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首页> 外文期刊>Archives of Toxicology >Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats
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Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

机译：大鼠5天暴露后N，N-二甲基-P-甲苯胺（DMPT）和对甲苯胺的肝转录组改变

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N,N-dimethyl-p-toluidine (DMPT), an accelerant for methyl methacrylate monomers in medical devices, was a liver carcinogen in male and female F344/N rats and B6C3F1 mice in a 2-year oral exposure study. p-Toluidine, a structurally related chemical, was a liver carcinogen in mice but not in rats in an 18-month feed exposure study. In this current study, liver transcriptomic data were used to characterize mechanisms in DMPT and p-toluidine liver toxicity and for conducting benchmark dose (BMD) analysis. Male F344/N rats were exposed orally to DMPT or p-toluidine (0, 1, 6, 20, 60 or 120 mg/kg/day) for 5 days. The liver was examined for lesions and transcriptomic alterations. Both chemicals caused mild hepatic toxicity at 60 and 120 mg/kg and dose-related transcriptomic alterations in the liver. There were 511 liver transcripts differentially expressed for DMPT and 354 for p-toluidine at 120 mg/kg/day (false discovery rate threshold of 5 %). The liver transcriptomic alterations were characteristic of an anti-oxidative damage response (activation of the Nrf2 pathway) and hepatic toxicity. The top cellular processes in gene ontology (GO) categories altered in livers exposed to DMPT or p-toluidine were used for BMD calculations. The lower confidence bound benchmark doses for these chemicals were 2 mg/kg/day for DMPT and 7 mg/kg/day for p-toluidine. These studies show the promise of using 5-day target organ transcriptomic data to identify chemical-induced molecular changes that can serve as markers for preliminary toxicity risk assessment.
机译：N，N-二甲基-P-甲苯胺（DMPT），医疗器械中甲基丙烯酸甲酯单体的促进剂，是雄性和雌性F344 / N大鼠的肝脏致癌物质和B6C3F1小鼠在2年期口腔暴露研究中。对结构相关的化学品，对小鼠的肝癌是肝癌，但在18个月的饲料暴露研究中的大鼠中是一种肝脏致癌物质。在本前研究中，肝转录组数据用于表征DMPT和对甲苯胺肝毒性的机制以及进行基准剂量（BMD）分析。将雄性F344 / N大鼠口服暴露于DMPT或对甲苯胺（0,1,6,20,60或120mg / kg /天）5天。检查肝脏的病变和转录组改变。两种化学物质在60％和120毫克/千克/千克中引起温和的肝毒性，肝脏中的剂量相关的转录组改变。在120mg / kg /天（假发现率阈值为5％），有511名肝脏转录物差异表达DMPT和354的对甲苯胺（假发现率阈值）。肝脏转录组改变是抗氧化损伤反应的特征（NRF2途径的激活）和肝毒性。在暴露于DMPT或对甲苯胺的肝脏中改变的基因本体（GO）类别的顶部细胞过程用于BMD计算。这些化学物质的较低的置信基准剂剂量为DMPT为2mg / kg /天，对甲苯胺的7mg / kg /天。这些研究表明，使用5天的靶器官转录组数据以鉴定化学诱导的分子变化，该分子变化可以用作初步毒性风险评估的标志物。

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