Nitrate induces a type 1 diabetic profile in alligator hatchlings
Nitrate induces a type 1 diabetic profile in alligator hatchlings
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DOI：
10.1016/j.ecoenv.2017.09.052
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发表时间：
2018-01-01
影响因子：
6.8
通讯作者：
Guillette, Louis J., Jr.
中科院分区：
文献类型：
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作者：
Edwards, Thea M.;Hamlin, Heather J.;Guillette, Louis J., Jr.
1型糖尿病（T1 D）是一种慢性自身免疫性疾病，每300名儿童中就有1名18岁。T1 D是由炎症诱导的产生胰岛素的胰腺β细胞的损失引起的，导致高血糖和一系列下游并发症。虽然多个基因与T1 D风险相关，但只有5%的遗传易感个体实际上会发展为临床疾病。此外，越来越多的T1 D病例发生在地理集群和低风险基因型儿童中。这些观察结果表明，环境因素有助于T1 D病因。一个主要由流行病学研究支持的潜在因素是饮用水中存在硝酸盐和亚硝酸盐。为了验证这一假设，女性孵化短吻鳄暴露于环境相关浓度的硝酸盐在他们的水箱水（参考，10毫克/升，或100毫克/升NO3-N）从孵化到5周或5个月的年龄。在每个时间点，研究与T1 D相关的终点：血糖、甘油三酯、睾酮、雌二醇和甲状腺素的血浆水平;胰腺、脂肪体和甲状腺重量;体重增加或减轻;胰腺中免疫细胞的存在;以及通过nkx6.1蛋白的抗体染色评估的胰腺β细胞数量。通过测量血浆和尿液硝酸盐水平和全血高铁血红蛋白证实了硝酸盐的内部剂量。聚类分析表明，高硝酸盐暴露（大多数动物暴露于100 mg/L NO3-N和一个短吻鳄暴露于10 mg/L NO3-N）诱导的端点配置文件与早期T1 D，可以检测到5周后，更强烈地存在5个月后。我们的研究支持了硝酸盐升高与人类T1 D发病相关的流行病学数据，并强调硝酸盐可能是T1 D病因的环境因素，可能是通过其作为一氧化氮前体的作用。
Type 1 diabetes (T1D) is a chronic autoimmune disease that affects 1 in 300 children by age 18. T1D is caused by inflammation-induced loss of insulin-producing pancreatic beta cells, leading to high blood glucose and a host of downstream complications. Although multiple genes are associated with T1D risk, only 5% of genetically susceptible individuals actually develop clinical disease. Moreover, a growing number of T1D cases occur in geographic clusters and among children with low risk genotypes. These observations suggest that environmental factors contribute to T1D etiology. One potential factor, supported primarily by epidemiological studies, is the presence of nitrate and nitrite in drinking water. To test this hypothesis, female hatchling alligators were exposed to environmentally relevant concentrations of nitrate in their tank water (reference, 10 mg/L, or 100 mg/L NO3-N) from hatch through 5 weeks or 5 months of age. At each time point, endpoints related to T1D were investigated: plasma levels of glucose, triglycerides, testosterone, estradiol, and thyroxine; pancreas, fat body, and thyroid weights; weight gain or loss; presence of immune cells in the pancreas; and pancreatic beta cell number, assessed by antibody staining of nkx6.1 protein. Internal dosing of nitrate was confirmed by measuring plasma and urine nitrate levels and whole blood methemoglobin. Cluster analysis indicated that high nitrate exposure (most animals exposed to 100 mg/L NO3-N and one alligator exposed to 10 mg/L NO3-N) induced a profile of endpoints consistent with early T1D that could be detected after 5 weeks and was more strongly present after 5 months. Our study supports epidemiological data correlating elevated nitrate with T1D onset in humans, and highlights nitrate as a possible environmental contributor to the etiology of T1D, possibly through its role as a nitric oxide precursor.