Perfluoroalkyl chemicals have been used since the 1950s in a wide variety of industrial and consumer products. Among them, perfluofooctanoic acid (PFOA) was used primarily in an ammonium salt form as an emulsifier in the production of fluoropolymers, such as poly(tetrafluoroethylene) and poly(vinylidine fluoride).1) These polymers have been used in various consumers and industrial products, such as water-repellants for leather paper and textiles. The toxicity of PFOA has been characterized in numerous studies with various species.2) Early studies have shown that organic fluorine accumulated in the serum of occupationally exposed people.3) Resent studies have revealed that PFOA and pefluorooctanesulfonic acid have been found in water, [4][5][6] sediment, 7) wildlife 8-10) and human. [11][12][13][14][15] These findings suggest that general population is exposed to such perfluorochemicals which have globally spread at very low levels.PFOA is thought to remain in humans for long time by the study that has estimated PFOA half-life for 9 retirees from chemical plant to be 4.37 years on the average. 16) On the other hand, several studies that have been carried out on the fate of PFOA in experimental animals including rats have shown that biological half-life of PFOA in male rats was calculated to be 105 h after an intraperitoneal administration at the dose of 50 mg/kg, 17) 9 d after an intraperitoneal administration at a dose of 4 mg/kg, 18) and 6.8 d after an intravenous administration at a dose of 20 mg/kg, 19) respectively. In the studies using experimental animals, PFOA has been shown to be mainly distributed to the liver and serum/plasma, and easily excreted into urine. [18][19][20] The reason for such species difference in half-life of PFOA between humans and experimental animals may be due to the differences in the proteins responsible for distribution, binding and transport of PFOA. Alternative explanation is that the concentrations of PFOA used for the calculation of half-life of PFOA were quite different between humans and the experimental animals. In fact, serum concentrations of PFOA were shown be 11.7 mg/ml 24 h after an intraperitoneal administration at a dose of 4 mg/kg 18) and 61.5 mg/ml 24 h after an intravenous injection at a dose of 20 mg, 19) respectively, while serum samples of human that have been used for the calculation of half-life contained PFOA at the concentrations of 0.06-1.84 mg/ml.16) To date, however, toxicokinetic study has not been performed at the serum concentrations of PFOA corresponding to the levels in serum of humans.In the view of toxicological aspects, it is important to know the toxicokinetic data of PFOA at very low serum concentrations. In the present study, we demonstrated that tissue distribution of PFOA at very low dose is markedly different from those at high doses in experimental animals. MATERIALS AND METHODSMaterials PFOA was purchased from Sigma Aldrich Japan (Tokyo, Japan Faculty of Pharmaceutical Sciences, Josai University; 1-1 Keyakidai, Sakado, Saitama 350-0295,...

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The mechanism by which perfluorooctanoic acid (PFOA) is transported in the kidney was studied in rats. We hypothesized that some transporters that are expressed in the basolateral and/or brush border membrane of proximal tubular cells mediate the transport of PFOA. Mannitol infusion, which caused an increase in the urine flow rate, significantly increased the renal clearance (CL R ) of PFOA in both male and female rats. Feeding a low-phosphate diet that causes an increase in the expression of rat type II sodium-dependent phosphate transporter (Npt2) reduced the CL R in both male and female rats. These suggest that PFOA is reabsorbed in the proximal tubules, and that a phosphate transporter may be responsible for the renal transport of PFOA. The CL R of PFOA in Eisai hyperbilirubinemic rats that lack multidrug resistance-associated protein 2 (MRP2) was not different from that of the wild type, suggesting that MRP2 is not responsible for the renal transport of PFOA. Three candidate transporters, organic anion-transporting polypeptide 1 (oatp1), Npt2, and organic anion transporter 3 (OAT3) were studied to clarify whether these transporters facilitate [14 C]PFOA transport in functional studies in Xenopus laevis oocytes. Both oatp1 and OAT3 facilitated [ 14 C]PFOA transport while Npt2 did not. These results suggest that both oatp1 and OAT3 mediate, at least in part, the transport of PFOA in the proximal tubules of rat kidney.

Diabetes mellitus is known to exacerbate cerebral ischemic injury. In the present study, we investigated antiapoptotic and anti-inflammatory effects of oral supplementation of ascorbic acid (AA) on cerebral injury caused by middle cerebral artery occlusion and reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. We also evaluated the effects of AA on expression of sodium-dependent vitamin C transporter 2 (SVCT2) and glucose transporter 1 (GLUT1) after MCAO/Re in the brain. The diabetic state markedly aggravated MCAO/Re-induced cerebral damage, as assessed by infarct volume and edema. Pretreatment with AA (100 mg/kg, p.o.) for two weeks significantly suppressed the exacerbation of damage in the brain of diabetic rats. AA also suppressed the production of superoxide radical, activation of caspase-3, and expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) in the ischemic penumbra. Immunohistochemical staining revealed that expression of SVCT2 was upregulated primarily in neurons and capillary endothelial cells after MCAO/Re in the nondiabetic cortex, accompanied by an increase in total AA (AA + dehydroascorbic acid) in the tissue, and that these responses were suppressed in the diabetic rats. AA supplementation to the diabetic rats restored these responses to the levels of the nondiabetic rats. Furthermore, AA markedly upregulated the basal expression of GLUT1 in endothelial cells of nondiabetic and diabetic cortex, which did not affect total AA levels in the cortex. These results suggest that daily intake of AA attenuates the exacerbation of cerebral ischemic injury in a diabetic state, which may be attributed to anti-apoptotic and anti-inflammatory effects via the improvement of augmented oxidative stress in the brain. AA supplementation may protect endothelial function against the exacerbated ischemic oxidative injury in the diabetic state and improve AA transport through SVCT2 in the cortex.