PDF(Pubmed)
Abstract：
Environmental exposure to endocrine-disrupting chemicals (EDCs) can lead to metabolic disruption, resulting in metabolic complications including adiposity, dyslipidemia, hepatic lipid accumulation, and glucose intolerance. Hepatic nuclear receptor activation is one of the mechanisms mediating metabolic effects of EDCs. Here, we investigated the potential to use a repeated dose 28-day oral toxicity test for identification of EDCs with metabolic endpoints. Bisphenol A (BPA), pregnenolone-16α-carbonitrile (PCN), and perfluorooctanoic acid (PFOA) were used as reference compounds. Male and female wild-type C57BL/6 mice were orally exposed to 5, 50, and 500 μg/kg of BPA, 1000, 10 000, and 100 000 µg/kg of PCN and 50 and 300 μg/kg of PFOA for 28 days next to normal chow diet. Primary endpoints were glucose tolerance, hepatic lipid accumulation, and plasma lipids. After 28-day exposure, no changes in body weight and glucose tolerance were observed in BPA-, PCN-, or PFOA-treated males or females. PCN and PFOA at the highest dose in both sexes and BPA at the middle and high dose in males increased relative liver weight. PFOA reduced plasma triglycerides in males and females, and increased hepatic triglyceride content in males. PCN and PFOA induced hepatic expression of typical pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR)α target genes, respectively. Exposure to BPA resulted in limited gene expression changes. In conclusion, the observed changes on metabolic health parameters were modest, suggesting that a standard repeated dose 28-day oral toxicity test is not a sensitive method for the detection of the metabolic effect of EDCs.
摘要：
环境暴露于内分泌干扰化学物质（EDC）可能导致代谢破坏，导致包括肥胖在内的代谢并发症，血脂异常,肝脏脂质积累，和葡萄糖不耐受。肝核受体激活是介导EDC代谢作用的机制之一。这里,我们研究了使用重复剂量28天口服毒性试验来鉴定具有代谢终点的EDC的可能性.双酚A(BPA),孕烯醇酮-16α-甲腈(PCN)，和全氟辛酸(PFOA)用作参考化合物。雄性和雌性野生型C57BL/6小鼠口服暴露于5、50和500μg/kg的BPA，1000、10.000和100000µg/kg的PCN和50和300μg/kg的PFOA，在正常饮食下持续28天。主要终点是葡萄糖耐量，肝脏脂质积累，和血浆脂质。暴露28天后,在BPA中没有观察到体重和葡萄糖耐量的变化-，PCN-,或PFOA治疗的男性或女性。男性中最高剂量的PCN和PFOA，男性中高剂量的BPA增加了相对肝脏重量。PFOA降低了男性和女性的血浆甘油三酯，男性肝脏甘油三酯含量增加。PCN和PFOA诱导典型孕烷X受体（PXR）和过氧化物酶体增殖物激活受体（PPAR）α靶基因的肝表达，分别。暴露于BPA导致有限的基因表达变化。总之,观察到的代谢健康参数变化是适度的，提示标准重复剂量28天口服毒性试验不是检测EDCs代谢作用的灵敏方法。
