BaP 诱导的肌肉减少症的一种治疗选择，但需要进一步的验证研究。
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