Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
EA3878, European University of Occidental Brittany, Brest, France.
Environ Health Perspect. 2021 May;129(5):57008. doi: 10.1289/EHP8171. Epub 2021 May 17.
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 via the action of arsenic ( 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.
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 () mice and evaluated whether mice lacking As3MT expression were susceptible to this effect.
We exposed or mice to 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.
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 mice had significantly larger plaque size compared with control .
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.
流行病学研究表明，生命早期砷暴露与心血管疾病风险增加有关。砷在环境中存在不同的氧化和甲基化状态，是通过砷（氧化态）甲基转移酶（As3MT）的作用形成的。甲基化砷在出生后具有促动脉粥样硬化作用，但出生前和围产期的影响尚不清楚。这一点尤为重要，因为已知甲基化砷可穿过胎盘。
我们检测了生命早期接触无机砷和甲基化砷对载脂蛋白 E 敲除（）小鼠动脉粥样硬化斑块形成及其组成的影响，并评估了缺乏 As3MT 表达的小鼠是否易受此影响。
我们从受孕到断奶期间，让或小鼠在饮用水中接触无机砷或甲基化砷，并在 18 周龄时评估后代的动脉粥样硬化斑块。采用混合回归模型，根据性别调整模型，估计每个结局相对于对照组的平均差异，并纳入随机效应项，以考虑到同窝内的聚类效应。
生命早期接触无机砷，更显著的是接触甲基化砷，导致雌雄两性主动脉弓和窦部的斑块明显增大。这些斑块中的脂质水平升高，但巨噬细胞数量没有显著差异。平滑肌细胞含量没有改变，但胶原含量较低。重要的是，这些观察结果存在性别特异性差异，即雄性斑块中的脂质含量较高，胶原含量较低，但雌性斑块中则没有。在缺乏 As3MT 的小鼠中，尽管斑块大小高度可变，但砷并未改变斑块大小。此外，与对照相比，对照的小鼠的斑块大小显著增大。
本研究表明，生命早期接触无机砷和甲基化砷具有促动脉粥样硬化作用，并存在性别特异性斑块组成差异，As3MT 可能在小鼠中发挥作用。https://doi.org/10.1289/EHP8171.
