Tributyltin (TBT) and dioxin-like polychlorinated biphenyls (PCBs) are environmental contaminants that are highly toxic to fish and co-occur in New Bedford Harbor (NBH), an estuarine Superfund site located in Massachusetts, USA. Atlantic killifish (Fundulus heteroclitus) that reside in NBH (and other highly contaminated sites along the east coast of the United States) have developed resistance to activation of the aryl hydrocarbon receptor (AHR) pathway and the toxicity of dioxin-like chemicals, such as 3,3',4,4',5-pentachlorobiphenyl, PCB126. In many biological systems, TBT disregulates adipose and bone development via the PPARγ-RXR pathway; AHR activation also disrupts adipose and bone homeostasis, potentially through molecular crosstalk between AHR and PPARγ. However, little is known about how co-exposure and the interaction of these pathways modulate the toxicological effects of these contaminants. Here, we tested the hypotheses that TBT would induce teratogenesis in killifish via activation of PPARγ and that PCB126 co-exposure would suppress PPARγ pathway activation in PCB-sensitive killifish from a reference site (Scorton Creek, SC, PCB-sensitive) but not in PCB-tolerant NBH killifish. Killifish embryos from both populations exposed to TBT (50 and 100 nM) displayed caudal fin deformities. TBT did not change the expression of pparg or its target genes related to adipogenesis (fabp11a and fabp1b) in either population. However, expression of osx/sp7, an osteoblast marker gene, and col2a1b, a chondroblast marker gene, was significantly suppressed by TBT only in SC killifish. An RXR-specific agonist, but not a PPARγ-specific agonist, induced caudal fin deformities like those observed in TBT-treated embryos. PCB126 did not induce caudal fin deformities and did not exacerbate TBT-induced fin deformities. Further, PCB126 increased expression of pparg in SC embryos and not NBH embryos, but did not change the expression of fabp1b. Taken together, these results suggest that in killifish embryos the PPARγ pathway is regulated in part by AHR, but is minimally active at least in this early life stage. In killifish, RXR activation, rather than PPARγ activation, appears to be the mechanism by which TBT induces caudal fin teratogenicity, which is not modulated by AHR responsiveness.

中文翻译：

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三丁基锡破坏了PCB敏感人群和抗药性人群的异脚底鳍的发育：AHR和PPARγ之间潜在相互作用的研究。

三丁基锡（TBT）和类二恶英类多氯联苯（PCBs）是对鱼类有高毒性的环境污染物，在美国马萨诸塞州的河口超级基金所在地新贝德福德港（NBH）同时发生。居住在NBH（以及美国东海岸其他受高度污染的地点）的大西洋鲑鱼（Fundulus heteroclitus）已发展出对芳基烃受体（AHR）途径活化和二恶英类化学物质（例如二恶英）的毒性的抵抗力3,3'，4,4'，5-五氯联苯，PCB126。在许多生物系统中，TBT通过PPARγ-RXR途径调节脂肪和骨骼的发育。AHR激活还可能通过AHR与PPARγ之间的分子串扰来破坏脂肪和骨骼的体内稳态。然而，关于共同暴露和这些途径的相互作用如何调节这些污染物的毒理学作用，人们知之甚少。在这里，我们测试了以下假设：TBT会通过激活PPARγ诱导致死鱼类致畸，而PCB126共同暴露会抑制来自参考部位（Scorton Creek，SC，PCB敏感）的PCB敏感的致死鱼类中的PPARγ途径激活。耐PCB的NBH致死鱼类。暴露于TBT（50和100 nM）的两个种群的illi鱼胚胎均显示出尾鳍畸形。在两个人群中，TBT均未改变pparg或其与脂肪形成相关的靶基因（fabp11a和fabp1b）的表达。但是，仅在SC kill鱼中，TBT显着抑制了成骨细胞标记基因osx / sp7和软骨细胞标记基因col2a1b的表达。RXR专用激动剂，但不是PPARγ特异性激动剂引起的尾鳍畸形，就像在TBT处理过的胚胎中观察到的那样。PCB126不会诱发尾鳍畸形，也不会加剧TBT诱发的鳍畸形。此外，PCB126增加了pparg在SC胚胎而不是NBH胚胎中的表达，但没有改变fabp1b的表达。综上所述，这些结果表明，在致死鱼胚胎中，PPARγ途径部分受AHR的调节，但至少在此生命早期阶段，其活性最低。在比目鱼中，RXR激活而不是PPARγ激活似乎是TBT诱导尾鳍致畸性的机制，该机制不受AHR反应性的调节。PCB126不会诱发尾鳍畸形，也不会加剧TBT诱发的鳍畸形。此外，PCB126增加了pparg在SC胚胎而不是NBH胚胎中的表达，但没有改变fabp1b的表达。综上所述，这些结果表明，在致死鱼胚胎中，PPARγ途径部分受AHR的调节，但至少在此生命早期阶段，其活性最低。在比目鱼中，RXR激活而不是PPARγ激活似乎是TBT诱导尾鳍致畸性的机制，该机制不受AHR反应性的调节。PCB126不会诱发尾鳍畸形，也不会加剧TBT诱发的鳍畸形。此外，PCB126增加了pparg在SC胚胎而不是NBH胚胎中的表达，但没有改变fabp1b的表达。综上所述，这些结果表明，在致死鱼胚胎中，PPARγ途径部分受AHR的调节，但至少在此生命早期阶段，其活性最低。在比目鱼中，RXR激活而不是PPARγ激活似乎是TBT诱导尾鳍致畸性的机制，该机制不受AHR反应性的调节。但至少在这个早期阶段就很少活跃。在比目鱼中，RXR激活而不是PPARγ激活似乎是TBT诱导尾鳍致畸性的机制，该机制不受AHR反应性的调节。但至少在这个早期阶段就很少活跃。在比目鱼中，RXR激活而不是PPARγ激活似乎是TBT诱导尾鳍致畸性的机制，该机制不受AHR反应性的调节。