全氟碳化物於大鼠中分配係數之研究

Abstract

全氟碳化物的種類繁多，而大部分文獻聚焦在PFOS(C8)或PFOA(C8)等環境中濃度較高的全氟碳化物，為了建立更多種類的全氟碳化物之生理型藥物動力學 (Physiologically based pharmacokinetic, PBPK) 模式，其中，化合物在生物體內各臟器之分配係數(Partition coefficient, PC) 可以說是重要的參數之一。本研究對雄性SD 大鼠(N=40)經單一胃管灌食的方式，暴露個別劑量為500μg/kg之PFBA、PFBS、PFPeA、PFHxA、PFHxS、PFHpA等六種全氟碳化物，在為期10天的動物實驗其間於不同犧牲點(2、4、8、12、24、48、96、144、196、240小時)，每個時間點包含暴露組(N=3)、控制組(N=4)，收集SD大鼠的血清、肝臟、腎臟、小腸、副睪旁之脂肪等五種臟器，經由前處理後以液相層析串聯質譜儀(LC-MS/MS)方法分析全氟碳化物之濃度，用於後續分配係數之運算。並根據選擇碳數不同(4~7C)以及官能基不同(-COOH與-SO3)之全氟碳化物，探討碳數與官能基對於SD 大鼠全氟碳化物分配係數之影響。實驗結果發現除PFHxS以外，大部分的全氟碳化物在暴露後的48小時內，便經由小腸快速吸收至血液中進行循環並分配到不同的臟器，隨後經由腎臟排出體外；而PFHxS則是在收樣時間結束(240小時)後，仍持續存在於SD大鼠各臟器之中。在分配係數的部分，帶有羧基(R-COOH)之全氟碳化物(PFBA、PFPeA、PFHxA、PFHpA)其分配係數由大到小依序為腎臟>肝臟>小腸>脂肪，碳鏈長度的增加對於任何臟器/血清分配係數並無顯著影響；而帶有硫酸基(-SO3)之全氟碳化物(PFBS、PFHxS)其分配係數由大到小依序為肝臟>腎臟>小腸>脂肪。這樣的差異歸因於帶有硫酸基(-SO3)之全氟碳化物易與肝細胞脂肪酸結合蛋白(Hepatic fatty acid-binding protein)結合累積於肝臟之中，因而推算出較高的肝臟/血清分配係數(PCLiver/plasma)，另外，隨著碳鏈長度增加PFHxS(6C)相較於PFBS(4C)其肝臟/血清分配係數(PCLiver/plasma)則有增加之現象發生。

The widespread environmental distribution of Perflourinated chemicals (PFCs) has been considered as a public health issue for a long time. Most of the current reserch focus on perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) compare to other PFCs. In order to know the metabolism progress of the chemical in biota. Physiologically based pharmacokinetic model (PBPK model) is a well-known method. Among numerous parameters, the paeririon coefficient (PC) for each of the organ in biota is indispensable. The male SD rats(N=40) were treated with a single dose of PFBA、PFBS、PFPeA、PFHxA、PFHxS、PFHpA by oral gavage at 500μg/kg. Subsequently, the SD rats were classified into exposure group (N=3) and control group (N=1) in each of the sacrified time point (2, 4, 8, 12, 24, 48, 96, 144, 196, 240 hour). Serum, liver, kidney, small intestine, epididymis fat were collected. After pre-treatment, the samples were analyzed for these PFCs via liquid chromatograph tandem mass spectrometer (LC-MS/MS). The aims of this study are finding out how the influences for partition coefficient of different carbon chain length and different fuction groups in male SD rats. After the gavage exposure, results shows that apart form PFHxS, most of the PFCs were quickly absorb from small intestine into blood circulation.Then distribute into other organs, at last exceret out of the body via kidney in 48 hours. On the other hand, PFHxS keep exist in biota after 240 hours. PFCs with carboxyl group (-COOH), such as PFBA, PFPeA, PFHxA, PFHpA. The descending order of partition coefficient is kidney, liver, small intestine, epididymis fat. As the carbon chain length increase, the partition coefficient for each of the organ does not change significantly. PFCs with sulfur trioxide group (-SO3), such as PFBS and PFHxS. The descending order of partition coefficient is liver, kidney, small intestine, epididymis fat. These differences attribute to PFCs with sulfur trioxide group (-SO3) are likely combined with hepatic fatty acid-binding protein in hepatic cells. Therefore, we can estimate a higher value of partition coefficient in liver.