Hepatic indices of thyroid status in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

The functional thyroid status of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats is unknown. Therefore, activities of certain thyroid-responsive enzymes were examined in the livers of adult male Sprague-Dawley rats 1 week after treatment with TCDD (6.25, 25 or 100 micrograms/kg). Activity of the thyroid-responsive flavin L-glycerol-3-phosphate dehydrogenase (per mg mitochondrial protein) was decreased slightly in livers of TCDD-treated rats, while that of succinate dehydrogenase remained unchanged. In contrast, activities (per mg supernatant protein) of three thyroid-responsive NADP-dependent cytosolic enzymes, malic enzyme, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, were increased by TCDD treatment in a dose-dependent manner. Lactate dehydrogenase (activity per mg supernatant protein) was also augmented slightly 1 week after TCDD administration. Liver mass was increased by TCDD treatment in a dose-dependent manner, but DNA content per liver was similar at all doses examined. Total hepatic protein, expressed per liver or mg hepatic DNA, was increased in TCDD-treated rats when compared to their pair-fed counterparts. The decreased activity of the mitochondrial L-glycerol-3-phosphate dehydrogenase, in contrast to the increased activities of the supernatant enzymes, malic enzyme, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, is not consistent with a shift in functional thyroid status following TCDD treatment.     

Androgenic deficiency in male rats treated with perfluorodecanoic acid

Effects of perfluorodecanoic acid (PFDA, 20-80 mg/kg, ip) on the androgenic status of sexually mature male rats were investigated 7 days after treatment. PFDA decreased plasma androgen concentrations in a dose-dependent fashion with an ED50 of approximately 30 mg/kg. The highest dose of PFDA decreased plasma testosterone and 5 alpha-dihydrotestosterone concentrations to 12 and 18%, respectively, of ad libitum-fed control (ALC) values. Secondary to the decreased plasma androgen concentrations were dose-related decreases in the weights and epithelial heights of accessory sex organs. Results from pair-fed control (PFC) rats show that hypophagia in PFDA-treated rats was not a major cause of the low plasma androgen concentrations. When rats were castrated and implanted with testosterone-containing capsules, PFDA-treated and ALC rats had similar plasma testosterone concentrations and secondary sex organ weights. Therefore, the androgenic deficiency in intact PFDA-treated rats does not result from increased plasma clearance of androgens. Rather, PFDA must cause the androgenic deficiency by decreasing the secretion of testosterone from the testis. The decrease in testosterone secretion does not appear to result from a decrease in plasma luteinizing hormone (LH) concentrations, because plasma LH concentrations were not significantly altered by PFDA treatment. This finding suggests that PFDA treatment decreases testicular responsiveness to LH stimulation. The observation that PFDA treatment reduced the secretion of testosterone by testes stimulated in vitro with the LH analog human chorionic gonadotropin demonstrates that this is the case. In addition, since plasma LH concentrations did not increase in response to the low plasma androgen concentrations in PFDA-treated rats, we suggest that PFDA disrupts the normal feedback relationship which exists between plasma androgen and LH concentrations.     

Effects of perfluorodecanoic acid on thyroid status in rats

Treatment of rats with toxic doses of perfluorodecanoic acid (PFDA) results in reduction in feed intake, body weight, serum thyroxine (T4) and triiodothyronine (T3) concentrations, resting heart rates, and body temperatures. Some of these effects resemble changes characteristic of hypothyroidism. Therefore the effects of PFDA on functional thyroid status were examined to relate changes in thyroid status with signs of PFDA toxicity. In the present study, the dose-related effects of PFDA on plasma thyroid hormone concentrations and a number of indices of thyroid status were investigated and compared with signs of PFDA toxicity. Young adult male Sprague-Dawley rats were given single intraperitoneal doses of PFDA (20, 40, or 80 mg/kg), and subsequent changes were evaluated 7 days after dosing. Decreases in body weight and feed intake were used as measures of PFDA toxicity and ranged from minimal to severe. Plasma T4 concentrations and free thyroxine index were drastically reduced at all doses, and these changes were mimicked by pair feeding only at the high dose of PFDA (80 mg/kg). Plasma T3 concentrations were not affected by PFDA treatment, whereas pair feeding at the high-dose level (80 mg PFDA/kg) resulted in a significant reduction (ca. 50% from unlimited-fed control) in T3. Although PFDA caused a dose-dependent decrease in thyroid gland weight which was not completely paralleled by pair feeding, thyroid histology was unremarkable. PFDA treatment resulted in a small decrease in basal metabolic rate (8% at 80 mg PFDA/kg). A greater reduction (ca. 18%) in basal metabolic rate was observed in vehicle-treated controls pair-fed to rats of the 80 mg PFDA/kg dose group. Thermogenesis, as measured by oxygen consumption and body core temperatures, was not greatly affected by PFDA treatment, and these changes were paralleled by pair feeding. Reductions in plasma T4 concentration and free thyroxine index at a low dose of PFDA (20 mg/kg) indicate that PFDA-induced hypothyroxinemia can be dissociated from its overtly toxic effects (i.e., severe hypophagia and body weight loss) observed at higher doses. The results obtained here suggest that despite alterations in plasma thyroid hormone levels there is no consistent pattern of effects on functional thyroid status which could explain the overt toxicity of PFDA.     

The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-Coenzyme A 1 Desaturase and Mixed Function Oxidase Activities in Rats

The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-CoenzymeA Desaturase and Mixed Function Oxidase Activities in Rats.VANRAFELGHAM, M. J., AND ANDERSON, M. E. (1988). Fundam. Appl.Toxicol. 11, 503-510. Perfluorodecanoic acid (PFDA) causes adioxin-lilce toxic syndrome and alters the hepatic oleate/stearateratio in rats. The acute toxic effects of a single ip dose (50mg/kg) of PFDA on hepatic stearoyl-CoA desaturase and mixedfunction oxidases were studied in male Fischer-344 rats, 14days after dosing. PFDA causes a marked decrease in food intakein rats, resulting in severe body weight loss with delayed lethality(2-3 weeks after dosing). To distinguish the effects of hypophagiafrom those caused by PFDA, pair-fed control rats were used inaddition to ad libitum-fed controls. Stearoyl-CoA desaturaseactivity, responsible for the conversion of stearoyl-CoA tooleoyl-CoA, was absent in both PFDA dosed rats and their pair-fedcontrols at Day 14. Electron transfer through the desaturasesystem was significantly reduced in PFDA-treated rats only,and in these rats there was a significant reduction in microsomalcytochrome an important component of this electron transfersystem. Pentobarbital sleeping times were significantly prolongedin both the PFDA-dosed and pairfed rats, as compared with thead libitumfed controls. This effect was more pronounced in PFDA-dosedrats. Waking plasma pentobarbital concentration was similarin all treatment groups. Hepatic microsomal cytochrome PASOcontent was unaffected. Aminopyrine N-de-methylase activitywas greatly reduced in PFDA-dosed rats. Although pairfed controlsalso had reduced demethylase activity, it was not as pronouncedas in PFDA-dosed rats, and was probably due to the fasted conditionof these animals. Although the mechanism of action of PFDA isnot known, it is possible that PFDA affects microsomal enzymesby altering the structure and/or function of the membranes inwhich they are located, through effects on lipid metabolism.     

Dose-related effects of perfluorodecanoic acid on growth,feed intake and hepatic peroxisomal β-oxidation

The effects of the persistent peroxisome proliferator, perfluorodecanoic acid (PFDA), on growth, feed intake and the enzyme activities associated with peroxisomal β-oxidation were studied in female Sprague Dawley rats. Rats received one of six levels of PFDA (0, 0.3, 1.0, 3.0, 10.0 or 30.0 mg/kg/injection) in four IP doses at 2-week intervals. Rats with cumulative doses of ≤ 12.0 mg/kg did not differ from control rats in growth or feed intake, while rats receiving cumulative doses of ≥40 mg/kg lost weight and decreased their feed intake. Rats which received cumulative doses between these levels increased their feed intake but did not significantly alter their body weight. Total peroxisomal β-oxidation was decreased in a dose-related manner, whereas the liver to body weight ratio and the activities of individual enzymes comprising the peroxisomal β-oxidation system, namely fatty acyl-CoA oxidase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and thiolase, were increased. This study clearly shows that the inhibition of peroxisomal ß-oxidation by PFDA is not reflected in the in vitro measurement of the individual enzyme activities comprising this pathway.     

Dose-response hapatotoxicity of the peroxisome proliferator, perfluorodecanoic acid and the relationship to phospholipid metabolism in rats.

Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator that causes hepatotoxicity but lacks tumor-promoting activity in rats. We previously showed that a single dose of PFDA at 50 mg/kg (approximately LD50) causes an elevation in liver phosphocholine (PCho) and other effects related to phospholipid metabolism. In this study, we examined metabolic effects in the dose range 2-50 mg/kg in rats. At doses < or =20 mg/kg, PFDA is significantly less hepatotoxic than the LD50 as manifested by electron microscopy and measurements of daily food consumption and body weight. At 50 mg/kg rat serum tumor necrosis factor (TNF)-alpha concentration was increased 8-fold, while at 15 mg/kg there was no apparent increase in this cytokine. This lower dose, however, induces metabolic effects similar to those seen at the LD50. Liver fatty acyl-CoA oxidase activity showed a dose-dependent increase from 5-25 mg/kg PFDA. Treatments at 15 and 50 mg/kg caused a significant increase in liver phosphatidylcholine (28 and 66%) and phosphatidylethanolamine (31 and 74%). Both doses caused a significant increase in liver PCho but did not affect liver ATP levels, as manifested in 31P nuclear magnetic resonance (NMR) spectra from rat livers in vivo. These data suggest that the increase in liver [PCho] observed following PFDA exposure in rats represents a specific metabolic response, rather than a broad-range hepatotoxic effect.     

Reduced activities of key enzymes of gluconeogenesis as possible cause of acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats.

Male Sprague--Dawley rats (350-375 g) were injected i.p. with TCDD (25 [sublethal dose] and 125 micrograms/kg [lethal dose], respectively, in corn oil/acetone), or vehicle only; vehicle-treated animals were pair-fed to their TCDD-treated counterparts. 1, 2, 4, 8, 16, and 32 days (28 days for lethal dose) thereafter, animals were sacrificed and activities of two key enzymes of gluconeogenesis determined in livers of rats. In livers of pair-fed rats both enzyme activities were little affected. In the livers of TCDD-treated animals the activity of phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) decreased rapidly, exhibiting significant losses by the 2nd day after treatment. Time course and extent of loss of PEPCK activity (about 50%) were similar after either dose. The activity of glucose-6-phosphatase (G-6-Pase, EC 3.1.3.9) decreased more slowly as a result of TCDD treatment; statistically significant losses were observed by 4 or 8 days after the lethal and sublethal dose, respectively. These results confirm the hypothesis that reduced in vivo rates of gluconeogenesis in TCDD-treated rats are due to decreased activities of gluconeogenic enzymes. In an additional set of experiments, rats were treated with 125 micrograms/kg TCDD, 25 micrograms/kg TCDD, or with vehicle alone. The 25 micrograms/kg or vehicle-treated rats were then pair-fed to rats dosed with 125 micrograms/kg of TCDD. Mean time to death and body weight loss at the time of death were essentially identical in all groups, lending additional support to the hypothesis that reduced feed intake is the major cause of TCDD-induced death in male Sprague--Dawley rats. Both appetite suppression and reduced total PEPCK activity in whole livers occurred in the same dose-ranges of TCDD, suggesting the possibility of a cause-effect relationship.     

The effects of perfluoro-n-decanoic acid in the rat heart

Perfluoro-n-decanoic acid (PFDA) is a synthetic chemical resembling a 10-carbon fatty acid. Several studies have suggested that the toxic mechanism of PFDA may involve impaired lipid metabolism and/or altered cell membrane function. We examined the possibility that altered cell membrane structure in the heart might lead to changes in the functional activity of the organ. Functional characteristics were determined in the isolated perfused rat heart by measuring the ability of the heart to respond to either sympathetic nerve stimulation or infused norepinephrine. PFDA reduced the intrinsic resting heart rate and the inotropic response to a stimulus with maximal effects occurring 8 days after dosing. In addition, resting heart rate measured in vivo was found to be reduced in PFDA-treated rats 6 to 8 days after dosing. beta-Receptor binding studies conducted 8 days after a single dose of PFDA showed that the maximum binding capacity was reduced by PFDA treatment without significant changes in receptor affinity. It is concluded that the reduction in the inotropic response to catecholamines following PFDA treatment may be explained in part by lower beta-receptor density in the myocardial cell membrane. These effects may be related to the early fall in serum thyroid hormone levels as previously reported.     

The biochemical toxicity of perfluorodecanoic acid in the mouse is different from that of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Perfluorodecanoic acid (PFDA) is an industrial surfactant that has been reported to produce signs of toxicity in rats similar to those due to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In order to characterize the biochemical toxicity of PFDA in the mouse and to determine whether PFDA toxicity is mediated by the Ah locus, congenic female C57BL/6J mice differing only at the Ah locus (normal homozygous responsive Ahb/b, heterozygous responsive Ahb/d, and homozygous nonresponsive Ahd/d) were administered a single oral dose of PFDA. The wild type (Ahb/b) mice were killed 2, 7, 14, or 30 days after administration of 0, 40, 80, 100, 120, or 160 mg PFDA/kg. Mice from the other two congenic strains were killed 30 days after dosing with 0, 40, 80, or 160 mg/kg. PFDA produced a 2.5-fold increase in absolute liver weight, a 5- to 15-fold increase in hepatic fatty acyl Co-A oxidase activity, and a 70% decrease in hepatic ethoxyresorufin O-deethylase (EROD) activity. These effects were dose and time dependent. Total hepatic lipids were increased at an early time point and at the lowest dose. At later time periods and/or higher doses, the lipid concentration was decreased approximately 20% from that of controls. Hepatic protein concentrations were depressed approximately 25% from control levels 30 days after treatment. There was little difference in any of these parameters between responsive (Ahb/b, Ahb/d) and nonresponsive (Ahd/d) mice. These results suggest that the Ah allele has little effect in regulating the toxicity of PFDA in the mouse and that the biochemical response to PFDA in the mouse is markedly different from that of TCDD. Furthermore, the biochemical response to PFDA in the mouse is different from that reported in the rat.     

Effect of the peroxisome proliferator perfluorodecanoic acid on growth and lipid metabolism in Sprague Dawley rats fed three dietary levels of selenium

The possible interrelationships between the effects of dietary selenium and perfluorodecanoic acid (PFDA) on growth and lipid metabolism were studied in the male Sprague Dawley rat. Rats were divided into groups and placed on diets containing three levels of selenium (0.04, 0.2, and 1.0 ppm as sodium selenite). Two weeks later, half the rats in each group received a single 35 mg/kg IP injection of PFDA in corn oil, while their pair-fed companion received only vehicle. Rats injected with PFDA stopped gaining weight, and weighed less than pair-fed controls, despite equal food intakes. Two weeks following PFDA administration the rats were killed and plasma cholesterol and triglycerides, and liver peroxisomal enzyme activities were quantified. In contrast to other peroxisome proliferators, PFDA increased plasma triglycerides while decreasing plasma cholesterol. The rate of peroxisomal fatty acid -oxidation was decreased, even though the activity of fatty acyl-CoA oxidase, the first enzyme in the peroxisomal fatty acid -oxidation pathway, was increased. Dietary selenium, other than increasing the liver to body weight ratio, did not alter growth or lipid metabolism. This study demonstrates, for the first time, the existence of a non-hypotriglyceridemic peroxisome proliferator-PFDA.     

Age-dependent toxicity of acorn extract in young and old male rats

Intraperitoneal administration of acorn extract of dosage levels of 200, 400 and 600 mg/kg body weight did not produce significant change in the hepatic microsomal cytochrome P-450 levels and the activities of NADPH-cytochrome c reductase, benzphetamine N-demethylase and aniline hydroxylase in young, adult rats (weighing 200-250 g), with the exception of the activity of benzphetamine N-demethylase at the 600 mg/kg dose which was decreased significantly. On the other hand, a dose of only 100 mg/kg body weight ip to old rats (weighing 400-450 g) caused significant decreases in the microsomal cytochrome P-450, benzphetamine N-demethylase and NADPH-cytochrome c reductase activities. However, there was no significant change in the activity of aniline hydroxylase in these rats, indicating selective inhibition of the microsomal enzymes and higher susceptibility of old rats than young ones to acorn toxicants. When the serum samples from the treated young rats were analyzed for sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as markers of liver toxicity, these activities were significantly higher in the treated rats than the corresponding control values. Similar changes were noted for old rats receiving a dose of 100 mg/kg body weight of acorn extract. The results indicate that acorn extract affects old rats more than young rats as measured by its effect on liver and liver microsomal enzymes.     

The effect of phenobarbital on the metabolism and excretion of thyroxine in rats

The effect of phenobarbital on thyroid function and the metabolism and biliary excretion of thyroxine in rats was determined. Phenobarbital, administered for 2 weeks at a dose of 100 mg/kg/day, resulted in an increase in hepatic and thyroid gland weights, decreased circulating levels of T4, T3 and rT3, and increased TSH levels in male and female rats. After 3 months of treatment liver and thyroid weights were still increased; however, hormone values were not as markedly affected indicating that the rats had partially compensated for the effect on thyroid function. In thyroidectomized rats the plasma clearance of thyroxine was increased with phenobarbital. In bile duct cannulated phenobarbital-treated male rats the hepatic uptake at 4 hr was markedly increased. Bile flow was increased and the 4-hr cumulative biliary excretion of administered radioactivity was increased by 42%. Most of the increase in the excretion (76%) was accounted for by an increase in the excretion of thyroxine-glucuronide in phenobarbital-treated rats. Hepatic thyroxine-glucuronyltransferase activity in phenobarbital-treated rats expressed as picomoles per milligram of protein was increased by 40%; enzyme activity per gram of liver was increased by about twofold which, coupled with increased hepatic weight, resulted in about a threefold increase in total hepatic thyroxine-glucuronyltransferase activity in phenobarbital-treated rats as compared to that of controls. Qualitatively similar effects on metabolism, excretion, and enzyme induction were noted in female rats; however, the magnitude of increase was less than that observed in male rats. It is concluded that the effect of phenobarbital on thyroid function in rats is primarily a result of its effects on the hepatic disposition of thyroid hormone. The induction of thyroxine-glucuronyltransferase appears to play an important role in the increased metabolism and excretion of thyroxine in phenobarbital-treated rats.     

Disulfiram as a Tool in the Studies on the Metabolism of Acetaldehyde in Rats

Abstract The liver acetaldehyde dehydrogenases and the acetaldehyde level in the blood during ethanol metabolism were studied in rats 24 hrs after the administration of disulfiram. High doses of disulfiram (150–600 mg/kg) caused a threefold decrease in the activity of the mitochondrial low-K_m enzyme, whereas no significant effects were found on the activity of the high-K_m enzymes present in the mitochondrial, the microsomal and the cytosolic fractions. The concentration of acetaldehyde was threefold higher in the hepatic venous blood and fivefold higher in the peripheral blood in rats given disulfiram compared to rats given ethanol only. Low doses of disulfiram (25–50 mg/kg) decreased the activity of the low-K_m enzyme by 26 %, and caused a significant increase in the liver output of acetaldehyde. The rate of ethanol elimination decreased by 35 % at a high dose of disulfiram, whereas the alcohol dehydrogenase activity was not influenced. It is suggested that the mitochondrial low-K_m enzyme has a primary role in the regulation of the hepatic output of acetaldehyde, and the results will be discussed with special reference to the site and kinetics of acetaldehyde oxidation during ethanol metabolism in rat liver.     

Tissue distribution and elimination of perfluorodecanoic acid in the rat after single intraperitoneal administration

Tissue distribution, metabolism, and excretion of perfluorodecanoic acid (PFDA) after a single intraperitoneal dose (20 mg/kg) were studied in female and male Wistar rats. PFDA accumulated in the serum and tissues of the rats. In the serum, more than 99% of PFDA was bound by the serum proteins. In the liver, anionic and esterified PFDA were detected. Metabolic oxidation of PFDA was not observed. PFDA was not excreted in urine either by females or males during 14 days after the administration. At the same time, about 0.5% of the administered PFDA dose was excreted daily in the faeces by both sexes. In spite of the analogical structure with perfluorooctanoic acid (PFOA), which is rapidly eliminated in urine by the female rats, PFDA accumulated similarly in females and males. The reduced elimination of PFDA partially explains its greater toxicity to rats in comparison with PFOA.     

Disrupted G1 to S phase clearance via cyclin signaling impairs liver tissue repair in thioacetamide-treated type 1 diabetic rats

Previously we reported that a nonlethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic (DB) rats because of irreversible acute liver injury owing to inhibited hepatic tissue repair, primarily due to blockage of G(0) to S phase progression of cell division cycle. On the other hand, DB rats receiving 30 mg TA/kg exhibited equal initial liver injury and delayed tissue repair compared to nondiabetic (NDB) rats receiving 300 mg TA/kg, resulting in a delay in recovery from liver injury and survival. The objective of the present study was to test the hypothesis that impaired cyclin-regulated progression of G(1) to S phase of the cell cycle may explain inhibited liver tissue repair, hepatic failure, and death, contrasted with delayed liver tissue repair but survival observed in the DB rats receiving 300 in contrast to 30 mg TA/kg. In the TA-treated NDB rats sustained MAPKs and cyclin expression resulted in higher phosphorylation of retinoblastoma (pRb), explaining prompt tissue repair and survival. In contrast, DB rats receiving the same dose of TA (300 mg/kg) exhibited suppressed MAPKs and cyclin expression that led to inhibition of pRb, inhibited tissue repair, and death. On the other hand, DB rats receiving 30 mg TA/kg exhibited delayed up regulation of MAPK signaling that delayed the expression of CD1 and pRb, explaining delayed stimulation of tissue repair observed in this group. In conclusion, the hepatotoxicant TA has a dose-dependent adverse effect on cyclin-regulated pRb signaling: the lower dose causes a recoverable delay, whereas the higher dose inhibits it with corresponding effect on the ultimate outcomes on hepatic tissue repair; this dose-dependent adverse effect is substantially shifted to the left of the dose response curve in diabetes.     

Inhibition of long-chain acyl-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes

Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator and is known to affect hepatic lipid metabolism in rats. The effects of PFDA on fatty acid utilization were examined in isolated rat hepatocyte suspensions and in rat liver mitochondria and microsomes. PFDA inhibited the oxidation of palmitic acid but not octanoic or pyruvic acids when hepatocytes were incubated with 1 mM PFDA. At this PFDA concentration the esterification of palmitic acid into triacylglycerols was also reduced. The activity of long-chain acyl-CoA synthetase (ACS), an enzyme essential for both oxidation and esterification of fatty acids, was reduced in hepatocytes incubated with 1 mM PFDA. Carnitine palmitoyltransferase (CPT), an important enzyme for the oxidation of long-chain fatty acids, was not altered in hepatocytes incubated with this PFDA concentration. In rat liver mitochondria, palmitate oxidation and ACS activity were reduced significantly (P less than 0.01) at a PFDA concentration that had no effect on CPT activity. The inhibition of ACS by PFDA was similar in liver mitochondria and microsome preparations. In mitochondria incubated with PFDA, the inhibition of ACS appears to be noncompetitive for the substrates palmitic acid and CoA. However, the ACS inhibition by PFDA appeared to be competitive for the ATP binding site of the enzyme. Several chain length perfluorinated fatty acids were examined for their ability to inhibit mitochondrial ACS. Short-chain perfluorinated fatty acids (perfluoroproprionic and -butyric acid) did not inhibit ACS activity. However, medium-chain perfluorinated acids (perfluorooctanoic, -ananoic and -decanoic acid) were found to be potent inhibitors of ACS in isolated mitochondria. Whether ACS inhibition is causally related to PFDA-induced peroxisome proliferation and altered lipid metabolism seen in vivo is yet to be determined.     

Short-term toxicity of photomirex in the rat.

When photomirex (8-monohydromirex) was fed to rats at dietary levels of 0, 0.5, 5.0, 50, or 500 ppm, all 10 animals receiving the highest dose levels died within 7 days, and two of 10 animals in the 50-ppm group died after 24 days. All other animals (10 per group) survived until the experiment was terminated at 28 days. Animals receiving 50 ppm showed decreased body weight gain and food consumption. Liver hypertrophy and increased microsomal enzyme activity (aniline hydroxylase) were observed in groups of animals receiving 5.0 ppm and greater. Serum sorbitol dehydrogenase activity was increased in animals receiving 5.0 ppm and greater. Photomirex accumulated in all tissues examined, with fat and liver having the highest residues. Histological alterations were observed in the liver at 0.5 ppm and consisted of mild midzonal cytoplasmic enlargement. At a level of 5 ppm, the midzonal cytoplasmic enlargement was more pronounced and was accompanied by mild anisokaryosis and nuclear hyperchromicity. At the highest dose, these alterations were accompanied by perivenous fatty infiltration. Lesions of the thyroid were observed in the group of animals receiving 50 ppm (6.61 mg/kg/day) and consisted of a generalized reduction in follicle size and colloid density. Animals which died showed pronounced thyroid follicular atrophy accompanied by severe colloid depletion and epithelial exfoliation. Animals receiving 50 ppm also had lesions in the testes consisting of a mild to marked reduction in spermatogonia and complete cessation of spermatogenesis.     

A comparative toxicological investigation of perfluorocarboxylic acids in rats by fluorine-19 NMR spectroscopy.

Male Fischer-344 rats administered a single intraperitoneal dose of perfluoro-n-octanoic acid (PFOA) or perfluoro-n-decanoic acid (PFDA) display a similar "wasting toxicity" characteristic of perfluorocarboxylic acids, with marked differences in temporal expression. Food/water consumption and urine output were monitored daily in PFOA-treated, PFDA-treated, and control rats. Fluorine-19 nuclear magnetic resonance (NMR) spectroscopy was used to monitor these fluorocarbons and possible fluoro metabolites in vivo, and to correlate differences in elimination with differences in effective toxicity. The data reveal a prolonged hypophagic response to PFDA and a more acute but transient response associated with PFOA treatment. PFOA causes a greater decline in food consumption than PFDA within the first 24 h postdose. PFOA-treated rats also show a ca. 2.5-fold increase in urine output on day 1, with only a slight increase in water consumption. In contrast to PFDA, PFOA-treated rats recover from hypophagia within 8 days. Fluorine-19 NMR spectra of various bodily fluids and liver in vivo display resonances of the parent PFOA or PFDA compounds and do not reveal any evidence of metabolism. Inorganic fluoride from dietary sources is detected in urine from both exposed and control rats. Differences in the route of excretion of PFOA vs PFDA are apparent from the spectral signal-to-noise ratio. The data suggest that PFOA is more readily excreted in the urine while PFDA is preferentially carried in bile. These apparent differences in elimination may account for their observed differences in effective toxicity. The acute transient toxicity and higher LD50 associated with PFOA may result from its rapid renal clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of short-term in vivo exposure to polybrominated diphenyl ethers on thyroid hormones and hepatic enzyme activities in weanling rats.

Polybrominated diphenyl ethers (PBDEs), used as flame retardants, are ubiquitous environmental contaminants. PBDEs act as endocrine disruptors via alterations in thyroid hormone homeostasis. We examined thyroid hormone concentrations and hepatic enzyme activity in weanling rats exposed to three commercial PBDE mixtures: DE-71, DE-79, and DE-83R. Female Long-Evans rats, 28 days old, were orally administered various doses of DE-71, DE-79, or DE-83R for 4 days. Serum and liver samples were collected 24 h after the last dose and analyzed for serum total thyroxine (T(4)), triiodothyronine (T(3)), thyroid-stimulating hormone (TSH), hepatic microsomal ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD), and uridinediphosphate-glucuronosyltransferase (UDPGT) activities. The PBDE-treated groups did not exhibit significant changes in body weight; however, increased liver weights, as well as 10- to 20-fold induction in EROD and 30- to 40-fold induction in PROD were found in the DE-71-- and DE-79--treated animals. DE-71 and DE-79 caused dose-dependent depletion of T(4), accompanied by up to 3- to 4-fold induction in UDPGT activities. Serum total T(4) was decreased a maximum of 80% for DE-71 and 70% for DE-79 in the highest dose, with benchmark doses (BMDs) of approximately 12.74 mg/kg/day for DE-71 and 9.25 mg/kg/day for DE-79. Dose-related effects in serum T(3) levels were less apparent, with maximal reductions of 25-30% at the highest dose for both DE-71 and DE-79. The two mixtures showed no effect on serum TSH levels. Benchmark dose analysis revealed that the two mixtures were comparable in altering thyroid hormone levels and hepatic enzyme activity. DE-83R was not effective in altering any of the measured parameters. The present study suggests that short-term exposure to some commercial PBDE mixtures interferes with the thyroid hormone system via upregulation of UDPGTS:     

Disposition of perfluorodecanoic acid in male and female rats

The elimination, tissue distribution, and metabolism of [1-14C]PFDA were examined in male and female rats for 28 days after a single ip dose (9.4 mumol/kg, 5 mg/kg). A sex difference in the fecal elimination of perfluorodecanoic acid (PFDA) was observed with 51 and 24% of the administered 14C being recovered in the feces of male and female rats, respectively, by 28 days post-treatment. The cumulative excretion of PFDA-derived 14C in the urine in 28 days was less than 5% of the administered dose in both sexes. The sex-related difference in the rate of fecal elimination resulted in the observed difference in whole body elimination t1/2 of PFDA in males (t1/2 = 23 days) and females (t1/2 = 45 days). The liver contained the highest concentration of PFDA-derived 14C in both males and females, followed by the plasma and kidneys. The heart, fat pads, testes, and gastrocnemius muscle of males, and the ovaries of females contained much lower concentrations of PFDA. The reason for the high percentage of the ip dose of [1-14C]PFDA in the liver (53% males and 41% females, 2 hr post-treatment) was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that approximately 25% of the [14C]PFDA in the perfusate was extracted by the liver in a single pass. The basis for the sex difference in fecal elimination of PFDA does not appear to be due to a sex difference in biliary excretion. In a 6-hr period, male and female rats with kidneys ligated eliminated essentially the same percentage dose of [14C]PFDA into bile. We had hypothesized that the persistence of PFDA in rats was due to formation of a PFDA-containing lipid (i.e., a [14C]PFDA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid). However, no evidence that PFDA is conjugated to form persistent hybrid lipids was obtained, nor were polar metabolites of PFDA detected in urine or bile. In addition, daily urinary excretion of fluoride in male and female rats before and after PFDA treatment was similar, suggesting that the parent compound is not defluorinated. Thus, the disposition of PFDA in male and female rats is characterized by an apparent lack of biotransformation.