Influence of carbon chain length on the hepatic effects of perfluorinated fatty acids. A F-19- and P-31-NMR investigation

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 (C-7-PFA), perfluoro-n-nonanoic acid (C-9-PFA), or perfluoro-n-undecanoic acid (C-11-PFA). Data from previous studies involving perfluoro-n-octanoic acid (C8-PFA) and perfluoro-n-decanoic acid (C-10-PFA) are included for comparison. Food consumption/body weight was monitored daily for all groups. C-9- and C-11-PFA treatment yields a prolonged hypophagic response while C-7-PFA shows a more acute response. Fluorine-19 NMR spectra of urine and bile samples show no evidence of nuorometabolites and suggest that the distribution of perfluorocarbons into urine or bile is dependent upon carbon chain length. The aqueous solubility of C-7-PFA appears to facilitate rapid urinary excretion, similar to that observed for C-8-PFA. The relative hydrophobicity of C-9- and C-11-PFA appears to favor biliary enterohepatic recirculation, yielding a more protracted toxicity, similar to C-10-PFA. Phosphorus-31 NMR studies of liver in vivo and liver extracts show that perfluorocarbons of greater than or equal to C-9 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 C-7-, C-9-, and C-11-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.