School of Biological and Population Health Sciences, Oregon State University, 103 Milam Hall, Corvallis, OR, 97331, USA.
Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR, 97331, USA.
Biometals. 2019 Dec;32(6):845-859. doi: 10.1007/s10534-019-00217-0. Epub 2019 Sep 21.
Pancreatic beta cells produce and release insulin, a hormone that regulates blood glucose levels, and their dysfunction contributes to the development of diabetes mellitus. Zinc deficiency and inorganic arsenic exposure both independently associate with the development of diabetes, although the effects of their combination on pancreatic beta cell health and function remain unknown. We hypothesized zinc deficiency increases the toxicity associated with arsenic exposure, causing an increased susceptibility to DNA damage and disruption of insulin production. Zinc deficiency decreased cell proliferation by 30% in pancreatic INS-1 rat insulinoma cells. Arsenic exposure (0, 50 or 500 ppb exposures) significantly decreased cell proliferation, and increased mRNA levels of genes involved in stress response (Mt1, Mt2, Hmox1) and DNA damage (p53, Ogg1). When co-exposed to both zinc deficiency and arsenic, zinc deficiency attenuated this response to arsenic, decreasing the expression of Mt1, Hmox1, and Ogg1, and significantly increasing DNA double-strand breaks 2.9-fold. Arsenic exposure decreased insulin expression, but co-exposure did not decrease insulin levels beyond the arsenic alone condition, but did result in a further 33% decline in cell proliferation at the 500 ppb arsenic dose, and a significant increase in beta cell apoptosis. These results suggest zinc deficiency and arsenic, both independently and in combination, adversely affect pancreatic beta cell health and both factors should be considered in the evaluation of health outcomes for susceptible populations.
胰腺β细胞产生并释放胰岛素，胰岛素是一种调节血糖水平的激素，其功能障碍导致糖尿病的发生。锌缺乏和无机砷暴露都与糖尿病的发生独立相关，尽管它们联合作用对胰腺β细胞健康和功能的影响尚不清楚。我们假设锌缺乏会增加砷暴露的毒性，导致对 DNA 损伤和胰岛素产生的破坏的易感性增加。锌缺乏使胰腺 INS-1 大鼠胰岛素瘤细胞的增殖减少了 30%。砷暴露（0、50 或 500 ppb 暴露）显著降低了细胞增殖，并增加了应激反应（Mt1、Mt2、Hmox1）和 DNA 损伤（p53、Ogg1）相关基因的 mRNA 水平。当同时暴露于锌缺乏和砷时，锌缺乏会减弱砷对这种反应的作用，降低 Mt1、Hmox1 和 Ogg1 的表达，并使 DNA 双链断裂增加 2.9 倍。砷暴露降低了胰岛素的表达，但联合暴露并没有使胰岛素水平降低到仅砷暴露的水平以下，而是在 500 ppb 砷剂量下导致细胞增殖进一步下降 33%，并显著增加β细胞凋亡。这些结果表明，锌缺乏和砷，无论是单独存在还是联合存在，都会对胰腺β细胞的健康产生不利影响，在评估易感人群的健康结果时，应同时考虑这两个因素。
