* Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135;
Toxicol Sci. 2014 Jan;137(1):36-46. doi: 10.1093/toxsci/kft227. Epub 2013 Oct 4.
Inorganic arsenic (iAs) is a known human carcinogen at high exposures, increasing the incidences of urinary bladder, skin, and lung cancers. In most mammalian species, ingested iAs is excreted mainly through urine primarily as dimethylarsinic acid (DMA(V)). In wild-type (WT) mice, iAs, DMA(V), and dimethylarsinous acid (DMA(III)) exposures induce formation of intramitochondrial urothelial inclusions. Arsenite (iAs(III)) also induced intranuclear inclusions in arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice. The arsenic-induced formation of inclusions in the mouse urothelium was dose and time dependent. The inclusions do not occur in iAs-treated rats and do not appear to be related to arsenic-induced urothelial cytotoxicity. Similar inclusions in exfoliated urothelial cells from humans exposed to iAs have been incorrectly identified as micronuclei. We have characterized the urothelial inclusions using transmission electron microscopy (TEM), DNA-specific 4',6-diamidino-2-phenylindole (DAPI), and non-DNA-specific Giemsa staining and determined the arsenical content. The mouse inclusions stained with Giemsa but not with the DAPI stain. Analysis of urothelial mitochondrial- and nuclear-enriched fractions isolated from WT (C57BL/6) and As3mt KO mice exposed to arsenate (iAs(V)) for 4 weeks showed higher levels of iAs(V) in the treated groups. iAs(III) was the major arsenical present in the enriched nuclear fraction from iAs(V)-treated As3mt KO mice. In conclusion, the urothelial cell inclusions induced by arsenicals appear to serve as a detoxifying sequestration mechanism similar to other metals, and they do not represent micronuclei.
无机砷（iAs）是一种已知的人类致癌物，高暴露会增加膀胱癌、皮肤癌和肺癌的发病率。在大多数哺乳动物物种中，摄入的 iAs 主要通过尿液排出，主要形式为二甲基砷酸（DMA(V)）。在野生型（WT）小鼠中，iAs、DMA(V) 和二甲基砷酸（DMA(III)）暴露会诱导形成线粒体中的尿路上皮内含物。亚砷酸盐（iAs(III)）也会诱导砷 (+3 氧化态) 甲基转移酶敲除（As3mt KO）小鼠的核内内含物。砷诱导的小鼠尿路上皮内含物的形成具有剂量和时间依赖性。这些内含物不会出现在 iAs 处理的大鼠中，也似乎与砷诱导的尿路上皮细胞毒性无关。在暴露于 iAs 的人类脱落的尿路上皮细胞中发现的类似内含物被错误地鉴定为微核。我们使用透射电子显微镜（TEM）、DNA 特异性 4'，6-二脒基-2-苯基吲哚（DAPI）和非 DNA 特异性吉姆萨染色对尿路上皮内含物进行了表征，并确定了砷含量。Giemsa 染色可对小鼠内含物进行染色，但 DAPI 染色不可。对用亚砷酸盐（iAs(V)）处理 4 周的 WT（C57BL/6）和 As3mt KO 小鼠分离的尿路上皮线粒体和核富集部分进行分析显示，处理组中的 iAs(V) 水平较高。在用 iAs(V) 处理的 As3mt KO 小鼠的富集核部分中，主要的砷化物为 iAs(III)。总之，砷诱导的尿路上皮细胞内含物似乎作为一种解毒隔离机制，类似于其他金属，它们不代表微核。
