Abstract

Background:

Epidemiologic studies indicate that early life arsenic exposures are linked to an increased risk of cardiovascular diseases. Different oxidation and methylation states of arsenic exist in the environment and are formed in vivo via the action of arsenic ($+3$ oxidation state) methyltransferase (As3MT). Methylated arsenicals are pro-atherogenic postnatally, but pre- and perinatal effects are unclear. This is particularly important because methylated arsenicals are known to cross the placenta.

Objectives:

We tested the effects of early life exposure to inorganic and methylated arsenicals on atherosclerotic plaque formation and its composition in apolipoprotein E knock-out (${\text{apoE}}^{-/-}$) mice and evaluated whether ${\text{apoE}}^{-/-}$ mice lacking As3MT expression were susceptible to this effect.

Methods:

We exposed ${\text{apoE}}^{-/-}$ or ${\text{apoE}}^{-/-}{/\mathrm{As}3\text{MT}}^{-/-}$ mice to $200\text{\hspace{0.17em}ppb}$ inorganic or methylated arsenic in the drinking water from conception to weaning and assessed atherosclerotic plaques in the offspring at 18 wk of age. Mixed regression models were used to estimate the mean difference in each outcome relative to controls, adjusting for sex and including a random effects term to account for within-litter clustering.

Results:

Early life exposure to inorganic arsenic, and more profoundly methylated arsenicals, resulted in significantly larger plaques in the aortic arch and sinus in both sexes. Lipid levels in these plaques were higher without a substantial difference in macrophage numbers. Smooth muscle cell content was not altered, but collagen content was lower. Importantly, there were sex-specific differences in these observations, where males had higher lipids and lower collagen in the plaque, but females did not. In mice lacking As3MT, arsenic did not alter the plaque size, although the size was highly variable. In addition, control ${\text{apoE}}^{-/-}{/\mathrm{As}3\text{MT}}^{-/-}$ mice had significantly larger plaque size compared with control ${\text{apoE}}^{-/-}$.

Conclusion:

This study shows that early life exposure to inorganic and methylated arsenicals is pro-atherogenic with sex-specific differences in plaque composition and a potential role for As3MT in mice. https://doi.org/10.1289/EHP8171

中文翻译：

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产前和早期无机砷和甲基化砷暴露对成年 ApoE-/- 小鼠动脉粥样硬化斑块发育和组成的性别特异性影响

摘要

背景：

流行病学研究表明，早年接触砷与心血管疾病风险增加有关。环境中存在不同氧化态和甲基化态的砷，并在体内通过砷的作用形成。$+3$氧化态）甲基转移酶（As3MT）。甲基化砷在出生后会促动脉粥样硬化，但对产前和围产期的影响尚不清楚。这一点特别重要，因为已知甲基化砷化物可以穿过胎盘。

目标：

我们测试了生命早期接触无机和甲基化砷对动脉粥样硬化斑块形成及其在载脂蛋白 E 敲除中的组成的影响。${\text{载脂蛋白E}}^{-/-}$) 小鼠并评估是否 ${\text{载脂蛋白E}}^{-/-}$ 缺乏 As3MT 表达的小鼠容易受到这种影响。

方法：

我们暴露了 ${\text{载脂蛋白E}}^{-/-}$ 或者 ${\text{载脂蛋白E}}^{-/-}{/\mathrm{作为}3\text{公吨}}^{-/-}$ 老鼠 $200\text{\hspace{0.17em}ppb}$从受孕到断奶期间饮用水中的无机或甲基化砷，并评估了 18 周龄后代的动脉粥样硬化斑块。混合回归模型用于估计每个结果相对于对照的平均差异，调整性别并包括随机效应项以解释窝内聚类。

结果：

早年接触无机砷和更严重的甲基化砷，导致男女主动脉弓和窦内的斑块明显更大。这些斑块中的脂质水平较高，而巨噬细胞数量没有显着差异。平滑肌细胞含量没有改变，但胶原蛋白含量较低。重要的是，这些观察结果存在性别特异性差异，男性斑块中的脂质较高，胶原蛋白较低，而女性则没有。在缺乏 As3MT 的小鼠中，砷不会改变斑块大小，尽管大小变化很大。此外，控制${\text{载脂蛋白E}}^{-/-}{/\mathrm{作为}3\text{公吨}}^{-/-}$ 与对照组相比，小鼠的斑块大小明显更大 ${\text{载脂蛋白E}}^{-/-}$.

结论：

这项研究表明，生命早期接触无机和甲基化砷会促动脉粥样硬化，斑块组成存在性别差异，并且 As3MT 在小鼠中具有潜在作用。https://doi.org/10.1289/EHP8171