Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure.
Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure.
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DOI：
10.1007/s00204-016-1676-0
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发表时间：
2017-01
影响因子：
6.1
通讯作者：
Stýblo M
中科院分区：
文献类型：
--
作者：
Huang MC;Douillet C;Su M;Zhou K;Wu T;Chen W;Galanko JA;Drobná Z;Saunders RJ;Martin E;Fry RC;Jia W;Stýblo M
砷（+3氧化态）甲基转移酶（As 3 mt）是无机砷（iAs）甲基化途径中的关键酶。在实验室模型和人体中，改变的As 3 mt表达和AS 3 MT多态性与iAs代谢的变化和对iAs毒性的易感性有关。As 3 mt基因敲除小鼠已被用于研究iAs代谢和iAs暴露的不良反应之间的关联。然而，关于这些小鼠代谢的全身变化以及这些变化如何导致其对iAs毒性的易感性增加，知之甚少。在这里，我们比较了雄性和雌性野生型（WT）和As 3 mt-KO（KO）C57 BL 6小鼠的血浆和尿液代谢组，并检查了与饮用水中iAs暴露相关的代谢组学变化。令人惊讶的是，暴露于1 ppm的作为引起的WT或KO小鼠的代谢物谱中只有很小的变化。相比之下，KO小鼠与WT小鼠的比较显示与脂质（磷脂酰胆碱、胞苷、酰基肉毒碱）、氨基酸（马尿酸、乙酰甘氨酸、尿素）和碳水化合物（L-山梨糖、半乳糖酸、葡萄糖酸）代谢相关的血浆和尿液代谢物存在显著差异。值得注意的是，这些差异大多数是性别特异性的。WT和KO小鼠之间的血浆甘油三酯和脂蛋白胆固醇水平也存在性别特异性差异。一些差异变化的代谢物（磷脂酰胆碱、肌肽和肌氨酸）是由其他甲基转移酶催化的反应的底物或产物。这些结果表明，As 3 mt KO以性别特异性方式改变主要代谢途径，独立于iAs治疗，并且As 3 mt可能参与iAs甲基化以外的其他细胞过程。
Arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered As3mt expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. As3mt-knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure. However, little is known about systemic changes in metabolism of these mice and how these changes lead to their increased susceptibility to iAs toxicity. Here, we compared plasma and urinary metabolomes of male and female wild-type (WT) and As3mt-KO (KO) C57BL6 mice and examined metabolomic shifts associated with iAs exposure in drinking water. Surprisingly, exposure to 1 ppm As elicited only small changes in the metabolite profiles of either WT or KO mice. In contrast, comparisons of KO mice with WT mice revealed significant differences in plasma and urinary metabolites associated with lipid (phosphatidylcholines, cytidine, acyl-carnitine), amino acid (hippuric acid, acetylglycine, urea), and carbohydrate (L-sorbose, galactonic acid, gluconic acid) metabolism. Notably, most of these differences were sex-specific. Sex-specific differences were also found between WT and KO mice in plasma triglyceride and lipoprotein cholesterol levels. Some of the differentially changed metabolites (phosphatidylcholines, carnosine, and sarcosine) are substrates or products of reactions catalyzed by other methyltransferases. These results suggest that As3mt KO alters major metabolic pathways in a sex-specific manner, independent of iAs treatment, and that As3mt may be involved in other cellular processes beyond iAs methylation.