芳烃受体(AhR)是一种配体激活的转录因子,参与调节对更平面芳烃的生物反应,比如TCDD.我们先前描述了雄性大鼠暴露于二恶英样多氯联苯(PCB)同源物后的事件顺序,3,3\',4,4\',5-五氯联苯(PCB126),与AhR结合并引起各种类型的毒性,包括代谢综合征,脂肪肝,和能量稳态的破坏。这项研究的目的是,研究AhR在亚急性暴露于PCB126后介导这些毒性表现的作用,并检查可能的性别差异。为了这个目标,我们使用CRISPR/Cas9创建了AhR敲除(AhR-KO)模型。对野生型(WT)雄性和雌性HoltzmanSpragueDawley大鼠进行比较。给大鼠注射单一IP剂量的玉米油载体或在玉米油中的5μmol/kgPCB126,并在28天后进行尸检。PCB126导致明显的体重减轻,减少相对胸腺重量,WT雄性和雌性大鼠的相对肝脏重量增加,但不是在AhR-KO老鼠身上.同样,可见显著的病理变化,包括雌性大鼠的坏死和再生,男性的微小和大泡状肝细胞空泡化,仅WT大鼠的两性肝脏中糖原缺乏。在WT大鼠的两种性别的血清中发现低血糖和较低的IGF1以及降低的血清非酯化脂肪酸(NEFA),只有女性的血清胆固醇水平低,AhR-KO大鼠没有变化.编码与生物异源代谢相关的酶(例如CYP1A1)的基因的表达,糖异生,糖原分解,PCB126暴露后AhR-KO大鼠的脂肪酸氧化不受影响,而WT大鼠的表达显着上调(PPARα,仅限女性)或下调,表明能量稳态中断。有趣的是,Acox2,Hmgcs,G6Pase和Pc在男女中均受到影响,糖异生和葡萄糖转运蛋白基因Pck1,Glut2,Sds,和Crem仅在雄性WT-PCB大鼠中。这些结果表明AhR在糖原分解中的重要作用,糖异生,和脂肪酸氧化,即在能量生产和稳态的调节中,但也证明了PCB126对男性和女性的影响的显着差异,提示男性葡萄糖稳态的脆弱性更高,女性脂肪酸/脂质稳态的变化更多。这些效果的差异,这可能适用于更多/所有AhR激动剂,应进一步分析,以确定特定人群的健康风险。
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in the regulation of biological responses to more planar aromatic hydrocarbons, like TCDD. We previously described the sequence of events following exposure of male rats to a dioxin-like polychlorinated biphenyl (PCB) congener, 3,3\',4,4\',5-pentachlorobiphenyl (
PCB126), that binds avidly to the AhR and causes various types of toxicity including metabolic syndrome, fatty liver, and disruption of energy homeostasis. The purpose of this study was, to investigate the role of AhR to mediate those toxic manifestations following sub-acute exposure to
PCB126 and to examine possible sex differences in effects. For this goal, we created an AhR knockout (AhR-KO) model using CRISPR/Cas9. Comparison was made to the wild type (WT) male and female Holtzman Sprague Dawley rats. Rats were injected with a single IP dose of corn oil vehicle or 5 μmol/kg
PCB126 in corn oil and necropsied after 28 days.
PCB126 caused significant weight loss, reduced relative thymus weights, and increased relative liver weights in WT male and female rats, but not in AhR-KO rats. Similarly, significant pathologic changes were visible which included necrosis and regeneration in female rats, micro- and macro-vesicular hepatocellular vacuolation in males, and a paucity of glycogen in livers of both sexes in WT rats only. Hypoglycemia and lower IGF1, and reduced serum non-esterified fatty acids (NEFAs) were found in serum of both sexes of WT rats, low serum cholesterol levels only in the females, and no changes in AhR-KO rats. The expression of genes encoding enzymes related to xenobiotic metabolism (e.g. CYP1A1), gluconeogenesis, glycogenolysis, and fatty acid oxidation were unaffected in the AhR-KO rats following PCB126 exposure as opposed to WT rats where expression was significantly upregulated (PPARα, females only) or downregulated suggesting a disrupted energy homeostasis. Interestingly, Acox2, Hmgcs, G6Pase and Pc were affected in both sexes, the gluconeogenesis and glucose transporter genes Pck1, Glut2, Sds, and Crem only in male WT-PCB rats. These results show the essential role of the AhR in glycogenolysis, gluconeogenesis, and fatty acid oxidation, i.e. in the regulation of energy production and homeostasis, but also demonstrate a significant difference in the effects of
PCB126 in males verses females, suggesting higher vulnerability of glucose homeostasis in males and more changes in fatty acid/lipid homeostasis in females. These differences in effects, which may apply to more/all AhR agonists, should be further analyzed to identify health risks to specific groups of highly exposed human populations.