Perfluoro-n-decanoic Acid Research Articles

Intrauterine exposure to long-chain perfluorocarboxylic acids (PFCAs) were associated with reduced primary bile acids in three-year-old children: Findings from a prospective birth cohort study

Bile acids (BAs) play a crucial role in lipid metabolism of children. However, the association between per- and polyfluoroalkyl substance (PFAS) exposure and BAs in children is scarce. To address this need, we selected 252 children from the Maoming Birth Cohort and measured 32 PFAS, encompassing short- and long-chain perfluorocarboxylic acids (PFCAs) and perfluorosulfonic acids (PFSAs) in the cord blood. Additionally, we analyzed nine primary and eight secondary BAs in the serum of three-year-old children. Generalized linear models with FDR-adjusted and Bayesian kernel machine regression (BKMR) were used to explore the associations of individual and mixture effects of PFAS and BAs. We found negative associations between cord blood long-chain PFCAs exposure and serum primary BAs in three-year-old children. For example, one ln-unit (ng/mL) increase of perfluoro-n-tridecanoic acid (PFTrDA), perfluoro-n-undecanoic acid (PFUnDA) and perfluoro-n-decanoic acid (PFDA) were associated with decreased taurochenodeoxycholic acid, with estimated percentage change of −24.28% [95% confidence interval (CI): −36.75%, −9.35%], −25.84% (95% CI: −39.67%, −8.83%), and −22.97% (95% CI: −34.45%, −9.47%) respectively. Notably, the observed associations were more pronounced in children with lower vegetable intake. Additionally, the BKMR model also demonstrated a monotonical decline in primary BAs as the PFAS mixture increased. We provided the first evidence of the association between intrauterine exposure to PFAS and its mixture with BAs in children. Further large-sample-size studies are needed to verify this finding.

Association between exposure to perfluoroalkyl substances and uric acid in Chinese adults

BackgroundA growing body of evidence suggests the deleterious effects of perfluoroalkyl substances (PFASs) on kidney, but little is known on the association between PFASs joint exposure and uric acid. MethodsSerum PFASs concentrations were measured in 661 participants recruited from Tianjin, China using liquid chromatography/mass spectrometry. The associations of single PFASs exposure with uric acid levels and hyperuricemia were assessed using multivariable linear and logistic regression models, respectively. Restricted cubic spline models were established to investigate the dose-response relationships between PFASs concentrations and uric acid levels. Bayesian Kernel Machine Regression (BKMR) model with a hierarchical variable selection was performed to assess the joint effect of PFASs on uric acid. ResultsPotassium perfluoro-1-octanesulfonate (PFOS) and perfluoro-n-octanoic acid (PFOA) were the dominated contributors with median concentrations of 16.80 ng/ml and 9.42 ng/ml, respectively. Increased PFOA concentration (per log2-unit) was associated with elevated uric acid level (β = 0.088, 95% CI: 0.033–0.143) and higher risk of hyperuricemia (OR = 1.134, 95% CI: 1.006–1.289). Conversely, the estimated change of uric acid associated with log2-unit increment in perfluoro-n-decanoic acid (PFDA) was −0.081 mg/dL (95% CI: -0.154, −0.009). A significant linear dose-response pattern was found between log2-transformed PFOA concentration and uric acid level. BKMR analyses indicated a non-significant overall effect of PFASs mixture on uric acid. ConclusionsSignificant associations between PFOA and PFDA and uric acid, and between PFOA and hyperuricemia were found in the single-pollutant models, but the joint effect of PFASs mixture on uric acid was not observed in the BKMR model, which provided new insights in regulation policies and risk assessment of PFASs.

Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case–control study in Chinese population

BackgroundPerfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population.MethodsParticipants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer.ResultsPerfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (ORER+ = 1.47, 95% CI: 1.19, 1.80; ORPR+ = 1.36, 95% CI: 1.09, 1.69; ORHER2 = 1.62, 95% CI: 1.19, 2.21).ConclusionsOverall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal.

Association between Per- and Polyfluoroalkyl Substances (PFAS) and Semen Quality in Men of Reproductive Age in China

Background/Aim: The relation between per- and polyfluoroalkyl substances (PFAS) and semen quality is evolving, but current epidemiologic results remain equivocal. We examined the associations between PFAS and semen quality among men of reproductive age.Methods: Included were 654 men who came for preconception care in the preconception cohort of the Shanghai Birth Cohort. Seven general semen parameters were assessed, along with the measurement of 31 targeted PFAS and PFOS (Perfluoro-1-octanesulfonate)/ Perfluoro-n-octanoic acid (PFOA) isomers in serum. PFAS were ln-transformed to improve their normality. Box-Cox transformation was used to improve normality of semen indexes. Multiple linear regression and sparse partial least square (SPLS) regression, a multi-pollutant model, were used for association analyses. All analyses were limited to the PFAS detected in > 50% of serum samples.Results:After adjusting for age, body mass index, family annual income, smoking status, alcohol consumption and abstinence time, the SPLS analyses suggested that perfluoro-n-decanoic acid (PFDA), perfluoro-n-undecanoic acid (PFUDA) were consistently inversely associated with semen concentration [beta= -0.07(95% confidence interval: -0.13,-0.01) and-0.07 (-0.14,-0.01) for each standard unit increase in PFDA and PFUDA, respectively], progressive motile rate (-0.61 (-1.02,-0.25) and -0.66 (-1.04,-0.34) for PFDA and PFUDA, respectively) or semen motile index [-0.76 (-1.33,-0.32) for PFUDA]. Consistent inverse associations of perfluoro-n-nonanoic acid (PFNA) with progressive motile rate, average velocity and semen motile index were also observed in SPLS analyses. In addition, perfluoro-n-heptanoic acid (PFHpA) was significantly inversely associated with semen motile rate and progressive motile rate. Other PFAS congeners showed less associations with semen quality. In general, the direction of associations in SPLS analyses was consistent with that in multiple linear regression. Conclusions:Our results suggested that exposure to certain PFAS congeners were inversely associated with general semen quality among men of reproductive age. These associations were robust to the adjustment of multi-collinearity among PFAS congeners.

Optimization and validation of a method based on QuEChERS extraction and liquid chromatographic–tandem mass spectrometric analysis for the determination of perfluoroalkyl acids in strawberry and olive fruits, as model crops with different matrix characteristics

A QuEChERS method was optimized and validated for the LC–MS/MS analysis of perfluoro-n-pentanoic acid (PFPeA), perfluoro-1-butanesulfonic acid (PFBuS), perfluoro-n-hexanoic acid (PFHxA), perfluoro-n-heptanoic acid (PFHpA), perfluoro-1-hexanesulfonic acid (PFHxS), perfluoro-n-octanoic acid (PFOA), perfluoro-n-nonanoic acid (PFNA), perfluoro-1-octanesulfonic acid (PFOS) and perfluoro-n-decanoic acid (PFDA) in freeze-dried strawberry and olive, as model fruits characterized by very different chemical compositions. The method was evaluated for apparent recovery, intra-day and inter-day precision, matrix effect and recovery. The method optimized for strawberry provided for most compounds absolute values of matrix effect (|ME%|) ≤ 11%, except for PFHxA, which showed a signal suppression of 22%. The extraction efficiency was tested at the spike levels 500–5000 pg/g d.w. for PFPeA, PFBuS, and PFHxA, and 100–1000 pg/g d.w. for the other target analytes, evidencing as a whole recoveries in the range of 65–89%. For olive fruits, due to their high fat content, an ultrasound-assisted extraction was necessary to obtain an efficient sample disgregation so as to increase the extraction yield and its precision. Moreover, a d-SPE clean-up with GCB allowed to achieve |ME%| ≤ 8% (except for PFBuS, which showed a signal enhancement of 19%) and recoveries calculated at the aforementioned spike levels were in the range 75–97%. The two methods provided very good linearity (R2 ≥ 0.9984) from 10,000 pg/g down to compound specific quantification limits, which were included in the ranges of 2.9–393 pg/g and 2.6–127 pg/g for strawberry and olive fruit, respectively. The methods were applied to the analysis of PFAAs in strawberry and olive fruits commercially available in two Italian supermarkets, as well as obtained under irrigation with various treated wastewaters (TWWs), evidencing in both cases a higher PFAAs occurrence in olives than in strawberry. However, PFAAs concentrations determined in the investigated fruit matrixes were quite low, being their sum 1.9 ng/g d.w. in the worst case (i.e. olive fruits grown under irrigation with TWWs).

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days

Poly- and perfluoroalkyl substances (PFAS) are chemically and thermally stable, hydrophobic, lipophobic compounds used in stain repellants and water and oil surfactants, and associated with immunosuppression and peroxisome proliferator activity. Perfluoro-n-decanoic acid (PFDA, (CF3(CF2)8COOH), a fluorinated straight chain fatty acid compound, is reported to induce thymic atrophy and reversible bone marrow hypocellularity in rodent models. The objective of this study was to assess potential immunotoxicity of PFDA, due to its structural similarity to other immunosuppressive PFASs. Female Harlan Sprague–Dawley rats were exposed to 0–2.0 mg PFDA/kg by oral gavage daily for 28 d. Female B6C3F1/N mice were exposed once/week to 0–5.0 mg PFDA/kg by gavage for 4 weeks. Animals were evaluated for effects on immune cell populations in spleen and bone marrow, and innate, humoral-, and cell-mediated immunity. Mice were also evaluated for resistance to Influenza virus. Treatment-related hepatocyte necrosis and hepatomegaly were observed in rats treated with 0.5 mg PFDA/kg/d. In mice, hepatomegaly (26–89%) was observed following exposure to ≥0.625 mg PFDA/kg/week, while splenic atrophy (20%) was observed at 5.0 mg PFDA/kg/week. At 5.0 mg PFDA/kg/week, total spleen cells, and Ig + and NK + cells were decreased (17.6–27%). At ≥ 1.25 mg PFDA/kg/week the numbers of splenic CD3+, CD4+, CD8+, and Mac3+ cells were decreased (10.5–39%). No changes were observed in leukocyte subpopulations in PFDA-exposed rats. Phagocytosis by fixed-tissue macrophages was decreased in liver (specific activity, 24–39%) at ≥0.25 mg PFDA/kg/d in rats. PFDA-induced effects on humoral- and cell-mediated immunity, host resistance, and bone marrow progenitor cells were limited. These data suggest that exposure to PFDA may induce adverse effects in rat liver in a manner consistent with the PFAS class, and may also alter the balance of immune cell populations in lymphoid tissues in mice.

Effect of the peroxisome proliferator perfluoro-n-decanoic acid on glucose transport in the isolated perfused rat liver.

The perfluorinated carboxylic acid, perfluoro-n-decanoic acid (PFDA), is a known peroxisome proliferator which displays toxicity in rodents. Using a paired-tracer first-pass extraction technique, the effect of PFDA on hepatic glucose transport was determined in the isolated perfused rat liver. In brief, livers isolated from PFDA-treated and control rats on day 5 posttreatment were administered the radiolabeled glucose analog, 3-O-[14C]methyl-D-glucose ([14C]3-O-MG) in addition to [fructose-1-3H(N)]sucrose ([3H]sucrose), which served as a measure of extracellular volume. Hepatic glucose transport was calculated from the change in the ratio [14C]3-O-MG/[3H]sucrose during passage through the liver. Data from this study indicate that PFDA inhibits hepatic glucose transport. Percent hepatic glucose extraction is 1.8-fold greater in controls than in PFDA-treated rats. No significant difference in lactate dehydrogenase levels was observed in the liver perfusate from PFDA-treated and control rats. This suggests that the difference in percent glucose extraction between PFDA-treated and control groups is specifically due to the PFDA treatment and is not attributed to differences in liver viability between groups. Although the exact mechanism for this inhibition in hepatic glucose transport is not known, it is hypothesized that PFDA may have a major impact on membrane structure/function which, in turn, may alter glucose transport.

Modification of Hepatic Immunoglobulin Heavy Chain Binding Protein (BiP/Grp78) Following Exposure to Structurally Diverse Peroxisome Proliferators

Modification of Hepatic Immunoglobulin Heavy Chain Binding Protein (BiP/Grp78) Following Exposure to Structurally Diverse Peroxisome Proliferators. Witzmann, F. A., Parker, D. N., Jarnot, B. M., and Clack, J. W. (1994). Fundam. Appl. Toxicol. 23, 1-8.This investigation was conducted to determine the comparative effect of structurally diverse peroxisome proliferators (PP) on the two-dimensional protein pattern of rat liver whole homogenates. Perfluoro-n-decanoic acid (PFDA), perfluoro-n-octanoic acid (PFOA), clofibrate, and di(2-ethylhexyl)phthalate (DEHP) are all known to cause the proliferation of hepatic peroxisomes and the induction of peroxisomal β-oxidative and microsomal ω-oxidative enzymes. To clarify the mechanistic differences between these compounds with regard to the liver, we examined the unique patterns of protein alteration produced by in vivo exposure to them. Following exposure to various doses, whole liver homogenates were prepared and separated by two-dimensional gel electrophoresis (2DE) using the ISO-DALT system. Stained gels were digitized and protein patterns analyzed using the Kepler 2D gel analysis system. Immunoglobulin heavy chain binding protein (BiP), also known as 78-kDa glucose-regulated protein (Grp78), was identified immunologically and by comigration of recombinant Grp78. BiP is a luminal endoplasmic reticular protein that functions in the assembly and folding of nascent proteins as they enter the ER. The present results suggest a selective posttranslational modification of BiP following PFDA exposure. Single-dose exposure to PFDA was associated with a notable charge modification of BiP that persists up to 30 days. PFOA, clofibrate, and DEHP had less effect in this regard. The identity of BiP/Grp78 as the halothane hepatitis-associated trifluoroacetylated protein was also demonstrated. The nature of this PFDA-associated protein modification (reactive metabolite conjugation, abnormal ribosylation, or phosphorylation) is currently under investigation. These results document PFDA's unique toxicity as a PP and support the utility of 2D gel analysis in toxicity testing.

Effects of Perfluoro- n-octanoic Acid, Perfluoro- n-decanoic Acid, and Clofibrate on Hepatic Phosphorus Metabolism in Rats and Guinea Pigs in Vivo

Phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy was used to study the effects of perfluoro- n-octanoic acid (PFOA), perfluoro- n-decanoic acid (PFDA), and clofibrate (CLOF) on liver phosphorus metabolism in rats and guinea pigs in vivo. All three compounds are known to cause peroxisome proliferation in rats but not in guinea pigs. The data indicate that indices related to overall tissue viability (i.e., adenosine triphosphate levels) remain unaffected at the doses and experimental times investigated for all treatments and both species. PFDA-treated rats revealed a marked increase in a liver phosphomonoester resonance compared with corresponding controls ( p ≤ 0.01); no such effect was observed in guinea pigs. This particular 31P NMR signal was identified as phosphocholine (PCho) and was found to steadily increase in concentration at consecutive days post-PFDA treatment, reaching 6.26 ± 0.29 μmol/g liver at 5 days. This is fourfold greater than the PCho levels determined in livers from corresponding pair-fed control rats. The elevation in liver PCho is a specific response of PFDA treatment in rats and is not simply related to peroxisome proliferation in general, since neither PFOA nor CLOF produce such an effect. The data suggest a unique effect of PFDA on liver phospholipid metabolism, specifically phosphatidylcholine, which may involve enhanced phospholipid turnover via phosphatidylcholine-specific phospholipase C activity.

Modification of Hepatic Immunoglobulin Heavy Chain Binding Protein (BiP/Grp78) Following Exposure to Structurally Diverse Peroxisome Proliferators

This investigation was conducted to determine the comparative effect of structurally diverse peroxisome proliferators (PP) on the two-dimensional protein pattern of rat liver whole homogenates. Perfluoro-n-decanoic acid (PFDA), perfluoro-n-octanoic acid (PFOA), clofibrate, and di(2-ethylhexyl)phthalate (DEHP) are all known to cause the proliferation of hepatic peroxisomes and the induction of peroxisomal beta-oxidative and microsomal omega-oxidative enzymes. To clarify the mechanistic differences between these compounds with regard to the liver, we examined the unique patterns of protein alteration produced by in vivo exposure to them. Following exposure to various doses, whole liver homogenates were prepared and separated by two-dimensional gel electrophoresis (2DE) using the ISO-DALT system. Stained gels were digitized and protein patterns analyzed using the Kepler 2D gel analysis system. Immunoglobulin heavy chain binding protein (BiP), also known as 78-kDa glucose-regulated protein (Grp78), was identified immunologically and by comigration of recombinant Grp78. BiP is a luminal endoplasmic reticular protein that functions in the assembly and folding of nascent proteins as they enter the ER. The present results suggest a selective posttranslational modification of BiP following PFDA exposure. Single-dose exposure to PFDA was associated with a notable charge modification of BiP that persists up to 30 days. PFOA, clofibrate, and DEHP had less effect in this regard. The identity of BiP/Grp78 as the halothane hepatitis-associated trifluoroacetylated protein was also demonstrated. The nature of this PFDA-associated protein modification (reactive metabolite conjugation, abnormal ribosylation, or phosphorylation) is currently under investigation.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the potential genotoxicity of perfluorodecanoic acid and chlorotrifluoroethylene trimer and tetramer acids

Perfluoro- n-decanoic acid (PFDA) is a perfluorinated fatty acid that produces hepatomegaly and increased peroxisomal β-oxidation when administered to rodents. Chlorotrifluoroethylene (CTFE) trimer acid and CTFE tetramer acid are metabolites of the six- and eight-carbon oligomers of CTFE, respectively. They are structurally related to PFDA, and CTFE, tetramer acid has caused toxic effects in rodents that are similar to those observed following PFDA administration. Because of the correlation between peroxisome proliferation and hepatocarcinogenesis, CTFE trimer acid, CTFE tetramer acid, and PFDA were evaluated in in vitro and in vivo/in vitro bioassays to assess their potential genotoxic activity. The assays conducted were the Ames Salmonella/microsomal mutagenicity assay, the hypoxanthineguanine phosphoribosyltransferase (HGPRT) locus Chinese hamster ovary gene mutation assay, the sister chromatid exchange (SCE) assay, chromosomal aberration assay, and an in vivo/in vitro unscheduled DNA synthesis (UDS) and S-phase DNA synthesis assay. All test articles were negative in the Ames assay, the HGPRT assay, and the SCE assay. In the chromosomal aberration assay CTFE trimer acid and CTFE tetramer acid were negative in cultures with and without S9 metabolic activation. PFDA was also negative in the absence of metabolic activation, but chromosmal aberrations were observed when PFDA was incubated in the presence of S9 fraction. All test articles were negative for inducing UDS but all induced S-phase replicative DNA synthesis 16 hr after administration of the test article to the test animals; only CTFE tetramer acid and PFDA induced S-phase synthesis 48 hr after dosing: the usual timepoint examined for this response.

Hepatic protein pattern alterations following perfluorodecanoic acid exposure in rats

The effect after 8 days of 20 and 50 mg/kg in vivo exposure to perfluoro-n-decanoic acid (PFDA) on the protein pattern of rat liver whole homogenates was studied using high-resolution, large-scale two-dimensional polyacrylamide gel electrophoresis. PFDA exposure altered 13 proteins reproducibly in each of 5 samples tested. While most of the altered proteins remained unidentified, several known mitochondrial proteins were induced by PFDA as were others in a dose-related manner. Conversely, PFDA caused the reduction of albumin as well as several unknown proteins, also in a dose-related manner. Cytoskeletal proteins were unaffected by PFDA. The present results suggest that PFDA's toxic mechanism may involve more than membrane integration and lipid accumulation. Changes in the two-dimensional protein pattern indicate that selective protein synthetic or catabolic processes may undergo qualitative alterations after PFDA treatment as well.

Perfluorodecanoic acid decreases the enzyme activity and the amount of glutathione S-transferases proteins and mRNAs in vivo

The effects of the anti-wetting agent perfluoro- n-decanoic acid (PFDA) on various glutathione S-transferase (GST) enzyme activities were studied in vitro and in vivo. In addition the effects of PFDA treatment on the amount of some glutathione S-transferase subunits and their corresponding translatable mRNA were studied in vivo. PFDA like some other peroxisome proliferators was a non-competitive inhibitor of several GST enzyme activities in vitro. In vivo PFDA reduced the enzyme activity towards substrates which are indicative for the Ya, Yb 1 and Yb 2 subunits of GSTs to a larger extent than the enzyme activity towards the substrate indicative for the Yc subunit. Whereas the reduction of GST enzyme activities by other peroxisome proliferators was shown to be caused by an inhibition of the relevant enzymes in vivo, PFDA was found to decrease the GST enzyme activities at least in part by lowering the amount of the various GST subunits in vivo due to a lowered concentration of translatable mRNA coding for these enzymes. In addition PFDA abolished the inducibility of GST mRNAs by phenobarbital. Thus PFDA might be an interesting tool for mechanistic studies of the control of GST expression in the liver.

Perfluoro‐n‐decanoic acid: Induction of peroxisomal β‐oxidation by a fatty acid with dioxin‐like toxicity

Perfluoro-n-decanoic acid (PFDA) produces toxic effects in rodents similar to those caused by 2,3,7,8-tetrachloro-dibenzo-p-dioxin. A single, intraperitoneal dose (50 mg/kg) of PFDA to Sprague-Dawley rats caused disruption of the endoplasmic reticulum, mitochondrial swelling and increases in intracellular lipid droplets in hepatocytes similar to effects reported previously in dioxin toxicity. PFDA treatment led to large decreases in the activity of plasma membrane alkaline phosphodiesterase and mitochondrial cytochrome c oxidase without affecting lysosomal N-acetyl-beta-glucosaminidase, endoplasmic reticulum NADPH-cytochrome c reductase or peroxisomal catalase activities. PFDA treatment led to moderate peroxisome proliferation and to very large (20-40-fold) increases in the activity of fatty acyl-CoA oxidase, the rate-limiting enzyme in the peroxisomal system of fatty acid beta-oxidation.

Time-course of perfluoro- n-decanoic acid (PFDA)-induced changes in [ 14C]-palmitare oxidation measured in vivo in male fischer-344 rats

Time-course of perfluoro- n-decanoic acid (PFDA)-induced changes in [ 14C]-palmitare oxidation measured in vivo in male fischer-344 rats

Pathological and hepatic ultrastructural effects of a single dose of perfluoro- n-decanoic acid in the rat, hamster, mouse, and guinea pig

In rats, the liver is the primary target organ of perfluoro- n-decanoic acid (PFDA) toxicity. Therefore, the effects of PFDA on hepatic ultrastructure were studied in rats. Pathological changes induced by PFDA in hamsters, mice, and guinea pigs were also examined. PFDA caused a severe reduction in body weight in all four species studied. A reduction in food intake was observed in rats and hamsters. However, hamsters continued to consume food at a reduced level, while rats stopped eating for a 5- to 6-day period about 6 days after dosing. The PFDA-induced pathological changes in the hamsters, mice, and guinea pigs resembled those seen in rats to varying degrees. As in the rat, PFDA caused a marked liver enlargement in mice and hamsters and a moderate swelling in guinea pigs. This hepatomegaly was ascribed primarily to individual cell swelling. Thymic atrophy was noted in PFDA-treated hamsters, mice, and guinea pigs. Seminiferous tubular degeneration observed in hamsters and guinea pigs, but not in mice, was not as severe as in the rat, where in some cases frank necrosis has been seen. Ultrastructural changes in the livers of all PFDA-treated animals, regardless of species, included disruption of the rough endoplasmic reticulum, rounding and swelling of the mitochondria with related structural alterations, and mild to extensive proliferation of peroxisomes. This peroxisome proliferative response was greatest in mice and almost absent in guinea pigs. Accumulation of lipid droplets in liver cells due to PFDA treatment was more pronounced in hamsters and guinea pigs than in rats and mice. PFDA-induced hepatomegaly with a concomitant increase in peroxisomes in several rodent species may be associated with an impairment of normal lipid metabolism in the liver by PFDA.

Synthesis of 14C‐labeled perfluorooctanoic and perfluorodecanoic acids; purification of perfluorodecanoic acid

AbstractPerfluoro‐n‐octaboic acid (PFOA) and perfluoro‐n‐decanoic acid (PFDA), two widely used industrial products, have been synthesized with 14C‐labeling in the C‐1 position. The carboxyl labeled materials were prepared in 48% and 53% yield by carbonation of perfluoroheptyllithium and perfluorononyllithium at −100°C. An efficient chemical method for purification of PFDA was also developed. Treatment of commercial PFDA with refluxing potassium hydroxide solution resulted in removal of the mono and diprotio impurities to give 99% pure PFDA.

The effects of perfluoro- n-decanoic acid (PFDA) on rat heart β-receptors, adenylate cyclase, and fatty acid composition

Perfluoro- n-decanoic acid (PFDA) is a member of a family of surfactants with numerous industrial applications. The acute toxicity of PFDA is characterized by body wasting and delayed lethality. Recent reports have indicated that the effects of PFDA may involve an action on the structure of biological membranes which results in an alteration of function. In the present study we extend our work on the membrane actions of PFDA by examining its effects on myocardial β-adrenoceptor binding characteristics and adenylate cyclase. Following a single injection of PFDA the apparent number of β-receptor binding sites was reduced compared to pair-fed controls. This change in β-receptor binding capacity was reflected in a reduced ability of norepinephrine to activate adenylate cyclase. No alterations were observed in basal adenylate cyclase activity or in the ability of NaF or guanylyl imidodiphosphate to stimulate the enzyme. The fatty acid composition of the heart was changed by PFDA treatment. Our results suggest that the toxic effects of PFDA may be due to an alteration of the membrane lipid bilayer leading to changes in the functional activity of myocardial membranes.

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. β-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 β-receptor density in the myocardial cell membrane. These effects may be related to the early fall in serum thyroid hormone levels as previously reported.

Perfluorodecanoic acid inactivation of a channel for 2-aminopurine in the L5178Y cell membrane and recovery of the channel

Treatment of L5178Y mouse lymphoma cells with perfluoro- n-decanoic acid (PFDA) in growth medium for 24 hr at 30°C produces a dose-dependent inactivation of a channel in the cell membrane. Activity of the channel was estimated from the initial rate of efflux of a fluorescent purine, 2-aminopurine (AP). The L5178Y cells were preloaded with 100 μ m AP and excess AP was removed. The preloaded cells were put in a flow system, and AP efflux was estimated continuously at 21°C from the fluorescence emission of AP at 370 nm. The AP channel was markedly inactivated by a treatment with 150 μg/ml PFDA for 24 hr at 30°C. There was no significant recovery of AP flux after 3 days at 30°C in fresh growth medium; however, recovery was significant after 6 days. Recovery of activity of the AP channel occurs in 1 day at 37°C. The initial rate of AP efflux for control cells increases with AP concentration; the reaction is not saturated at 1000 μ m AP. The efflux of AP was inhibited by the presence of uric acid in the external buffer. An apparent inhibition constant value of 355 μ m was determined for urate inhibition of AP efflux. These observations suggest the presence of a urate-sensitive channel for AP in the membrane of L5178Y cells. The channel was inactivated by PFDA under conditions that had no significant effect on cell viability.