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

Reo, Nicholas V.; Goecke, Carol M.; Narayanan, Lakshmi; Jarnot, Bruce M.

doi:10.1006/taap.1994.1020

Cited by 13 publications

(18 citation statements)

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“…Consistent with these results, previous data from our laboratory showed that PFDA treatment caused a sustained elevation in liver PCho (4-fold) and DAG (3-fold) which was attributed to the PLC-induced degradation of PtdCho (23,25). Our present data suggest that a portion of the PCho pool is derived from SphM since this phospholipid was observed to decline following PFDA treatment.…”

Section: Discussionsupporting

confidence: 92%

“…Pair-fed control animals were dosed according to the same regimens with an equal volume of the appropriate vehicle solution (propylene glycol/H2O, saline, or olive oil); DEHP controls were administered olive oil. Doses and treatment protocols match those previously used in our laboratory or are similar to that used by others and reported to produce maximal hepatic effects (i.e., hepatomegaly, peroxisome proliferation, and P450 enzyme induction) (7,(23)(24)(25)(40)(41)(42)(43)(44)(45)(46)(47)(48). PFDA and PFOA doses were based upon the 30-day LD50 for these compounds and have been shown to produce maximal hepatic peroxisomal marker induction (7,48).…”

Section: Methodsmentioning

confidence: 99%

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Effects of Peroxisome Proliferators on Rat Liver Phospholipids: Sphingomyelin Degradation May Be Involved in Hepatotoxic Mechanism of Perfluorodecanoic Acid

Adinehzadeh

Reo

1998

Chem. Res. Toxicol.

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Perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), clofibrate, di(2-ethylhexyl)phthalate (DEHP), and Wy-14,643 represent a class of compounds known as peroxisome proliferators (PPs). Such compounds induce biogenesis of liver peroxisomes and cause a varying degree of hepatotoxicity and carcinogenesis in rodents. We examined the effects of these PPs on rat hepatic lipids and phospholipid profiles using phosphorus-31 NMR spectroscopy. All PPs caused a 25-57% increase in hepatic phospholipid content, while all but clofibrate increased the total lipid content by 26-156%. Treatments also influenced the composition of liver phospholipids. Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEth) contents were significantly increased in all treatment groups. Most notably, PFDA caused the largest increase in PtdCho and PtdEth content (ca. 70%), while PFOA and Wy-14,643 were the only test compounds that influenced the PtdCho:PtdEth ratio. PFDA also caused an ca. 30% decrease in sphingomyelin (SphM) from 24 to 120 h postdose. SphM is a key lipid in signal transduction processes involved in apoptosis. Hydrolysis of SphM can be mediated through the action of tumor necrosis factor (TNF-alpha). We measured the TNF-alpha concentrations in rat sera at 24 h post-PFDA-exposure and found an 8-fold increase relative to vehicle-treated controls. These data demonstrate that an increase in the serum TNF-alpha level correlates with the time frame for the observed reduction in hepatic SphM. PFOA, a structurally similar compound, had no effect on hepatic SphM content, nor did it affect the serum TNF-alpha concentration. These effects may be related to differences in the tumorigenicity associated with these compounds. We postulate that PFDA activates the SphM signal transduction pathway via the release of TNF-alpha. This then stimulates cytotoxic responses and processes of apoptosis and may suppress cell proliferative and mitogenic responses.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Effects of Peroxisome Proliferators on Rat Liver Phospholipids: Sphingomyelin Degradation May Be Involved in Hepatotoxic Mechanism of Perfluorodecanoic Acid

Adinehzadeh

Reo

1998

Chem. Res. Toxicol.

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“…Doses used in this study were in the range from 50−150 mg/kg. The experimental treatment protocols were chosen to match previous studies ( , ) in which the hepatic toxicological effects of C 8 - and C 10 -PFA were investigated at doses approximating their ip 30-day LD 50 (i.e., 150 and 50 mg/kg, respectively). To the authors' knowledge, however, the 30-day LD 50 for C 7 -, C 9 -, and C 11 -PFA are unknown.…”

Section: Methodsmentioning

confidence: 99%

“…Using nuclear magnetic resonance (NMR) spectroscopy, we have previously investigated the toxicological effects of two PPs in rodents: perfluoro- n -octanoic acid (C 8 -PFA) and perfluoro- n -decanoic acid (C 10 -PFA) ( , ). These are straight-chain eight- and ten-carbon perfluorinated carboxylic acids.…”

Section: Introductionmentioning

confidence: 99%

Influence of Carbon Chain Length on the Hepatic Effects of Perfluorinated Fatty Acids. A ¹⁹F- and ³¹P-NMR Investigation

Goecke-Flora

Reo

1996

Chem. Res. Toxicol.

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Using nuclear magnetic resonance (NMR) spectroscopy, we investigated the importance of carbon chain length with regard to the hepatic effects associated with perfluoro-n-carboxylic acids. Male F-344 rats were administered a single intraperitoneal dose of either perfluoro-n-heptanoic acid (C7-PFA), perfluoro-n-nonanoic acid (C9-PFA), or perfluoro-n-undecanoic acid (C11-PFA). Data from previous studies involving perfluoro-n-octanoic acid (C8-PFA) and perfluoro-n-decanoic acid (C10-PFA) are included for comparison. Food consumption/body weight was monitored daily for all groups. C9- and C11-PFA treatment yields a prolonged hypophagic response while C7-PFA shows a more acute response. Fluorine-19 NMR spectra of urine and bile samples show no evidence of fluorometabolites and suggest that the distribution of perfluorocarbons into urine or bile is dependent upon carbon chain length. The aqueous solubility of C7-PFA appears to facilitate rapid urinary excretion, similar to that observed for C8-PFA. The relative hydrophobicity of C9- and C11-PFA appears to favor biliary enterohepatic recirculation, yielding a more protracted toxicity, similar to C10-PFA. Phosphorus-31 NMR studies of liver in vivo and liver extracts show that perfluorocarbons of > or = C9 carbons produce a significant increase in liver phosphocholine concentration. These data are discussed with regard to the impact of these chemicals on hepatic phospholipid metabolism. Hepatic peroxisomal fatty acyl CoA-oxidase activity (FAO) was measured to determine if C7-, C9-, and C11-PFA are peroxisome proliferators. Data indicate that the induction of peroxisomal enzyme activity by perfluorocarbons requires a chain length greater than seven carbons. In general, these results demonstrate the significance of carbon chain length in the hepatotoxic response and provide clues toward understanding the processes involved in the biological activities associated with exposure to these compounds.

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“…The general toxicity profile of PFOA has been characterized in monkeys (Butenhoff et al, 2002a;Griffith and Long, 1980), rats (Abdellatif et al, 1991;Biegel et al, 1995;Cook et al, 1992;Diaz et al, 1994;Griffith and Long, 1980;Kennedy, 1985;Kennedy et al, 1986;Kudo et al, 1999;Liu et al, 1996;Ohmori et al, 2003;Olson and Andersen, 1983;Pastoor et al, 1987;Reo et al, 1994), mice (Yang et al, 2000(Yang et al, , 2001, rabbits (Griffith and Long, 1980;Kennedy, 1985), fish (Martin et al, 2003a(Martin et al, , 2003b, and humans (Gilliland and Mandel, 1993, Olsen et al, 1999, and summarized in a recent review (Kennedy et al, 2004;Kudo and Kawashima, 2003). A preliminary risk assessment of the developmental toxicity of PFOA was recently conducted by the Office of Pollution Prevention and Toxic Substances of the U.S. Environmental Protection Agency (US EPA, 2003a).…”

Section: Toxicity Of Perfluorooctanoic Acidmentioning

confidence: 99%

The developmental toxicity of perfluoroalkyl acids and their derivatives

Lau

Butenhoff²,

Rogers

2004

Toxicology and Applied Pharmacology

767

480

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Perfluoroalkyl acids such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have applications in numerous industrial and consumer products. Although the toxicology of some of these compounds has been investigated in the past, the widespread prevalence of PFOS and PFOA in humans, as demonstrated in recent bio-monitoring studies, has drawn considerable interest from the public and regulatory agencies as well as renewed efforts to better understand the hazards that may be inherent in these compounds. This review provides a brief overview of the perfluoroalkyl chemicals and a summary of the available information on the developmental toxicity of the eight-carbon compounds, PFOS and PFOA. Although the teratological potentials of some of these chemicals had been studied in the past and the findings were generally unremarkable, results from recent postnatal studies on developmental and reproductive indices have prompted consideration of their relevance to human health risk. Based on current understanding of the developmental effects of PFOS and PFOA in rodents, several avenues of research are suggested that would further support the risk assessment of these perfluorinated organic chemicals.

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

Cited by 13 publications

References 0 publications

Effects of Peroxisome Proliferators on Rat Liver Phospholipids: Sphingomyelin Degradation May Be Involved in Hepatotoxic Mechanism of Perfluorodecanoic Acid

Effects of Peroxisome Proliferators on Rat Liver Phospholipids: Sphingomyelin Degradation May Be Involved in Hepatotoxic Mechanism of Perfluorodecanoic Acid

Influence of Carbon Chain Length on the Hepatic Effects of Perfluorinated Fatty Acids. A ¹⁹F- and ³¹P-NMR Investigation

The developmental toxicity of perfluoroalkyl acids and their derivatives

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

Cited by 13 publications

References 0 publications

Effects of Peroxisome Proliferators on Rat Liver Phospholipids: Sphingomyelin Degradation May Be Involved in Hepatotoxic Mechanism of Perfluorodecanoic Acid

Effects of Peroxisome Proliferators on Rat Liver Phospholipids: Sphingomyelin Degradation May Be Involved in Hepatotoxic Mechanism of Perfluorodecanoic Acid

Influence of Carbon Chain Length on the Hepatic Effects of Perfluorinated Fatty Acids. A 19F- and 31P-NMR Investigation

The developmental toxicity of perfluoroalkyl acids and their derivatives

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Influence of Carbon Chain Length on the Hepatic Effects of Perfluorinated Fatty Acids. A ¹⁹F- and ³¹P-NMR Investigation