Abstract

Background:

Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risks of iAs-induced diseases. Mechanisms underlying these diseases have been extensively studied using animal models. However, substantive differences between humans and laboratory animals in efficiency of iAs methylation have hindered the translational potential of the laboratory studies.

Objectives:

The goal of this study was to determine whether humanization of the As3mt gene confers a human-like pattern of iAs metabolism in mice.

Methods:

We generated a mouse strain in which the As3mt gene along with the adjacent Borcs7 gene was humanized by syntenic replacement. We compared expression of the mouse As3mt and the human AS3MT and the rate and pattern of iAs metabolism in the wild-type and humanized mice.

Results:

AS3MT expression in mouse tissues closely modeled that of human and differed substantially from expression of As3mt. Detoxification of iAs was much less efficient in the humanized mice than in wild-type mice. Profiles for iAs and its methylated metabolites in tissues and excreta of the humanized mice were consistent with those reported in humans. Notably, the humanized mice expressed both the full-length AS3MT that catalyzes iAs methylation and the human-specific $AS\mathit{3}M{T}^{d\mathit{2}d\mathit{3}}$ splicing variant that has been linked to schizophrenia.

Conclusions:

These results suggest that AS3MT is the primary genetic locus responsible for the unique pattern of iAs metabolism in humans. Thus, the humanized mouse strain can be used to study the role of iAs methylation in the pathogenesis of iAs-induced diseases, as well as to evaluate the role of $AS\mathit{3}M{T}^{d\mathit{2}d\mathit{3}}$ in schizophrenia. https://doi.org/10.1289/EHP6943

中文翻译：

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携带通过同线置换人源化的 BORCS7/AS3MT 基因座的小鼠的砷代谢。

摘要

背景：

长期接触无机砷 (iAs) 是一个重大的公共卫生问题。砷甲基转移酶 (AS3MT) 对 iAs 的甲基化控制 iAs 解毒并改变 iAs 诱发疾病的风险。已经使用动物模型广泛研究了这些疾病的潜在机制。然而，人类和实验室动物在 iAs 甲基化效率方面的实质性差异阻碍了实验室研究的转化潜力。

目标：

本研究的目的是确定As3mt基因的人源化是否赋予小鼠类似人类的 iAs 代谢模式。

方法：

我们生成了一个小鼠品系，其中As3mt基因和相邻的Borcs7基因通过同线置换进行了人源化。我们比较了小鼠As3mt和人AS3MT 的表达以及野生型和人源化小鼠中 iAs 代谢的速率和模式。

结果：

小鼠组织中的AS3MT表达与人类的相似，并且与As3mt 的表达存在显着差异。与野生型小鼠相比，人源化小鼠对 iAs 的解毒效率要低得多。人源化小鼠组织和排泄物中的 iAs 及其甲基化代谢物的谱与人类报道的一致。值得注意的是，人源化小鼠表达了催化 iAs 甲基化的全长AS3MT和人类特异性的$\mathrm{一种}秒\mathit{3}米{吨}^{d\mathit{2}d\mathit{3}}$ 与精神分裂症有关的剪接变体。

结论：

这些结果表明AS3MT是负责人类 iAs 代谢独特模式的主要遗传位点。因此，人源化小鼠品系可用于研究 iAs 甲基化在 iAs 诱导疾病发病机制中的作用，以及评估 iAs 的作用。$\mathrm{一种}秒\mathit{3}米{吨}^{d\mathit{2}d\mathit{3}}$在精神分裂症中。https://doi.org/10.1289/EHP6943