Perfluorooctanoic Acid Administration Research Articles

Distinct bile acid alterations in response to a single administration of PFOA and PFDA in mice

Per- and polyfluoroalkyl substances (PFASs), a group of synthetic chemicals that were once widely used for industrial purposes and in consumer products, are widely found in the environment and in human blood due to their extraordinary resistance to degradation. Once inside the body, PFASs can activate nuclear receptors such as PPARα and CAR. The present study aimed to investigate the impact of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) on liver structure and functions, as well as bile acid homeostasis in mice. A single administration of 0.1 mmole/kg of PFDA, not PFOA, elevated serum ALT and bilirubin levels and caused cholestasis in WT mice. PFDA increased total and various bile acid species in serum but decreased them in the liver. Furthermore, in mouse livers, PFDA, not PFOA, down-regulated mRNA expression of uptake transporters (Ntcp, Oatp1a1, 1a4, 1b2, and 2b1) but induced efflux transporters (Bcrp, Mdr2, and Mrp2–4). In addition, PFDA, not PFOA, decreased Cyp7a1, 7b1, 8b1, and 27a1 mRNA expression in mouse livers with concomitant hepatic accumulation of cholesterol. In contrast, in PPARα-null mice, PFDA did not increase serum ALT, bilirubin, or total bile acids, but produced prominent hepatosteatosis; and the observed PFDA-induced expression changes of transporters and Cyps in WT mice were largely attenuated or abolished. In CAR-null mice, the observed PFDA-induced bile acid alterations in WT mice were mostly sustained. These results indicate that, at the dose employed, PFDA has more negative effects than PFOA on liver function. PPARα appears to play a major role in mediating most of PFDA-induced effects, which were absent or attenuated in PPARα-null mice. Lack of PPARα, however, exacerbated hepatic steatosis. Our findings indicate separated roles of PPARα in mediating the adaptive responses to PFDA: protective against hepatosteatosis but exacerbating cholestasis.

Role of ABCB1 and ABCB4 in renal and biliary excretion of perfluorooctanoic acid in mice.

Perfluorooctanoic acid (PFOA) is one of the major per- and polyfluoroalkyl substances. The role of ATP-binding cassette (ABC) transporters in PFOA toxicokinetics is unknown. In this study, two ABC transporters, ABCB1 and ABCB4, were examined in mice with single intravenous PFOA administration (3.13 µmol/kg). To identify candidate renal PFOA transporters, we used a microarray approach to evaluate changes in gene expression of various kidney transporters in Abcb4 null mice. Biliary PFOA concentrations were lower in Abcb4 null mice (mean ± standard deviation: 0.25 ± 0.12 µg/mL) than in wild-type mice (0.87 ± 0.02 µg/mL). Immunohistochemically, ABCB4 expression was confirmed at the apical region of hepatocytes. However, renal clearance of PFOA was higher in Abcb4 null mice than in wild-type mice. Among 642 solute carrier and ABC transporters, 5 transporters showed significant differences in expression between wild-type and Abcb4 null mice. These candidates included two major xenobiotic transporters, multidrug resistance 1 (Abcb1) and organic anion transporter 3 (Slc22a8). Abcb1 mRNA levels were higher in Abcb4 null mice than in wild-type mice in kidney. In Abcb4 null mice, Abcb1b expression was enhanced in proximal tubules immunohistochemically, while that of Slc22a8 was not. Finally, in Abcb1a/b null mice, there was a significant decrease in the renal clearance of PFOA (0.69 ± 0.21 vs 1.1 mL ± 0.37/72 h in wild-type mice). A homology search of ABCB1 showed that several amino acids are mutated in humans compared with those in rodents and monkeys. These findings suggest that, in the mouse, Abcb4 and Abcb1 are excretory transporters of PFOA into bile and urine, respectively.

Perfluorooctanoic acid-induced liver injury is potentially associated with gut microbiota dysbiosis

Perfluorooctanoic acid (PFOA), an environmental pollutant, is widely engaged in industrial products and tends to accumulate in the liver. Emerging evidence has suggested that the gut microbiome is a pivotal player in maintaining animal health and can potentially altered by xenobiotic. However, few studies explored whether PFOA-induced liver injury is associated with gut microbiota dysbiosis. In the present study, the effects of subacute and subchronic PFOA exposure on liver and gut microbiota in C57BL/6J mice were investigated. Our findings showed that both subacute and subchronic exposure to PFOA induced the liver inflammation, disrupted antioxidative homeostasis and caused liver histological abnormalities with detectable hepatomegaly, ultimately triggering liver injury. Besides, 16S rRNA sequencing analysis revealed that subacute PFOA exposure caused significant changes in the abundances of intestinal flora known to contribute to liver inflammation and oxidative stress, such as the Dehalobacterium and Bacteroides genera. Exposure to subchronic toxicity mainly induced the decrease in commensal probiotics including Lactobacillus and Bifidobacterium genera, which are potentially beneficial to liver damage, compared with that in the untreated group. They also resulted in disturbed functional capabilities of the microbial communities by a Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis. Additionally, the levels of short-chain fatty acids (SCFAs), especially butyric acid, were significantly reduced by PFOA administration. Collectively, our observations suggested that liver damage induced by both subacute and subchronic PFOA exposures probably partly related to the gut microbiota dysbiosis and provided a new insight into the role of PFOA in liver injury.

Exposure of female mice to perfluorooctanoic acid suppresses hypothalamic kisspeptin-reproductive endocrine system through enhanced hepatic fibroblast growth factor 21 synthesis, leading to ovulation failure and prolonged dioestrus.

Perfluorooctanoic acid (PFOA) is widely used in household applications. High-dose exposure to PFOA has been associated with increased risks of infertility and premature ovarian insufficiency in woman. PFOA can alter hepatic gene expression by activating peroxisome proliferator-activated receptor α (PPARα). The present study investigated whether exposure to PFOA via PPARα activation alters the synthesis of hepatic fibroblast growth factor 21 (FGF21) to disturb female neuroendocrine and reproductive function. In the present study, we show that the oral administration of PFOA (2 or 5mgkg-1 ) in adult female mice (PFOA mice) caused prolonged dioestrous, a reduction in the number of corpora lutea and decreased levels of hypothalamic gonadotrophin-releasing hormone, serum progesterone and luteinising hormone (LH). Exposure to PFOA decreased the expression of vasopressin in the suprachiasmatic nucleus (SCN) and kisspeptin in the anteroventral periventricular nucleus (AVPV) with deficits in preovulation or oestrogen-induced LH surge. PFOA via activation of PPARα increased dose-dependently hepatic FGF21 expression, leading to elevated serum and hypothalamic FGF21 concentrations. Treatment of PFOA mice with the PPARα antagonist GW6471 or the FGF21 inhibitor PD173074 rescued SCN vasopressin and AVPV-kisspeptin expression. Either administration of GW6471 and PD173074 or treatment with vasopressin and the G protein coupled receptor 54 agonist kisspeptin-10 in PFOA-mice was able to recover the regular oestrous cycle, ovulation ability, LH surge production and reproductive hormone levels. The present study provides in vivo evidence that exposure to PFOA (≥2mgkg-1 ) in mice causes down-regulation of the kisspeptin-reproductive endocrine system by enhancing PPARα-mediated hepatic FGF21 expression. The liver-brain reproductive endocrine disorder caused by PFOA exposure may lead to prolonged dioestrous and ovulation failure.

Neurotoxicity of perfluorooctanoic acid and post-exposure recovery due to blueberry anthocyanins in the planarians Dugesia japonica

Perfluorooctanoic acid (PFOA) is a widely used synthetic industrial chemical which accumulates in ecosystems and organisms. Our study have investigated the neurobehavioral effects of PFOA and the alleviation effects of PFOA-induced neurotoxicity by blueberry anthocyanins (ANT) in Dugesia japonica. The planarians were exposed to PFOA and ANT for ten days. Researchs showed that exposure to PFOA affected locomotor behavior and ANT significantly alleviated the reduction in locomotion induced by PFOA. The regeneration of eyespots and auricles was suppressed by PFOA and was promoted by ANT. Following exposure to PFOA, acetylcholinesterase activity continually decreased and was unaffected in the ANT group, but was elevated after combined administration of PFOA and ANT. Oxidative DNA damage was found in planarians exposed to PFOA and was attenuated after administration of ANT by the alkaline comet assay. Concentrations of three neurotransmitters increased following exposure to PFOA and decreased after administration of ANT. Furthermore, ANT promoted and PFOA inhibited neuronal regeneration. DjotxA, DjotxB, DjFoxG, DjFoxD and Djnlg associated with neural processes were up-regulated following exposure to PFOA. Our findings indicate that PFOA is a neurotoxicant while ANT can attenuate these detrimental effects.

Lipid accumulation responses in the liver of Rana nigromaculata induced by perfluorooctanoic acid (PFOA)

Perfluorooctanoic acid (PFOA) is a perfluorinated compound that is widely distributed, is persistent in the environment, and has a low-level chronic exposure effect on human health. The aim of this study was to investigate the peroxisome proliferator activated receptors γ (PPARγ) and the sterol regulatory element-binding protein 2 (SREBP2) signaling pathways in regulating the lipid damage response to PFOA in the livers of amphibians. Male and female frogs (Rana nigromaculata) were exposed to 0, 0.01, 0.1, 0.5 and 1 mg/L PFOA. After treatment, we evaluated the pathological changes in the liver by Oil Red O, staining and examined the total cholesterol (T-CHO) and triglyceride (TG) contents. The mRNA expression levels of PPARγ, Fatty acid synthase (FAS), Acetyl-CoA carboxylase (ACC), Glycerol-3-phosphate acyltransferase (GPAT), SREBP2 and 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The administration of PFOA caused marked lipid accumulation damage in the amphibian livers. The T-CHO contents were elevated significantly after PFOA treatment; these results show a dose-dependent manner in both sexes. The TG content showed a significant increase in male livers, while it was elevated significantly in female livers. The RT-PCR results showed that the mRNA expression levels of PPARγ, ACC, FAS, GPAT, SREBP2 and HMG-CoA were significantly dose-dependently increased in the PFOA-treated groups compared with those of the control group. Our results demonstrated that PFOA-induced lipid accumulation also affected the expression levels of genes FAS, ACC, GPAT and HMG-CoA in the PPARγ and SREBP2 signaling pathways in the liver. These finding will provide a scientific theoretical basis for the protection of Rana nigromaculata against PFOA effects.

Peroxisomes proliferation and pharmacological stimulation of autophagy in rat liver: evidence to support that autophagy may remove the "older" peroxisomes.

Like mitochondria, peroxisomes produce reactive oxygen species (ROS), compounds which have been implicated to play an important role in many degenerative diseases and aging itself, and an exaggerated ROS production might occur in altered or older organelles. Growing evidence shows that autophagy, a required function in cell housekeeping during fasting, can remove damaged macromolecules, organelles, and membranes selectively. Proliferation of peroxisomes can be enhanced in liver cells by perfluorooctanoic acid (PFOA), which causes a marked increase of the Acyl-CoA oxidase (ACOX) activity and no significant change in urate oxidase (UOX) activity. The administration of antilipolytic drugs to fasted animals was shown to intensify autophagy. Here we tested the hypothesis that autophagy may distinguish and remove older from younger peroxisomes in rat liver. Male Sprague-Dawley rats were given PFOA (150mg/kg body weight) or vehicle. Animals were sacrificed at different times following PFOA administration, and 3h after the induction of autophagy with the antilipolytic agent 3,5-dimethyl pyrazole (DMP, 12mg/kg body weight). The levels of ACOX and UOX activity were measured in the liver tissue. Results showed that autophagy caused a parallel, significant decrease in both enzymes activity in control rats, and that in PFOA-treated rats the effects were different and changed with PFOA time administration. Changes are compatible with the hypothesis that newly formed ACOX-rich peroxisomes are resistant to pexophagy and that sensitivity to pexophagy increases with increasing peroxisomal "age." In conclusion, there is indirect evidence supporting the hypothesis that autophagy may recognize and degrade older peroxisomes.

Maternal exposure to perfluorooctanoic acid inhibits luteal function via oxidative stress and apoptosis in pregnant mice

Perfluorooctanoic acid (PFOA) is a synthetic perfluorinated compound, which has been reported to exert adverse effect on the pregnancy. However, whether it is associated with alteration of luteal function remains unknown. Mice were administered PFOA by gavage from gestational days (GD) 1–7 or 13. PFOA treatment did not significantly affect numbers of embryo implantation. Nevertheless, on GD 13, 10mg/kg PFOA treatment significantly increased numbers of resorbed embryo. Furthermore, PFOA exposure markedly reduced serum progesterone levels but did not affect estradiol levels. Treatment also showed concomitant decreases in transcript levels for key steroidogenic enzymes, and reduced numbers and sizes of corpora lutea. In addition, PFOA administration inhibited activities of superoxide dismutase and catalase, and increased generation of hydrogen peroxide and malondialdehyde, and down-regulated level of Bcl-2 and up-regulated p53 and BAX proteins. In conclusion, PFOA exposure significantly inhibits luteal function via oxidative stress and apoptosis in pregnant mice.

High fat diet feeding exaggerates perfluorooctanoic acid-induced liver injury in mice via modulating multiple metabolic pathways.

High fat diet (HFD) is closely linked to a variety of health issues including fatty liver. Exposure to perfluorooctanoic acid (PFOA), a synthetic perfluorinated carboxylic acid, also causes liver injury. The present study investigated the possible interactions between high fat diet and PFOA in induction of liver injury. Mice were pair-fed a high-fat diet (HFD) or low fat control with or without PFOA administration at 5 mg/kg/day for 3 weeks. Exposure to PFOA alone caused elevated plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels and increased liver weight along with reduced body weight and adipose tissue mass. HFD alone did not cause liver damage, but exaggerated PFOA-induced hepatotoxicity as indicated by higher plasma ALT and AST levels, and more severe pathological changes including hepatocyte hypertrophy, lipid droplet accumulation and necrosis as well as inflammatory cell infiltration. These additive effects of HFD on PFOA-induced hepatotoxicity correlated with metabolic disturbance in liver and blood as well as up-regulation of hepatic proinflammatory cytokine genes. Metabolomic analysis demonstrated that both serum and hepatic metabolite profiles of PFOA, HFD, or HFD-PFOA group were clearly differentiated from that of controls. PFOA affected more hepatic metabolites than HFD, but HFD showed positive interaction with PFOA on fatty acid metabolites including long chain fatty acids and acylcarnitines. Taken together, dietary high fat potentiates PFOA-induced hepatic lipid accumulation, inflammation and necrotic cell death by disturbing hepatic metabolism and inducing inflammation. This study demonstrated, for the first time, that HFD increases the risk of PFOA in induction of hepatotoxicity.

Effect of exposure to perfluorooctanoic acid on hepatic antioxidants in mice

The present study was undertaken to evaluate hepatic antioxidants status in female mice after exposure to perfluorooctanoic acid (PFOA). A total number of 20 female mice were subjected to the study; out of them, 15 mice were treated with PFOA. PFOA solutions were prepared at 0.1, 0.5, and 1 mg/ml of deionized water and administered to the mice by gavage once daily for 3 weeks at a volume of 10 ml/kg. Controls (five mice) received an equivalent volume of deionized water. The results revealed significant increase in liver weight at dose of 5 (p < 0.01) and 10 mg/kg body weight (b.w., p < 0.01). Both hepatic total glutathione level and hepatic catalase activity were significantly increased (p < 0.01) at dose of 5 mg/kg b.w. On the other hand, hepatic glutathione reductase activity was significantly increased at dose of 10 mg/kg b.w. In this model system, PFOA administration was effective in inducing oxidative stress particularly reflected in the liver.

Excretion of PFOA and PFOS in Male Rats During a Subchronic Exposure

Perfluorinated compounds (PFCs), a class of synthetic surfactants that are widely used, have become global environmental contaminants because of their high persistence and bioaccumulation. An increasing number of studies have described the pharmacokinetics of PFCs following in vivo exposure, however, few papers have focused on the excretion of these compounds during a period of consecutive exposure. In this study, the excretions of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) in male Sprague-Dawley rats gavaged consecutively for 28 days were investigated and compared. The faster elimination rate in urine compared to feces indicated that urinary excretion is the primary clearance route in rats for either PFOA or PFOS. During the first 24 h after administration of PFOA (5 and 20 mg/kg body weight/day), about 24.7-29.6% of the oral dose was excreted through urine and feces, while for PFOS, the excretion amounts were only 2.6-2.8% of the total gavaged doses (5 and 20 mg/kg body weight/day). The excretion rates of both PFCs increased with increasing exposure doses. The higher elimination rate of PFOA through excretion indicated its lower accumulation in rats, thus inducing possible lower toxicities compared to PFOS.

Fish Oil-Feeding Prevents Perfluorooctanoic Acid-Induced Fatty Liver in Mice

The effects of perfluorooctanoic acid (PFOA) on the levels of lipids in liver and serum were compared between mice fed a diet supplemented with soy bean oil (SO), perilla oil (PO), or fish oil (FO) for 4 weeks. Hepatic content of triglyceride (TG) was significantly lower in the mice fed the FO diet than that in the mice fed either the SO or the PO diet. The treatment with PFOA caused a marked accumulation of TG in the livers of SO-fed and PO-fed mice (seven- and twofold over their respective controls), whereas a level of TG remained low in the mice fed the FO diet. Incorporationin vivoof [3H]glycerol revealed that FO-feeding reduced synthesis of TG in the liver. The administration of PFOA increased the incorporation of [3H]glycerol into hepatic phospholipid (PL) regardless of the dietary oil, while synthesis of hepatic TG from [3H]glycerol was not altered by the treatment with PFOA. Serum level of TG was reduced by the administration of PFOA to the mice fed either the SO diet or the PO diet, while no change in the level was observed in the mice fed the FO diet. These results suggest that the accumulation of TG in the livers of PFOA-treated mice is due to the inhibition of the secretion of TG into circulation. PFOA-induced hepatic accumulation of TG is prevented by the feeding of the FO diet which inhibits TG formation. Among three dietary oils, FO-feeding alone prevented the PFOA-caused accumulation of TG in the liver. The importance of docosahexaenoic acid (22:6(n− 3)) is discussed in relation to the prevention of fatty liver induced by chemicals.

Characterization of hepatic responses of rat to administration of perfluorooctanoic and perfluorodecanoic acids at low levels

Male rats were fed a diet that contained perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) at concentrations ranging from 0.0025–0.04% (w/w) and from 0.00125–0.01% (w/w), respectively, for 1 week. The hepatic responses of the rats to PFOA and PFDA were examined. Upon the administration of PFOA and PFDA, three peroxisome proliferator-responsive parameters, peroxisomal β3-oxidation, microsomal 1-acylglycerophosphocholine (1-acyl-GPC) acyltransferase and cytosolic long-chain acyl-CoA hydrolase, were induced in a dose-dependent manner. A multiple regression analysis of the three parameters revealed that the data from rats treated with PFOA and PFDA shared one common line, indicating a marked correlation among the inductions of the three parameters. The activities of glutathione (GSH) S-transferases towards 1-chloro-2,4-dinitrobenzene (CDNB) and 1,2-dichloro-4-nitrobenzene (DCNB) were depressed by PFOA and PFDA. Significant inverse correlations were found between activities of GSH S-transferases and peroxisomal β-oxidation. The administration of PFOA and PFDA significantly increased hepatic concentration of triacylglycerol. The perfluorocarboxylic acids at relatively high doses caused accumulation of cholesterol in liver. Electron microscopic studies showed that the administration of PFOA and PFDA caused an increase in cell size and proliferations of peroxisomes, and that the treatment of rats with PFDA at dietary concentration of 0.01% caused a marked increase in small lipid droplet in hepatocytes, indicative of hepatotoxic manifestations. The present results suggest that when PFOA and PFDA are administered at low levels, there are no differences between the properties of the perfluorocarboxylic acids as peroxisome proliferators, although the administration of PFDA at the doses exceeding a certain level becomes markedly toxic to hepatocytes.

Effects of prolonged administration of perfluorooctanoic acid on hepatic activities of enzymes which detoxify peroxide and xenobiotic in the rat

Male and female rats were fed a diet containing 0.01% (w/w) perfluorooctanoic acid (PFOA) for 2 or 26 weeks, and the effects on enzymes that participate in the metabolism of peroxides and xenobiotics in liver were studied. Elevated activity of peroxisomal β-oxidation persisted throughout the treatment of male rats with PFOA for 26 weeks. The activity of glutathione (GSH) peroxidase towards hydrogen peroxide was depressed significantly by the prolonged administration. The long-term treatment of male rats with PFOA decreased the activity of GSH peroxidase towards cumene hydroperoxide and increased the activity of microsomal NADPH-dependent lipid peroxidation. The activities of GSH reductase and hepatic content of GSH remained unchanged. There was no difference in the content of conjugated dienes in microsomal lipid between male rats exposed to PFOA for 26 weeks and age-matched control. The activities of GSH S-transferase towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene were depressed by the short-term administration of PFOA to male rats, and this inhibition became pronounced during the prolonged treatment. Microsomal cytochrome P450 was induced by the short-term treatment of male rats with PFOA, and elevated levels persisted throughout the treatment for 26 weeks. Upon the administration of PFOA to male rats for 2 weeks, the activity of 7-ethoxycoumarin O-deethylase was increased markedly, whereas the activities of either aniline p-hydroxylase or aminopyrine N-demethylase were unchanged. Although an age-dependent decrease was observed in the activity of 7-ethoxycoumarin O-deethylase, the activity in male rats treated with PFOA for 26 weeks was higher than that of age-matched control, to the same extent as was observed with the short-term treatment. The prolonged administration of PFOA to male rats caused a significant increase in the activity of both aniline p-hydroxylase and aminopyrine N-demethylase. Little changes were found in the same parameters tested in female rats even after the prolonged administration of PFOA.

Perfluorooctanoic acid has persistent effects on peroxisome proliferation and related parameters in mouse liver.

Male C57Bl/6 mice were treated for 5 days with 0.05% perfluorooctanoic acid (PFOA) in their diet. This treatment resulted in a potent induction of peroxisomal fatty acid beta-oxidation in the liver. In order to investigate recovery from treatment with PFOA, mice were given normal laboratory chow for up to 20 days after termination of PFOA administration. It was established that the activities of peroxisomal lauoryl-CoA oxidase and palmitoyl-CoA oxidation were still elevated 2-3 weeks after termination of treatment. The catalase activity recovered in the cytosolic fraction was also still significantly elevated after 20 days with normal laboratory chow. Furthermore, the protein content of the mitochondrial fraction was increased by PFOA and had not returned to control level at the end of the recovery period. Perfluorooctanoic acid also caused a persistent effect in omega hydroxylation of lauric acid (cytochrome P-452). The activities of cytosolic DT-diaphorase and glutathione transferase were also enhanced by PFOA. However, these two enzymes recovered relatively rapidly from the treatment (2-20 days). This study reveals two different patterns of recovery from PFOA treatment, one involving parameters that recovered completely, or almost completely, from PFOA treatment after 20 days and another involving parameters that were still elevated at the end of the recovery period.

Induction by perfluorooctanoic acid of microsomal 1-acylglycerophosphocholine acyltransferase in rat kidney Sex-related difference

Response of rat kidney to the challenges by perfluorooctanoic acid (PFOA) was studied using microsomal 1-acyglycerophosphocholine (1-acyl-GPC) acyltransferase as a parameter. Marked induction of the enzyme was brought about in kidney of male rats, whereas the induction in kidney of female rats was far less pronounced. The sex-related difference in the response of kidney to PFOA was much more marked than those seen with p-chlorophenoxyisobutyric acid (clofibric acid) or 2,2′-(decamethylenedithio)diethanol (tiadenol). Hormonal manipulations revealed that the sex-related difference in the response of kidney to PFOA was strongly dependent on the state of gonadal hormones of rats. Even after a prolonged administration of PFOA for up to 26 weeks, this sex-related difference was still evident. Induction of peroxisomal β-oxidation was brought about concurrently with microsomal 1-acyl-GPC acyltransferase and a high correlation was confirmed between the induction of these two parameters.

Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats

The elimination, tissue distribution, and metabolism of [1-14C]perfluorooctanoic acid (PFOA) was examined in male and female rats for 28 days after a single ip dose (9.4 mumol/kg, 4 mg/kg). A sex difference in urinary elimination of PFOA-derived 14C was observed. Female rats eliminated PFOA-derived radioactivity rapidly in the urine with 91% of the dose being excreted in the first 24 hr. In the same period, male rats eliminated only 6% of the administered 14C in the urine. The sex-related difference in urinary elimination resulted in the observed difference in the whole-body elimination half-life (t1/2) of PFOA in males (t1/2 = 15 days) and females (t1/2 less than 1 day). Analysis of PFOA-derived 14C in tissues showed that the liver and plasma of male rats and the liver, plasma, and kidney of female rats were the primary tissues of distribution. The relatively high concentration of PFOA in the male liver was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that 11% of the PFOA infused was extracted by the liver in a single pass. The ability of the liver to eliminate PFOA into bile was examined in rats whose renal pedicles were ligated to alleviate sex differences in the urinary excretion of PFOA. In a 6-hr period following IP administration of PFOA, there was no apparent difference in biliary excretion, where both males and females eliminated less than 1% of the PFOA dose via this route. We hypothesized that the sex difference in the persistence of PFOA was due to a more rapid formation of a PFOA-containing lipid (i.e., a PFOA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid) in the male rat. Also, the increased urinary elimination of PFOA in females may have been due to increased metabolism to a PFOA-glucuronide or sulfate ester. However, no evidence that PFOA is conjugated to form a persistent hybrid lipid was obtained, nor were polar metabolites of PFOA in urine or bile detected. In addition, daily urinary excretion of fluoride in male and female rats before or after PFOA treatment were similar, suggesting that the parent compound is not defluorinated. Thus, the more rapid elimination of PFOA from female rats is not due to formation of a PFOA metabolite.

Effects of chronic administration of perfluorooctanoic acid on fatty acid metabolism in rat liver: Relationship among stearoyl-coenzyme A desaturase, 1-acylglycerophosphocholine acyltransferase, and acyl composition of microsomal phosphatidylcholine.

Male and female rats were fed on a diet containing 0.01% (w/w) perfluorooctanoic acid (PFOA) for 2, 22, or 26 weeks and effect of PFOA on activities of microsomal 1-acylglycerophosphocholine acyltransferase, microsomal stearoyl-coenzyme A (CoA) desaturase, peroxisomal beta-oxidation and on acyl composition of microsomal phosphatidylcholine in liver were studied. The treatment of male rats with PFOA for 2 weeks caused increases in the activities of stearoyl-CoA desaturase, 1-acylglycerophosphocholine acyltransferase, and peroxisomal beta-oxidation. The elevated activities of microsomal 1-acylglycerophosphocholine acyltransferase and peroxisomal beta-oxidation were unchanging throughout the long-term treatment. The induced activity of microsomal 1-acylglycerophosphocholine acyltransferase was found to be highly correlated with the induced activity of peroxisomal beta-oxidation. In contrast to these two enzymes, the increased activity of stearoyl-CoA desaturase by the short-term treatment of rats with PFOA did not last for 26 weeks, although the activity in rats treated for the long-term was higher than that of age-matched controls. The treatment of male rats with PFOA caused great alterations in the acyl composition of microsomal phosphatidylcholine. The high correlation seen between proportion of 18:1 in the C-2 position of phosphatidylcholine and activities of both stearoyl-CoA desaturase and 1-acylglycerophosphocholine acyltransferase suggest that these two enzymes participate actively in the regulation of acyl composition of phosphatidylcholine in rat liver. The present results show that hepatic responses to PFOA remain consistent throughout the period of the administration, but the elevated activities of the hepatic enzymes and the altered acyl composition of microsomal phosphatidylcholine returned to control levels within 4 weeks after PFOA was withdrawn from the diet. Even after the chronic administration of PFOA, these parameters of female rats responded only slightly to the challenges by the chemical, which indicates a marked sex-related difference being still apparent in the response of rat liver to PFOA.

Metabolic Handling of perfluorooctanoic acid in rats.

SummaryThe metabolic fate of perfluorooctanoic acid administered by stomach intubation to female rats was investigated. The nonionic fluorine level in the serum was increased 200-fold after administration of the dose but returned to baseline levels by 52.5 hr. Although perfluorooctanoic acid is rapidly absorbed and bound to nonultrafilterable components in the serum, the entire dose of nonionic fluorine was recovered in the urine and feces after 96 hr. Neither the ionic fluoride level in the serum nor the rate of ionic fluoride excretion in the urine was significantly altered by the administration of perfluorooctanoic acid. Although perfluorooctanoic acid has not been identified in the urine, the available data suggest that it has been excreted intact or in possibly conjugated form.