Time course analysis of the effect of embedded metal on skeletal muscle gene expression [Array]

As a consequence of military operations, many veterans suffer from penetrating wounds and long-term retention of military grade heavy metal fragments. Fragments vary in size and location, and complete surgical removal may not be feasible or beneficial in all cases. Increasing evidence suggests retention of heavy metal fragments may have serious biological implications, including increased risks for malignant transformation. Previous studies assessed the tumorigenic effects of metal alloys in rats, demonstrating combinations of metals are sufficient to induce tumor formation after prolonged retention in skeletal muscle tissue. In this study, we analyzed transcriptional changes in skeletal muscle tissue in response to eight different military-relevant pure metals over 12 months. We found that most transcriptional changes occur at 1 and 3 months after metal pellets are embedded in skeletal muscle and these effects resolve at 6 and 12 months. We also report significant immunogenic effects of nickel and cobalt and suppressive effects of lead and depleted uranium on gene expression. Overall, skeletal muscle exhibits a remarkable capacity to adapt to and recover from internalized metal fragments; however, the cellular response to chronic exposure may be restricted to the metal-tissue interface. This data suggests that unless affected regions are specifically captured by biopsy, it would be difficult to reliably detect changes in muscle gene expression that would be indicative of long-term adverse health outcomes.受军事行动影响，众多退伍军人会遭受穿透伤（penetrating wounds），并长期存留军用级重金属弹片（military grade heavy metal fragments）。这类弹片的尺寸与存留位置各不相同，且多数情况下，完全通过手术摘除（surgical removal）弹片既不可行，也无获益价值。越来越多的研究证据表明，存留的重金属弹片可能会产生严重的生物学影响，其中包括恶性转化（malignant transformation）风险升高。既往已有研究针对大鼠体内金属合金（metal alloys）的致瘤效应（tumorigenic effects）开展评估，结果证实，多种金属的组合在骨骼肌组织（skeletal muscle tissue）中长期存留后，足以诱发肿瘤形成。本研究针对8种与军事相关的纯金属，分析了其植入骨骼肌组织后12个月内的转录组变化（transcriptional changes）。结果发现，绝大多数转录组变化发生于金属颗粒（metal pellets）植入骨骼肌后的1个月与3个月，而这类效应会在植入后6个月及12个月时消退。本研究同时还发现，镍（nickel）与钴（cobalt）可产生显著的免疫原性效应（immunogenic effects），而铅（lead）与贫铀（depleted uranium）则会对基因表达（gene expression）产生抑制作用。总体而言，骨骼肌具备出色的适应内化金属弹片并从中恢复的能力；但针对慢性暴露（chronic exposure）的细胞应答（cellular response），可能仅局限于金属-组织界面（metal-tissue interface）区域。本研究数据提示，除非通过活检（biopsy）精准获取受影响区域，否则难以可靠检测到能够提示长期不良健康结局的肌肉基因表达变化。